WHITE BOOKON FRAILTYEditor-in-Chief
Bruno VELLAS, MD, PhD
Gérontopôle Toulouse University Hospital, INSERM UMR1027
Unit on Aging, Toulouse, France

Associate Editors
Matteo CESARI, MD, PhD Gérontopôle Toulouse University Hospital,
INSERM UMR1027 Unit on Aging, Université de Toulouse III
Paul Sabatier, Toulouse, France
Jun LI, MD
Center of Gerontology and Geriatrics, West China Hospital,
Sichuan University, Chengdu, China

A video on“BEWARE OF FRAILTY”

A short 40 seconds film was realized in collaboration with the IAGG and its GARN Network, to promote autonomy ofold people. It was funded by the CNSA (Caisse Nationale de Solidarité pour l'Autonomie), a French state organizationand is available in eleven versions:
English https://www.youtube.com/watch?v=T9-JPN_jY9I
French https://www.youtube.com/watch?v=YsmkRIooCz0
Italian https://www.youtube.com/watch?v=aFImlnydU80
Spanish https://www.youtube.com/watch?v=NcBG7Lefa1A
Portuguese https://www.youtube.com/watch?v=0oxn9IKRwmA
German https://www.youtube.com/watch?v=5wYa6NlceKM
Persian https://www.youtube.com/watch?v=A3euyAg4zIw
Korean https://www.youtube.com/watch?v=7kbfVDrZrxI
Chinese1 https://www.youtube.com/watch?v=n8cz-Adi1cw
Chinese2 https://www.youtube.com/watch?v=zyydMw9uim8Japanese https://www.youtube.com/watch?v=Z2_UGmg3ZGk
The film can be disseminated via any type of screen: social networks, websites, local TVs, or during events dedicatedto old people. We also invite you to target a large public, networks, colleagues, local authorities and all those whose
work to prevent dependency of older people.

SUMMARY

INTRODUCTIONSIII

INTERVENTIONS AGAINST FRAILTY            P.81

2

Introduction

82

3

IAGG mission for frailty of older persons

 aising awareness on the urgent need toR
implement frailty into clinical practice4

 eyond the bedside:  factors influencing theBprevalence and management of frailty

87I ncorporating frailty into clinical practiceand clinical research90

 railty is a complex geriatric syndrome withF
multiple functional needs: a comprehensive
approach is needed96 ow studies show the benefits of aH
multidisciplinary approach of care applied
to frail old adults

99

Frailty in general practice102

Frailty and drug use

I

GENERAL OVERVIEW                                         P.56

One precious model in China

7 	Multisectoral action for a life course
approach to healthy ageing
10 	Action Group on Prevention of Frailty of
the European Innovation Partnership (EIP)on Active and Healthy Ageing
13

I ntroducing frailty and the frailty process
within the disablement models

15 ow might deficit accumulation give rise toHfrailty?

II

FRAILTY IN CLINICAL PRACTICE                     P.21

22

Frailty: the search for underlying causes

107 	Exercise: an important key to prevent
physical and cognitive frailty
110 	The role of nutrition for the prevention andtreatment of frailty
115 	How to include the social factor for
determining frailty?
120

I mplementing frailty screening, assessment,
and sustained intervention: the experienceof the Gérontopôle

129

 ooking for frailty in community-dwellingLolder persons: the Gérontopôle Frailty
Screening Tool (GFST)

25 	Nutrition and frailty: a review of clinicalintervention studies
32

 easoning about frailty in neurology:
Rneurobiological correlates and clinicalperspectives132

 he integration of frailty into clinicalTpractice: preliminary results from the
Gérontopôle

35

Molecular crossroads of frailty and HIV

140

44

Cognitive frailty: frontiers and challenges

 railty and novel technologies - a step
F
ahead

48

Frailty and chronic respiratory diseases

53

Diabetes and frailty: an up to date synopsis

58

Frailty from an oral health point of view

66

Thinking about cognitive frailty

70

Frailty and pain: two related conditions

76

Use of biomarkers

143 	Innovative Medicines Initiative: theSPRINTT projectWHITE BOOK

WHITE BOOK ON FRAILTY
Bruno VELLAS, MD, PhD

IAGG Immediate Past President (2009-2013)
Head of the Gérontopôle - Toulouse University Hospital, France
Correspondence: Prof Bruno Vellas, Gérontopôle de Toulouse, Département de Médecine Interne et Gérontologie Clinique,Centre Hospitalier Universitaire de Toulouse, 170 avenue de Casselardit, 31300 Toulouse, France
E-mail: vellas.b@chu-toulouse.fr

Frailty is a clinical state in which there is an increasein an individual’s vulnerability for developing dependency and/or mortality when exposed to a
stressor. Frailty can occur as the result of a range of diseases and medical conditions, but this syndrome can be delayed, if identified and managed early enough.
Established in 1950, the International Association of Gerontology and Geriatrics (IAGG) has always been committed to promoting the highest quality of life and well-beingof all people as they experience aging at an individual andsocietal level. For this reason, IAGG launched the Global
Aging Research Network (GARN) in 2011 to get together
the world’s best research centers dedicated to biological andclinical Gerontology.
The White Book on Frailty, endorsed by the IAGG GARN
Network, aims to promote preventive interventions against
disability and to provide information on how to adequately implement frailty into everyday clinical practice. To thiseffect, it will highlight current knowledge on the identification of target population, the assessment of frail old adults,
and the development of tailored intervention programs. We
now know that early detection and intervention is critical toaddressing frailty.
The White Book presents a general overview of the topic
and details the main frailty pathologies. Assessment tools
and implementation initiatives are presented, in view of
preventing and/or delaying disability and dependence, athome, in the community and in hospital settings.
We hope that each contribution will help raise awareness on
frailty and its outcomes. We take this opportunity to thankthe authors for their support and input. It is our wish that
this book will encourage healthcare professionals aroundthe world to develop actions at a local, regional, national
and international level for the benefit of elder people.
Thank you very much for your consideration.

2

IAGG mission for frailty of older persons

IAGG MISSION FOR FRAILTY
OF OLDER PERSONSHeung Bong CHA, PhD

IAGG President (2013-2017)
Correspondence: Prof Heung Bong Cha, IAGG Headquarters, Room No. 1107, Gwanghwamun Platinum, Saemunanro 5ga-gil
28, Jongrogu, Seoul, Korea 110-052, Phone: +82-2-737-2548, Fax: +82-2-737-1042
E-mail: hbcha42@gmail.com

F

railty, a progressive physiologic decline in multiple
body systems, is defined as a state of increased
vulnerability to the stress that carries an increased
risk of disability, functional decline, hospitalization andmortality in older adults. Referring to the general population studies in the world, the prevalence of frailty varies
from 4.9% to 27.3%, and also that of pre-frailty varies from
34.6% to 50.9%.(1) Researchers have revealed that evenwhen individuals with acute and chronic medical conditions
were excluded, 7% of the population aged 65 and over and
20% of the population aged 80 and over are frail.(2) It
means that frailty is an elderly specific geriatric syndrome.

Good news is that not all older persons get frail. And thebetter is that many states of pre-frailty and some frailty canbe reversed to robust and pre-frail conditions. We must remember that frailty cannot be overcome by just combating with the traditional concepts of chronic diseases. We
should treat and manage the frailty with a new concept andapproach such as comprehensive functional assessments or
multidisciplinary interventions.
In recent years IAGG has involved in research and training on frailty through IAGG GARN networks all over
the world. The research findings of the networks imply
that early detection and intervention is most important toprevent and protect frailty. The collaboration among the
IAGG GARN institutes has been very precious. That is thejust way the members of IAGG GARN work on it.

Recognition of frailty or pre-frailty is important for clinical practitioners and also policy-makers because it posesa greater risk of adverse health outcomes such as falls, increased morbidity, physical and psychosocial dependence
and death. Frailty leads to the increase in long-term careneed for older persons. When we see the influence to thehealth policy, frailty leads to the increase in medical costs
and imposes bad influence on healthcare financing. So,
preventing the frailty is a very important issue now on the
globe, as such an effort can result in the reduction of dependency, institutionalization, long-term care needs andmedical/social expenditures.

The mission of IAGG is to promote the highest levels ofachievement of gerontological research and training worldwide in order to promote the highest quality of life andwell-being of all people. For this mission, IAGG will continue to support the research and training activities of the
IAGG GARN networks on frailty and the international cooperation for frailty.

(1) Choi J, Ahn A, Kim S, Won CW. Global Prevalence of Physical
Frailty by Fried's Criteria in Community-Dwelling Elderly With National Population-Based Surveys.J Am Med Dir Assoc. 2015 Jul 1;
16(7):548-550.

(2) Wilson JF. Frailty - and its dangerous effects - might be preventable. Ann Intern Med. 2004; 141:489-492.

3

WHITE BOOK

BEYOND THE BEDSIDE:
FACTORS INFLUENCING THE PREVALENCE
AND MANAGEMENT OF FRAILTYJohn W. ROWE, MD

IAGG President Elect (2017-2021)
Julius B Richmond Professor of Health Policy and Aging - Robert N. Butler Columbia Aging Center, Mailman School of Public
Health, Columbia University, New York, USA
Correspondence: Prof John Rowe. Mailman School of Public Health, Columbia University; 600 West 168th Street, 6th Floor,
Room 614, New York, NY 10032, USA. Phone: +1 (212) 305-3505; Fax: +1 (212) 305-3405
E-mail: jwr2108@mail.cumc.columbia.edu

T

his White Book on Frailty appears at a criticaltime in the development of our understandingof the pathophysiology, clinical course, incidence
and prevalence of this very important geriatric syndrome.
While we work to enhance early detection of frailty anddevelopment of effective prevention and treatment strategies, we must also be mindful of important societal trends
that may aggravate the incidence or severity of frailty andcomplicate its effective management. Two such changes
are changes in the structure and function of families andthe increasing gap in socioeconomic status between the“haves” and the “have not”s in many societies.

more common, the traditional nuclear family fades and reformed or “blended” families emerge. And in developing
nations dramatic migration of youth and young adults fromrural areas to urban centers is leaving the older generations
behind with weakened informal support systems.

CHANGES IN THE STRUCTURE AND FUNCTION
OF THE FAMILY

The gap between the rich and poor is widening in bothdeveloped and developing countries. With respect to healthcare for the elderly, there is concern regarding the long term
implications of this troubling divergence of “haves” and“have not”s. The cumulative disadvantage in wages, labormarket participation, and wealth accumulation, is reflectedin functional capacity and may lead to increases in the incidence of frailty as well as difficulties in bringing together
the resources needing to provide comprehensive care forfrail elders.

These changes in the structure and function of the family
place additional stresses on the health care workforce andcommunity-based resources, especially regarding the support of frail elders with multiple needs.
DISPARITIESAnyone with experience in the care of older persons isaware of the critical importance of family supports in serving as the primary safety net for the social, psychologicaland financial needs of older persons. The capacity of thefamily to serve this traditional role is threatened.
Simultaneous increases in life expectancy and decreases in
fertility are leading to more elders with fewer younger family members to support them. Increases in women’s participation in the workforce and the fact that as the oldest
old reach into their 90s and beyond, their children are also
becoming old and have problems of their own further aggravate the difficulty. As divorce and cohabitation become

These trends in families and socio-economic equity suggestthat major challenges are on the horizon for the management of frail elders and provide even greater impetus foracceleration of the development of effective strategies forthe prevention and management of frailty.
4

I
GENERAL OVERVIEW

5WHITE BOOKONE PRECIOUS MODEL IN CHINA
Birong DONG, MD, PhD

Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, China
Correspondence : Prof Birong Dong, The Center of Gerontology and Geriatrics, West China Hospital, Si Chuan University, No.
37 Guoxuexiang, Chengdu 610041, Sichuan Province, China. E-mail: Birongdong@163.com

T

he ageing population represents a special challenge for China, a country with 1.3 billion people(about 18% of the global population). It has been
estimated that by the end of 2010, older persons in China
were 178 million (13.3% of the Chinese population). Although the longer life expectancy is a clear sign of scientificand cultural advancements, it still potentially exposes the
public health systems to the risk of unsustainability due tothe parallel increase of age-related disabling conditions. In
particular, elders with partial or total disability in China were
33 million (19% of the older persons in China) in 2010.

In the past five years, the Center of Gerontology and Geriatrics of West China Hospital dedicated in promoting
the awareness, clinical practice and research about frailty
in Chinese geriatricians. As a member of IAGG GARN,
many geriatricians in the Center are trained through IAGGGARN networks all over the world about how to integrate
the frailty in clinical practice. The collaboration of research
work about frailty is in progress with Saint Louis University, the Gérontopôle in Toulouse, and Dalhousie University.
Just as President Heung Bong CHA said, the just way themembers of IAGG GARN work on the frailty is the collaboration. Our works in the Center provide one precious
model for the collaboration. That is also one shortcut tohelp Chinese clinical practitioners early detect and intervene frailty.

In these last decades, mounting interest has been devoted
by the scientific community to the so-called “frailty syndrome”, as frailty is considered an ideal target for conducting preventive activities against disabling conditions in theelderly. Unfortunately, very little evidence on the topic iscoming from China.

6Multisectoral action for a life course approach to healthy ageing

MULTISECTORAL ACTION FOR A LIFE COURSEAPPROACH TO HEALTHY AGEING

Policy Paper EB 134/19

Provided by WHO’s Department of Ageing and Life Course
Acknowledgements to John BEARD, MBBS, PhD, Director and Islene ARAUJO DE CARVALHO, MD, MSc, Senior Policy andStrategy AdviserT

he proportion of older people in the population
is increasing in almost every country. By 2050,
around 2000 million people in the world will beaged 60 years or over, with 400 million aged 80 years orover. Of them, 80% will be living in what are now low- or
middle-income countries.
The transition to older populations will challenge society inmany ways. Demand for health care, long-term care, social
care and pensions is likely to increase, while the proportionof the population in traditional working ages will fall. But
population ageing also presents many opportunities. Older
people make important social contributions as family members, volunteers and active participants in the workforce.
Indeed, older populations represent a substantial, but as yet
underutilized, human and social resource.
Health in older age will be a crucial determinant of where
the balance will lie between the costs and benefits associated with population ageing. Poor health undermines theability of older people to remain actively engaged in society,limits their contribution and increases the costs of population ageing. Investing in health across the life course lessens
the disease burden in older age, fosters the ongoing social
engagement of older people (helping to prevent isolation)and has broader benefits for society by enabling the multiple contributions of older people.
Poor health in older age is a burden not just for the individual but also for his or her family and for society as a whole.
The poorer the family or the setting, the greater the potential impact. Loss of good health can mean that an older
person who was previously a family resource may no longer
be able to contribute and may, instead, require significant
support. This care is often provided by women who mayneed to give up other career aspirations to deliver it. The
cost of health care for an older person can impoverish thewhole family. These burdens are spread inequitably. Thosewith the least resources, or who live in the poorest areas,
are most at risk.
Health in older age is determined by pathways or “trajectories” that develop across the life course. These trajectories
are influenced by an integrated continuum of exposures,experiences and interactions. The impact of many factors
is greatest at specific critical or sensitive periods of development. These can start very early in life, with experiencesthat can “program” an individual’s future health and development. Subsequently, risk and protective factors across life
have a cumulative effect on health trajectories.
Because of the cumulative nature of these influences, oneof the hallmarks of ageing is diversity. Many older people
will be healthy and well educated and will want to continue
to play an active role in society. Others of the same age
may be poor, illiterate and have no financial security. Policies to enable older people to maximize their capabilities
must address the broad spectrum of needs in these diverse
populations.
CHALLENGES AND RESPONSES

Health systems
Current health systems, particularly in low- and middle-income countries, are not adequately designed to meet thechronic care needs that arise from this complex burdenof disease. These needs span the life course and the care
continuum: from prevention to detection, early diagnosis,
treatment, rehabilitation, long-term care and palliative care.
7

WHITE BOOKIn many places, health systems will need to move from focusing on the delivery of curative interventions for single
acute problems to a more comprehensive continuum ofcare that links all stages of life and deals with multiple morbidities in an integrated manner.
Towards the end of life, many people will eventually requireassistance beyond that habitually required by a healthy adult.
Most of these individuals prefer this “long-term care” tobe provided in their home, and this is often delivered byfamily members. For those with severe functional decline,
institutional care may be required. There are few standards
or guidelines on the most appropriate care, family carers
often lack an understanding of the challenges they face, andcare may be disconnected from health services. This canleave the needs of the older person inadequately addressed,with carers facing a greater burden than is necessary andacute care services being inappropriately used to fill gaps inchronic care. Furthermore, changing social patterns meanthat it may not be sustainable to rely on families alone tomeet many of these needs. The relative number of older
family members is dramatically increasing; older people areless likely to live with younger generations and are more
likely to express a desire to continue living in their own
home; and women, the traditional family carers, may havechanging career expectations. New systems of long-termcare are therefore urgently required, to provide a continuum of care that is tailored to a continuum of need. Theseshould be focused on the individual, closely linked to healthsystems and designed to maintain the best possible function, well-being and social participation.

Ageing is interrelated with other major global trends, including migration, changing roles of women, urbanization,technological change and globalization. These and other aspects of the physical and social environment can strongly
influence both the health of an older person and his or her
capacity to participate actively in society. Innovation will bea crucial component of successful strategies to address thechallenges of population ageing.

GenderGender exerts a powerful influence on health and ageing
across the life course and in older age. Traditionally, women
have provided most of the unpaid care for family members
across the life course (from child care to elder care). This
is often to the detriment of their own participation in thepaid workforce and has many consequences in older age.
These include a greater risk of poverty, more limited accessto quality health and social care services, a higher risk ofabuse, poor health in later life and reduced access to pensions.
Knowledge
There are major knowledge gaps that prevent us from taking appropriate and effective action on ageing and health.
Even basic questions such as “are people living longer
healthy lives, or are the additional years gained experienced
in poor health?” cannot yet be answered. Other major gaps
include understanding the causes and management of key
conditions such as dementia. Even where strong evidence
exists, barriers remain to its translation into policy and practice.
Current approaches to the development of policies andhealth interventions often exclude older people, eventhough they may be the main users or targets. Older people
and those with comorbidities are routinely excluded fromclinical trials, so our understanding of which treatment options are best in older ages is limited. Much routine datacollection either excludes older people or aggregates all
people over a certain age (such as 70 years and above), so
we often cannot accurately assess health need or whether
this is being met.

Workforce
Health system limitations are compounded by major workforce gaps. Few members of either the formal or informal
workforce are adequately trained to meet the specific needsof older people, and demographic change means that as
the number of older people rises, the relative number ofpeople in traditional working ages will fall.
New social models
Rigid ideas about the life course and ageist stereotypes limit
our ability to find innovative solutions. For example, social
systems often artificially categorize people into life stages
based on chronological age (e.g. student, adult, retired).
These concepts have little biological basis. With people living 10 or 20 years longer, a range of life options that would
only rarely have been achievable in the past become possible. A life course approach to healthy ageing views life as acontinuum, recognizes and enables the valuable contributions of people at all ages, strengthens links between generations and develops strategies to build capabilities acrossall stages of life.

Leadership
While global attention on population ageing and healthis rapidly increasing, existing responses are disjointed andoutdated. There is no global strategy and no global action
plan. Both the Madrid International Plan of Action on
Ageing (1) and the WHO contribution Active ageing: a policy framework (2) are over 10 years old, and Member Statesneed more up-to-date guidance to help them prioritize theiractions in a rapidly changing world. To ensure that thisguidance is grounded in the best available evidence, there isan urgent need for a platform that brings together key ex8

Multisectoral action for a life course approach to healthy ageing

perts to advise decision-makers on global action priorities.
There is also an urgent need to coordinate global responses
on ageing and health between key agencies.

2014. The Secretariat is also working to support the development of physical and social environments that foster active and healthy ageing through the WHO Global Networkof Age-friendly Cities and Communities. This network encourages the exchange of experience and mutual learning
between cities and communities that are creating inclusive
and accessible “age-friendly” environments. It currently has
over 150 member cities and communities in 21 countries
worldwide, as well as 10 affiliated country programs.
However, more support is needed. This includes:• defining the best steps that countries at different levelsof development can take to build an integrated continuum of care spanning primary health care, inpatient care,long-term care and end-of-life care;• identifying evidence-based strategies to create environments that foster healthy and active ageing and enableintergenerational collaboration;• developing models and standards for monitoring andquantifying the health of older people;• elaborating strategies for capacity-building and workforce development to address the health needs of older
people;• identifying sustainable financing models to ensure access to services.

RECOMMENDATIONSAdvocacy
Population ageing is one of the biggest demographic transitions the world has ever faced. Good health is central toensuring that social and economic benefits are fully realized, and the development of sustainable health and social
care systems is crucial if costs are to be controlled. Thereis a need for powerful international and national advocacy
to ensure that the centrality of health is understood andthat the opportunities arising from it are fully appreciated.
As a step towards this goal, World Health Day 2012 had
the theme “Good health adds life to years”, to bring global
attention to bear on issues related to ageing and health. The
Secretariat continues to convey these messages in many forums, but these perspectives need to be given even greater
prominence in global development and research agendas.
Convening and coordinating
The Secretariat partners with many other organizations, including the International Association of Gerontology andGeriatrics and the International Federation on Ageing, tolink experts and decision-makers in this field. But a moreformal expert advisory mechanism is needed, to inform the
Director-General and other stakeholders about key knowledge gaps and priorities for research and action in the fieldof ageing and health.
A comprehensive global strategy on ageing and health, followed by a global ageing and health action plan with measurable outcomes, is needed to shape future global priorities
in this area.

Knowledge generation and management
WHO will release the first global report on ageing andhealth in 2015. This will constitute a crucial resource forMember States, defining what is currently known, outlining case studies of innovative responses and making clear
the gaps in our knowledge. Nonetheless, there is an urgent
need to ensure that these knowledge gaps are included in
global research agendas.
As a first step, data gathered by the Organization need tobe collected across the whole life 22.course and disaggregated by sex and age, to distinguish between different stages of ageing. The standards and practices recommended
by WHO for data collection by Member States should also
promote disaggregation by sex and age across the whole
life course. Furthermore, objective indicators are urgently
needed for monitoring the health of older adults, including determinants and consequences, and encouragement
should be given to research that identifies the most cost-effective interventions.

Support to Member States
The Secretariat currently supports Member States by providing guidance on key issues and promoting uptake of thisevidence into policy and action at country level. This workis carried out by all levels of the Organization. The project
on “Knowledge translation on ageing and health” supports
Member States in identifying priorities for action and developing evidence-based policy options. The approach waspiloted in Ghana in 2013 and will be applied in China in

REFERENCES
1. Political Declaration and Madrid International Plan of Action on
Ageing. New York: United Nations; 2002 (http://undesadspd.org/
Ageing/Resources/MadridInternationalPlanofActiononAgeing.
aspx, accessed 4 December 2013).

2. Active ageing: a policy framework. Geneva: World Health Organization; 2002.

9

WHITE BOOKACTION GROUP ON PREVENTION OF FRAILTY
OF THE EUROPEAN INNOVATION PARTNERSHIP(EIP) ON ACTIVE AND HEALTHY AGEINGMaria IGLESIA-GOMEZHead of the Unit on Healthcare Systems in DG SANTE European Commission
Correspondence: Ms Maria Iglesia-Gomez, European Commission, Direction Générale Santé et Consommateur, 1040 Brussels,
Belgium. E-mail: maria.iglesia-gomez@ec.europa.eu

T

he European Innovation Partnership on Activeand Healthy Ageing was launched in 2012 as aCommission response to demographic changes in the EU, in the framework of Europe 2020 strategy.
Three years since it was launched, the Partnership is helping to identify and develop new approaches for supportingchange, placing patients at the centre of the health and social care systems and moving away from hospital-centred,
reactive, disease-focused care, towards a proactive, community-based model of prevention and continuous care management, with the participation of the patient and informalcare-givers.
Within the Partnership, a specific Action Group on Prevention of Frailty started to work in June 2012. After two
invitations for commitments launched by the Commission,
160 partners expressing a total of 131 commitments areworking together in a multidisciplinary Action Group.
The aim of this group of partners is to provide older people with safe, effective, compassionate, high-quality careand to encourage care services to improve the organisational context supporting everyday life and clinical practiceencountered by frail older people and their care-givers. To
do this, the group of EIP partners working on preventionof frailty is implementing innovative solutions to better understand the underlying factors of frailty, is exploring theassociation between frailty and adverse health outcomes inolder people and is working to better prevent and manage
the frailty syndrome and its consequences.
The Partnership reflects a growing awareness that bettercare and sustainability of health services calls for innova-

tive ways to address the needs of the elderly. It has encouraged a wide range of stakeholders to join forces, to improvecooperation, and to foster political commitment, so as toencourage innovative solutions towards a better quality oflife as citizens grow older. It identifies a set of actions thathave started as early as 2012 and will deliver measurable
outcomes within the 2012-2020 timeframe.
WORK DEVELOPMENT

The group of partners working on prevention of frailty iscurrently implementing an agreed common Action Plan.
This was based on the objectives, activities, timing and deliverables specified in the 131 commitments sent in by agroup of stakeholders. This Action Plan frames the work to
be applied by all partners who adhere to this group.
The groups’ ambition is to create critical mass to push thefrailty prevention approach towards is tipping point in thefollowing domains. Specifically, their objectives and activities address the challenges that fall in any of the following
domains:
1. Frailty in general
2. Cognitive decline
3. Functional decline
4. Nutrition
5. Care givers and dependency
6. Physical activity

10Action Group on Prevention of Frailty of the European Innovation Partnership (EIP) on Active and Healthy Ageing

The strength and added-value of working in the Partnership has been that every member’s individual work contributes to the achievement of a grander common objective.
Together they explore common solutions for the key challenges related to frailty, physical and cognitive decline aswell as risks factors such as malnutrition or lack of physicalactivity for older people.
The group of partners has in particular focused their workon certain areas where actions related to frailty have thepotential to advance at a quicker pace (by joining efforts)such as:Research• Improving methodology for the screening and identification of pre-frail status.
• Basic research development on any of the six (jointly-identified) domains of frailty.
WHAT EVIDENCE HAS THIS WORK PROVIDED?

Framing the idea of the “frailty prevention approach” hasbeen the fundamental outcome of the work done by thepartners in the EIP. Through the work that has been conducted on advocacy, screening, research and coordinationof care, the partners have contributed to establish a common European approach to tackle frailty in older people.
In almost 3 years of collaboration the partners have contributed to establish a common European approach toprovide older people with safe, effective, compassionate,high-quality care and to encourage care services to improvein this regard by tackling frailty in older people.

Advocacy• Informing the opinion on frailty interventions at levels
where priorities are determined and decisions are taken.
• Bring attention to the issue of frailty in older people
being a common EU public health problem.
Protocols and programmes on screening and prevention• Preventing occurrence of frailty and avoiding its predictable negative consequences.
• Preventing factors, such as malnutrition or lack of regular physical activity, which have impact on different
components of the frailty syndrome.
• Supporting adequate nutrition and physical activity.
• Prevention, screening and early assessment of risk factors.

Although the activities are still in the early stage, the partners have already achieved some results, such as:• A more comprehensive and clear understanding of frailty and its priorities: the exchange of knowledge and expertise among partners has resulted in the identificationof clear benchmark on 6 main areas of intervention:
frailty in general, physical decline, cognitive decline, nutrition, dependency and care givers, physical exercise.
• More reliable trials: many partners had the opportunity to test their protocols and tools in broader settings,
allowing strengthening the reliability of both protocols
and tools.
• Shaping a new model for screening, treatment andmonitoring of frailty and functional decline.
• A more suitable training offer for healthcare professionals: different Group members have proposed improved training courses for nurses, social workers and
PhD students on frailty topics.
• A collection of good practices in frailty prevention.
The final text gathers 98 good practices coming from
14 Member States. It offers a grasp of what are themain achievements and what kind of experiences arebeing carried out in some European regions around the
topic of frailty and functional decline. The numerous
and varied examples of Good Practices, promote thevisibility of a wide range of interventions undertaken inclinical settings, research centers and in the community,
aimed to reduce age-related frailty, disability and suffering associated to it.
• Contribution to the policy debate at EU level, providing
technical inputs to the European Commission on frailty
and functional decline in particular through the international conferences on Frailty in April 2013 and June 2014.

Care management and assessment• Supporting evidence based interventions through appropriate pathways of Health and Social Care to avoid
incident frailty, its progression to disability and its negative consequences.
• Diminishing avoidable and recurrent hospitalizations.
• Training professionals to improve their knowledge andskills and keep pace with new needs.
• Supporting care-givers in their tasks of caring for theirdependant relatives.
• Identifying those patients whose outcomes have thehigher costs for the health system.
• Identifying those most at risk and those who will benefit most from the interventions.
• Supporting a multi-disciplinary approach to care andmanagement.
• Evaluating current interventions and supporting whatreally works.
• Supporting care and preventive interventions that canbe better delivered within the community.
• Sharing good practices ready to scale up.
• Implementing guidelines to improve management andprevention of frailty.

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WHITE BOOK

Some of the preliminary results and the collection of goodpractices can be a source of inspiration for further management improvement and policy development. In the coming
years efforts aimed at raising effectiveness of care delivery
will be crucial. Working closely and sharing ideas and solutions can help the EU as a whole to find and implement
new strategies to tackle frailty.
EU Member States are at different stages in their efforts
to address the need for help and care of frail and mostvulnerable older people. Whereas some are still developing their first strategies, others have accumulated more thanfour decades of experiences. The potential in the area offrailty prevention for the EU to add value by facilitating thetransfer of know-how is therefore particularly large.
The wealth of evidence that partners have brought to thetable provides a sound basis on how innovations in assessment and management of health and social needs can beused in new approaches of prevention and care for older
people, and how these can be implemented in daily life.
Through a process of informed deliberation the EIP process has selected cases that involve clear examples in which
policy intervention could reduce frailty and cognitive decline. These cases should be seen as illustrative examples
rather than constituting a comprehensive overview of all
the actual work being developed and all the thinking behindthe different projects and interventions.

cepted by a large number of stakeholders spanning policy
makers, professionals and researchers across EU Member
States.
The EIP partners are committed to work towards solutions
that can be easily implemented and replicated by others in
Europe. This aspect emphasizes the spirit of the Partnership in a broader context and strengthens the work alreadydone by many of them. These 3 years of work have established a solid ground on which to build common andeffective approaches to tackle frailty in old age. But still further work and policy support and resources are needed sothat tackling frailty in older people is no longer an issue of
public debate.
Finding new tools and strategies to prevent and treat frailty
in all its dimensions will not only improve dramatically thequality of life of old people, but will also reduce both thenumber and the length of hospitalisation and institutionalisation. The final results will be alleviation in the budgetary pressure of our health and social care systems, allowing
Members States to more efficiently allocate the resources
for the health and care of their citizens.
In the coming years efforts aimed at raising effectivenessof care delivery will be crucial. Working closely and sharing
ideas and solutions can help the EU as a whole to find andimplement new strategies to tackle frailty.
The Partnership provides a platform for national and regional authorities and key stakeholders to coordinate andmobilize actions in strategic areas, identify good and relevant practices, finally replicate and scale-up the most needed and successful solutions.

CONCLUSIONS

Framing the idea of the “frailty prevention approach” hasbeen the fundamental result of the work done since theEIP was launched three years ago. In this respect, the needto tackle frailty in the older people across EU is now ac-

12

Introducing frailty and the frailty process within the disablement models

INTRODUCING FRAILTY AND THE FRAILTYPROCESS WITHIN THE DISABLEMENT MODELS
Jean-Marie ROBINE, PhD1, Sandrine ANDRIEU, MD, PhD2

1 INSERM and EPHE, Paris & Montpellier, France
2 INSERM UMR 1027, Toulouse, France
Correspondence: Dr. Jean-Marie Robine, INSERM U710 Health and Demography Team, Centre de Recherche de Val d'Aurelle,
Parc Euromédecine, 34298 Montpellier Cedex 5, France, E-mail: jean-marie.robine@inserm.fr

T

wo main approaches have been proposed to assess frailty, the model of Fried (Fried et al, 2001)
and the model of Rockwood (Rockwood et al,1994). The Fried’s paper “Frailty in Older Adults: Evidence
for a Phenotype” has been cited more than 3,800 times since2001 and the Rockwood’s paper “Frailty in elderly people:
an Evolving Concept” has been cited more than 350 times
since 1994, illustrating the great popularity of the conceptof frailty in gerontology over the past 20 years. Althoughquite different, these two models have in common not tohave been involved in the debates of 1980s and 1990s on
models and classifications of health conditions, such as theInternational Classification of Impairments, disabilities andhandicaps (ICIDH), published by the World Health Organization (WHO) in 1980 as a classification of the consequences of disease (WHO, 1980), or the International Classification of Functioning, Disability and Health publishedby the same WHO twenty years later (WHO, 2001). The
result, for these models, is that there is some ambiguity inwhat is covered by the concept of frailty, especially in regard to the concepts of impairments and functional limitations of the disablement process. Does frailty measure thesame things than impairments and functional limitations oris it clearly distinct from the concepts of disability? This isespecially true for the Rockwood’s model that offers a fourpoint scale, ranging from the absence of any problem inphysical and cognitive functioning to total dependence on athird person (care giver) for daily living activities.
In the Fried's model, there is in theory a clear distinction
between frailty and disability. In this approach, not only

frailty is distinct from disability, but it is also from the accumulation of diseases (comorbidity). Frailty is presented as amajor risk factor for disability and death (Fried et al, 2001).
The state or states of frailty would concern individuals not
suffering disability and loss of independence or not yet. In
practice, as in the illustration given by Fried and his colleagues, it is more complicated because individuals with disabilities or dependent in daily life activities are not excluded
from the analyses. As most individuals with disabilities ordependent in daily life activities are found in the pre-frail orfrail categories, it is difficult to say what is the specific contribution of frailty in the prediction of worsen disability or
mortality. Accordingly, the French study of frailty (Sirven,2013) distributes the entire population of 50 years and overin all three categories, robust, pre-frail and frail, ignoring
the factors previously identified as determining the loss of
independence as, for instance, disabling diseases, functional limitations and activity restrictions. It is clear that suchstudies, replacing the concepts of disability by the conceptsof frailty, cannot bring a lot more knowledge about the lossof independence that studies based only on concepts ofdisability.
Actually, Fried and colleagues suggest that frailty measuresor indicates a decline in physiological reserves and resistance to stress regardless of existing pathologies. It wouldbe, in other words, a measure of the biological senescenceor an assessment of the remaining health capital. If theinternational classification of disability (WHO, 1980) andrelated models well apprehend the disablement process as
13

WHITE BOOKa consequence of illness and/or accidents, they ignore thepossibility of a biological process leading to the decrease
physiological reserves. This is where the concept of frailty
is interesting because it allows a second pathway that canlead to disability and loss of independence (Figure 1). The
first, the “disablement process” is based on accidental or
medically clearly identified causes, disabling diseases, impairments, functional limitations, etc. The second, the frailty process, requires no clearly identifiable medical causes. It
reflects at the level of the whole organism, reduced physiological reserves over time which may be due to small or
great causes that it is not necessarily needed to identify.

physiological reserves. When seeking to attribute, in advanced statistical models, disability to morbid causes, accidents and/or disabling diseases, a significant proportionof disability remains unexplained. The integration of theconcept of frailty in such models should be quite useful as
the unexplained part of disability increases with age.
The success of the international classification of disability(WHO, 1980) has led to a first revision, paying much more
attention to non-medical and non-accidental causes of disability (WHO, 2001). Similarly, the current success of theconcept of frailty leads to its extension to other domains
such as social or psychological frailty. The example of theFried’s frailty model, described above, reminds us that the
introduction of a new concept only values if it is not justrenaming existing concepts differently.

Of course the two processes must interact constantly. The
state of physiological reserves should depend, in a measure
to be determined, of past morbid events and the development of new disease must depend in part on the state of

Figure 1: Two processes leading to the loss of independency: the disablement process and the frailty process

REFERENCES- Fried LP, Tangen CM, Walston J et al. Frailty in Older Adults: Evidence for a Phenotype. J Gerontol A Biol Sci Med Sci (2001) 56 (3):M146-M157.
- Rockwood K, Fox RA, Stolee P, Robertson D, Beattie BL. Frailty inelderly people: an evolving concept. Cam Med Assoc J 1994; 150:
489-495.
- Sirven N. Fragilité et prévention de la perte d’autonomie: Une approche en économie de la santé. Questions d’économie de la santé184, Institut de Recherche et de Documentation en Economie de laSanté, Paris 2013.

- World Health Organization. International Classification of Impairments, Disabilities, and Handicaps. A manual of classification
relating to consequences of disease. World Health Organization,
Geneva 1980.
- World Health Organization. International Classification of Functioning, Disability and Health. World Health Organization, Geneva
2001.

14

HOW MIGHT DEFICIT ACCUMULATION GIVE RISE TO FRAILTY?

HOW MIGHT DEFICIT ACCUMULATION
GIVE RISE TO FRAILTY?
K. ROCKWOOD1, A. MITNITSKI2

1 Division of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia, Canada;
2 Departments of Medicine and Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada, December
2011-12-02.
Correspondence: Prof. Kenneth Rockwood, Centre for Health Care of the Elderly, Capital District Health Authority, 1421-5955
Veterans’, Memorial Lane, Halifax Nova Scotia, Canada, B3H 2E1. Telephone 001-902-473-8687; Fax 001-902-473-1050, E-mail:kenneth.rockwood@dal.ca

Abstract: Frailty is a multiply determined vulnerability
state. People who are frail are at risk of many adverse healthoutcomes, including death. For any individual, this risk can
only be expressed probabilistically. Even very fit people cansuddenly die or become catastrophically disabled, but theirrisk of both is much lower than a very frail person, who
might nevertheless suddenly succumb without worsening
health. Frailty occurs with ageing, a stochastic, dynamic
process of deficit accumulation. Deficits occur ubiquitously
at subcellular levels, ultimately affecting tissues, organs andintegrated organ action, especially under stress. Some people are disposed to accumulate deficits at higher rates, but
on average, deficit accumulation varies across the life course
and likely is mutable. In this way, the clinical definition offrailty is distinct from the statistical definition, which sees
frailty as a fixed factor for an individual. Recent, early animal work links subcellular deficits to whole body frailty.
In humans, clinically detectable health deficits combine
to increase the risk of adverse health outcomes. The rateof deficit accumulation occurs with remarkable regularity
around the world, as does a limit to frailty. Of note, when20+ deficits are counted, these characteristics are indifferent to which deficits are considered. The expression of riskin relation to deficit accumulation varies systematically. For
example, at any given level of deficit accumulation, men
are more susceptible to adverse health outcomes than are
women. Likewise, in China, the lethality of deficit accumulation appears to be higher than in Western countries. In
consequence, it may be necessary to better distinguish between frailty and physiological reserve; the latter may apply
chiefly in relation to microscopic deficits. The expressionof frailty risk in relation to deficit accumulation depends
on the environment, including both the physical and social
circumstances in which people find themselves.
Key words: Frailty, deficit accumulation, frailty index, aged,
frailty phenotype, physiological reserve, mathematical gerontology, stochastic dynamics.

A

s is well known, two general approaches are used
to characterize frailty (1-3). One sees frailty as aphenotype, with five key clinical features (4), thatsometimes are expanded to include impairments in cognition and mood (5), or at other times reduced to just impaired nmobility (6) or grip strength (7). Another sees frailty
arising as a consequence of the accumulation of deficits (8).

The two approaches have in common the idea that frailty
is a multiply determined vulnerability state, putting people
at risk for a range of adverse health outcomes, including
death. They also view frailty as an individual characteristic,
and one that can change over the life course. (This is incontrast to the statistical definition of frailty, which sees it
as a fixed individual factor (9), similar to Beard’s notion of a15

WHITE BOOK

longevity factor (10)). The two also share the idea that frailty underlies the variable vulnerability to adverse outcomesof people of the same chronological age. This last meansthat both approaches to measuring frailty have been validated in relation to mortality prediction; this is a reasonable, ifrough standard, but there is more to frailty than mortality
prediction, a point elaborated below. Acknowledging that
this is only one view, the purpose of this paper is to consider how deficit accumulation might give rise to frailty. It will
do this by first sketching clinical deficit accumulation andthen considering how this might link to deficit accumulation at the subcellular and tissue level.

them. The more things they have wrong with them, themore likely they are to die. Not everyone of the same age
has the same number of things wrong with them, and it is
this variability in the number of things they have wrong
with them which accounts for the variable likelihood of
death of older adults of the same age.
There is reasonable evidence for this view that variable deficit accumulation is associated with variability in the risk ofadverse health outcomes (11). To interpret the evidence a
few methodological points need to be reviewed. First, thenotion of “things people have wrong with them” has been
operationalized as “health deficits”. A health deficit can be
any symptom, sign, laboratory measurement, disease or disability. In contrast to the highly specified items that makeup the frailty phenotype, what gets counted as a health deficit is hardly specified at all. In fact, the only criteria are thatany candidate health deficit for inclusion in a frailty index
should increase with age, have a prevalence of at least 1%,
have <5% missing data, are related to an adverse outcome
and cover several organ systems.

FRAILTY AS CLINICAL DEFICIT ACCUMULATION –THE FRAILTY INDEXThe strong case for frailty as deficit accumulation reads
like this. As people age, they are more likely to die. But not
everyone of the same age has the same risk of death. Whataccounts for the relationship between age and death? As
people age, they are more likely to have things wrong with

Figure 1
Mean value of Frailty Index at each study cycle as a function of age (n=14.127, population weighted)(Reproduced from CMAJ, Rockwood et al., 2011)

In addition, enough deficits should be considered so that
all relevant bodily systems can be covered, as well as theirimpact on function. The health deficits qualitatively should
cover more than just co-morbidities; as they assay impact
on function they should include items such as measuresof mobility, strength, physical activity and health attitude.
Quantitatively, as few as 20 items can be considered, but ingeneral, more robust estimates are found when the frailty
index includes 50 or more potential health deficits; after
about 70 such deficits, there appears to be little gain in pre-cision. When many deficits exist which meet these criteria,
they can be sampled at random with little impact on overall risk classification (12), although the more items that are
selected, the narrower the confidence limits (13). By virtueof the liberal criteria for inclusion as a deficit, many clinicaland population datasets have enough information in themfor deficit accumulation to be studied using existing data.
Likewise, a typical Comprehensive Geriatric Assessment
carries enough information for frailty to be operationalized– and graded – even without performance measures, or the16

HOW MIGHT DEFICIT ACCUMULATION GIVE RISE TO FRAILTY?

precise items used in the frailty phenotype or like operational definitions that require (14). In either setting deficits
can be counted in a frailty index.

each year who have nothing wrong with them. Next, eventhough the cohort has aged 14 years, the upper limit of thefrailty index for the 99% of the population does not exceed
0.67 (16). That is because, on average, the risk of death isclosely linked to the value of the frailty index. The fact thatthe maximum value is much less than 1.0 reflects the common sense clinical observation that an individual might beas sick as they can be without having every known disease.

A frailty index is the measure by which the risk of adverse
health outcomes is calculated. A frailty index counts deficits
and standardizes the deficit count for an individual in relation to the total number of deficits considered. In short, thefrailty index score for any individual is the ratio of deficits
present in that individual to the number of deficits counted.
Consider, for example, that a health survey data set has 50
variables that each meet the criteria for being considered asa health deficit.

Although health deficits should cover both impairments ina range of body systems and some evidence that these deficits are impactful, some commentators insist that no definition of frailty should include mention of disability (17, 18).
As with other groups (19-28), this is not a convention towhich we subscribe. Amongst other reasons, the great majority of older adults have some degree of disability, especially when the “physical activity” criterion of the frailty
phenotype is operationalized as impairment in householdchores, mowing the lawn or gardening (29). Excluding disability from the evaluation of frailty also undermines thestrategy of staging frailty, which is essential for clinical decision making. Given that people with a greater degree offrailty are more at risk of adverse outcomes than those witha lesser degree of frailty, and that the notion of frailty ismeant in part to explain why some people of the same inthe stochastic nature of deficit accumulation, as well as in
the variable environments in which older adults might findthemselves. What is more, even systems with no redundancy and no ability to repair – a radioactive decay curve
illustrates an extreme example (30) – will show variablesurvival.

Someone who had none of these would have a frailty index
score of 0/50 = 0. (This is also referred to as the “zerostate” of frailty and has particular significance, discussed
below.) Someone with 35 things wrong would have a frailty
index score of 35/50 = 0.70. As it turns out, this, and not
1.0, is the likely maximum frailty index score.
Around the world, across different data sets, and using different variables and different numbers of the same variables to calculate a frailty index, community-dwelling people accumulate deficits at about the same rate – about 3%
per year, on a log scale (15). Deficit accumulation in theory starts before birth. Empirically, it can be demonstrated
from about age 15 onwards. (Figure 1). Figure One, which
reports a 40-item frailty index, shows its distribution over
7 successive waves of a cohort study. Several features are
remarkable. First, the distribution is about the same eachyear, with the notable exception of slightly fewer people

Figure 2
The probability of death as a function of the number of the Frailty Index during 4, 8 and 12 years amongst Canadians aged 55 years and older atbaseline. (The data came for the NPHS and adapted from Mitnitski et al., 2007, Exp Geront)

17

WHITE BOOK

Figure 3
The probability of death as a function of the Frailty Index during 4, 7 and 12 years Chinese people aged 55 and over.
[Reproducted from BMC Geriatric, Shi et al., 2011]

At any level, the presence of a deficit reflects that the capacity to resist or repair the insult which gave rise to thedeficit has been overwhelmed. As we have seen, in humans,
macroscopic deficit accumulation is tightly associated withmortality at the group level, where the relationship between
the mean frailty index and the risk of death increases exponentially with typically very high fit, manifest, for example,
by r2>0.95. Even so, at the individual level, the outcomes ofa given level of frailty range from improvement to stability
to worsening to death. These probabilities occur with great
regularity, described as a change in the Frailty Index whichcorresponds to a Poisson distribution (35). Although mortality risk, for example, increases with age, even very fit people can suddenly die or become catastrophically disabled,
but their risk of both is much lower than a very frail person,
who might nevertheless suddenly succumb without worsening health. These probabilities are in, turn influenced
systematically by other factors, including social ones (suchas social vulnerability) (36-38) or the country in which aperson lives. For example, in Canada, the frailty index mortality curve is convex to the baseline (Figure 2) (39) whereas in China, it is concave to the baseline (40) (Figure 3).
Systematic variability in the risk of an adverse outcome inrelation to the number of deficits also varies in relation tofactors more intrinsic to the individual, such as the level of
exercise or education (41, 42). What this variable tolerability appears to reflect is how deficits impact intrinsic repair
capacity, which typically is termed “physiological reserve”
or “physiological redundancy” and which perhaps can bemeasured separately (43). Given variable life circumstances,
it can be expected that some people are disposed to accumulate deficits at higher rates than others do, but on average, the tendency to deficit accumulation is variable, andlikely mutable, and varies across the life course (44).

HOW DO DEFICITS COME ABOUT?

Frailty occurs with ageing, a stochastic dynamic process of
deficit accumulation. A standard view of ageing is that deficits arise first (31) at subcellular levels, and ultimately affecttissues, organs and integrated organ action – i.e. function especially under conditions of stress. A variety of examples
exist, including many which overlap between key age-related diseases, such as Alzheimer’s disease and diabetes mellitus, which affect glucose metabolism and are related to longevity in lower order animals (32). Against this background,it might be tempting to see deficit accumulation simply asa matter of scale. Indeed, recent animal work has shownthat the accumulation of deficits in other systems (suchas changes in sodium handling or plasma glucose levels)
is associated with both structural and functional changes
in myocytes, and with impaired mobility (33). It should be
noted however that the scale varies amongst the items considered as health deficits in a frailty index. Some may wellreflect relatively specific processes having become disordered (e.g. low bone density) whereas others are much lessspecific (e.g. “heart disease”). Still others integrate across alarge number of organ systems, such as impaired mobility.
These last have been named “clinical state variables” (34).
The term was chosen to be exactly analogous to a statevariable in a physical system, such as temperature, whichreflects the average of the kinetic energies of the atoms
which make up that system. The link between subcellular
deficits and state variables needs to be better understood,
so that a more quantitative and less metaphorical language
can be employed.
Another consequence of the difference in scale between
subcellular deficits and how function might be impacted isthat is important to distinguish between levels of deficits.

18

HOW MIGHT DEFICIT ACCUMULATION GIVE RISE TO FRAILTY?

ed to make frailty modeling more precise. It also poses animportant challenge in clinical research, which is translatefrom the elegant reproducibility of the mathematics to themore divergent manifestations that frailty can take in humans.

CONCLUSIONSFrailty is a multiply determined vulnerability state which isrelated to ageing. Conceptually, it can be related to ageing
in body systems and their integrated action, and that too
can be related to subcellular deficit accumulation, although
this needs to be tested empirically, as has begun with animal
work. Considering frailty in relation to deficit accumulation
allows the interval nature of the frailty index to be exploit-

This article was published in the Journal of Frailty & Aging
Volume 1, Number 1, 2012
http://www.jfrailtyaging.com/

REFERENCES
1. Abellan van Kan G, Rolland Y, Bergman H, et al., The I.A.N.A Task
Force on frailty assessment of older people in clinical practice. J
Nutr Health Aging. 2008;12:29-37.
2. Crome P, Lally F. Frailty: joining the giants. CMAJ. 2011;183:889-90.
3. Martin FC, Brighton P. Frailty: different tools for different purposes? Age Ageing. 2008;37:129-31.
4. Fried LP, Tangen CM, Walston J, Frailty in older adults: evidence
for a phenotype. J Gerontol. 2001;56:146-157.
5. Sternberg S, Schwartz A, Karunananthan S, Bergman H, Clarkfield
A. The identification of frailty: A systematic literature review. Journal of the American Geriatrics Society. 2011;59(11):2129-2138.
6. Rothman MD, Leo-Summers L, Gill TM. Prognostic significance ofpotential frailty criteria. J Am Geriatr Soc 2008;56:2211-2216.
7. Ling CH, Taekema D, de Craen AJ, Gussekloo J, et al. Handgrip
strength and mortality in the oldest old population: the Leiden
85-plus study. CMAJ. 2010;182(5):429-35.
8. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits
as a proxy measure of aging. Scientific World Journal. 2001:1:323336.
9. Vaupel JW, Manton KG, Stallard E. The impact of heterogeneity
in individual frailty on the dynamics of mortality. Demography.
1979;16:439-54.
10. Beard RE, 1971. Some aspects of theories of morality cause ofdeath analysis, forecasting and stochastic processes. In Brass, W.
(Ed., Biological aspects of demography. Taylor & Francis, London,
pp.557-68
11. Rockwood K, Mitnitski A. Frailty in relation to deficit accumulation and geriatric medicine in relation to frailty. Clinics in GeriatricMedicine 2011;27:17-26.
12. Rockwood K, Mitnitski A, Song X, Steen B, Skoog I. Long-term risksof death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc. 2006;54(6):975-9.
13. Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol
Sci Med Sci. 2007;62(7):738-43.
14. Jones D, Song X, Mitnitski A, Rockwood K. Evaluation of a frailty
index based on a comprehensive geriatric assessment in a population based study of elderly Canadians. Aging Clin Exp Res.
2005;17:465-471.
15. Mitnitski A, Song X, Skoog I, Broe GA, Cox JL, Grunfeld E, et al.
Relative fitness and frailty of elderly men and women in developed
countries and their relationship with mortality. J Am Geriatr Soc.
2005;53: 2184-2189.
16. Rockwood K, Mitnitski A. Limits to deficit accumulation in elderly
people. Mech Ageing Dev 2006;127:494-6.

17. Abellan van Kan G, Rolland Y, Houles M, Gillette-Guyonnet S,
Soto M, Vellas B. The assessment of frailty in older adults. Clin
Geriatr Med. 2010;26:275-286.
18. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med
Sci. 2004;59(3):255-63
19. Gu D, Dupre ME, Sautter J, Zhu H, Liu Y, Yi Z. Frailty and mortality
among Chinese at advanced ages. J Gerontol B Psychol Sci Soc
Sci. 2009 Mar;64(2):279-89.
20. Hastings SN, Purser JL, Johnson KS, Sloane RJ, Whitson HE.
Frailty predicts some but not all adverse outcomes in older adults
discharged from the emergency department. J Am Geriatr Soc.
2008;56:1651-7.
21. Kulminski, AM., Yashin, AI., Ukraintseva SV, et al. 2006. Accumulation of health disorders as a systemic measure of aging: findings from the NLTCS data. Mech. Ageing Dev. 127(11):840-848.
22. Yang Y, Lee LC. Dynamics and heterogeneity in the process of human frailty and aging: evidence from the U.S. older adult population. J Gerontol B Psychol Sci Soc Sci. 2010;65B(2):246-55.
23. Woo J, Tang NL, Suen E, Leung JC, Leung PC. Telomeres and frailty. Mech Ageing Dev. 2008 Nov;129(11):642-8.
24. Armstrong JJ, Stolee P, Hirdes JP, Poss JW. Examining three frailty
conceptualizations in their ability to predict negative outcomes forhome- care clients. Age Ageing. 2010;39(6):755-8
25. Gobbens RJ, van Assen MA, Luijkx KG, Wijnen-Sponselee MT,
Schols JM. The Tilburg Frailty Indicator: psychometric properties.
J Am Med Dir Assoc. 2010 Jun;11(5):344-55.
26. Pol RA, van Leeuwen BL, Visser L, Izaks GJ, van den Dungen JJ,
Tielliu IF, Zeebregts CJ. Standardised frailty indicator as predictor
for postoperative delirium after vascular surgery: a prospective cohort study. Eur J Vasc Endovasc Surg. 2011 Dec;42(6):824-30.
27. Steverink N, Slaets JPJ, Schuurmans H, Lis van M: Measuring
Frailty. Development and testing of the Groningen Frailty Indicator(GFI). Gerontologist 2001, 41:236-237.
28. Martin FC, Brighton P: Frailty: different tools for different purposes? Age Ageing 2008, 37(2):129-131.
29. Eckel SP, Bandeen-Roche K, Chaves PH, Fried LP, Louis TA. Surrogate screening models for the low physical activity criterion offrailty. Aging Clin Exp Res. 2011;23(3):209-16.
30. Gavrilov LA and Gavrilova NS. Models of systems failure in Aging.
In P Michael Conn (ed): Handbook of Models for Human Aging,
Burlington, MA: Elsevier Academic Press, 2006, pp45-68.
31. Kirkwood TB. Frailty only occurs with ageing, a stochastic dynamic
process of deficit accumulation. Cell 2005;120:437-447.

19

WHITE BOOK

32. Gerozissis K, 2010. The Brain-insulin connection, metabolic diseases and related pathologies. In Craft S, Christen Y. (Eds.), Diabetes, Insulin and Alzheimer’s Disease. Springer-Verlag, Berlin
Heidelberg, pp.21-42.
33. Parks RJ, Fares E, Macdonald JK, et al., A procedure for creating afrailty index based on deficit accumulation in aging mice. J Gerontol A Biol Sci Med Sci. 2011 Oct 21 [Epub ahead of print].
34. Rockwood K, MacKnight C. Fitness, frailty and the mathematics ofdeficit accumulation. Rev Clin Gerontol. 2007;17:1-12.
35. Mitnitski A, Bao L, Rockwood K. Going from bad to worse: a stochastic model of transitions in deficit accumulation, in relation tomortality. Mech Ageing Dev. 2006;127(5):490-3.
36. Andrew MK, Mitnitski AB, Rockwood K. Social vulnerability, frailty
and mortality in elderly people. PLoS One. 2008;3(5):e2232.
37. Lang IA, Hubbard RE, Andrew MK, et al., Neighborhood deprivation, individual socioeconomic status, and frailty in older adults. J
Am Geriatr Soc. 2009;57(10):1776-80.
38. Woo J, Goggins W, Sham A, Ho SC. Social determinants of frailty.
Gerontology. 2005;51(6):402-8.

39. Mitnitski A, Song X, Rockwood K. Improvement and decline inhealth status from late middle age: modeling age-related changes
in deficit accumulation. Exp Gerontol. 2007 Nov;42(11):1109-15.
40. Shi J, Song X, Yu P, Tang Z, Mitnitski A, Fang X, Rockwood K.
Analysis of frailty and survival from late middle age in the Beijing
Longitudinal Study of Aging. BMC Geriatr. 2011 Apr20;11:17.
41. Hubbard RE, Fallah N, Searle SD, Mitnitski A, Rockwood K. Impact of exercise in community-dwelling older adults. PLoS One.
2009;4(7):e6174.
42. Fallah N, Mitnitski A, Searle SD, Gahbauer EA, Gill TM, Rockwood
K. Transitions in frailty status in older adults in relation to mobility:
a multistate modeling approach employing a deficit count. J Am
Geriatr Soc. 2011;59(3):524-9.
43. Rockwood K, Rockwood MR, Mitnitski A. Physiological redundancy in older adults in relation to the change with age in the slope ofa frailty index. J Am Geriatr Soc. 2010 Feb;58(2):318-23
44. Rockwood K, Song X, Mitnitski A. Changes in relative fitness andfrailty across the adult lifespan: evidence from the Canadian National Population Health Survey. CMAJ. 2011;183(8):E487-94.

20

II
FRAILTY IN CLINICALPRACTICE

21WHITE BOOKFRAILTY: THE SEARCH FOR
UNDERLYING CAUSES
Sandrine SOURDET, MD

Toulouse Gérontopôle Research Center, Department of Internal and Geriatric Medicine,
Toulouse University Hospital, Toulouse, France
Correspondence: Dr. Sandrine Sourdet, CHU de Toulouse, Département de Médecine Interne et de Gériatrie,
170 avenue de Casselardit, 31300 Toulouse, France; E-mail : sourdet.s@chu-toulouse.fr

Frailty is a state of increased vulnerability, which increases the risk of adverse health outcomes and/or death (1), after a stressor event. It is a dynamic
process and may be reversible or attenuated by interventions focused on the underlying causes of frailty. Many of
the causes of frailty are not necessarily age-related and irreversible. Most of them like physical inactivity, malnutrition
or depression, are treatable and even reversible with appropriate treatment, education and follow-up (1). The management of frailty involves:
1) to screen frail older adults in clinical practice,2) to assess them by looking after the causes of frailty and3) t o propose strong and long-term useful interventions.
A comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary evaluation designed to determine the underlying causes of frailty. The older person
is central to the process. The purpose is to plan and carryout a personalized multi-domain intervention plan. This intervention plan will vary because frailty has different causes
in different people.

The existence of a strong social support network can frequently be the determining factor of whether the patient
can remain at home. Elders may also qualify for being offered care resources, depending upon their income. The useof home care support services, home healthcare technologies, community programs, may be useful for avoiding social isolation and maintaining elderly adults at home.
MEDICAL DOMAIN AND MEDICATIONS

Frailty is not synonymous of comorbidity but many frail
older adults have multiple chronic conditions such as
chronic heart failure, diabetes mellitus, osteoporosis, osteoarthritis, chronic pulmonary disease or chronic renal
failure. A thorough medical examination is necessary to
identify relevant comorbid conditions, review their management, and determine their impact to prioritize medical
and pharmacological interventions. A detailed history andcomplete physical examination including a complete review
of system are necessary to identify new symptoms indicative of a new diagnosis or a worsening existing condition.
It is essential to ensure that there is a diagnosis or an explanation for all newly discovered symptoms and signs, andto look for reversible medical problems. The medical history should also include documentation and quantificationof alcohol and tobacco consumption. Because they havemultiple chronic conditions, many frail older people havealso a long list of medications, often prescribed by different health care providers. By following the guidelines forthe management of chronic disease, the prescription of an
extensive list of medications could be justified. But polypharmacy has negative consequences for older adults, with

SOCIAL, ENVIRONMENTAL AND FINANCIAL SUPPORTThe social evaluation includes aspects such as level of education, marital and living status, informal support available from family or friends, formal support and financial
situation. In addition, living arrangements (home comfort,
facilities and safety), use of telehealth technology, transportfacilities and accessibility to local resources should also be
evaluated. It is also important to assess the ability to fulfill
societal, community and family roles, as well as participate
in recreational or occupational tasks.
22

Frailty: the search for underlying causes

a risk of non-compliance, drug interactions, and adverse
drug reactions. Furthermore, prescriptions are often inappropriate in this population (anticholinergic drugs or longacting benzodiazepines for example); but some drugs arealso insufficiently prescribed because of concerns about
frailty (such ACE inhibitors in heart failure). A review of
medication lists (including over-the-counter medications
and herbal products), their indications, effects and doses isimportant. The utilization of validated guidelines such as
Beers Criteria (2) or STOPP and START criteria (3) can be
helpful to optimize medical prescriptions.

function in older person and preventing disability. These
exercise programs may not only improve the physical function of the patient but also their mood, nutritional status
and be integrated in social activities.
Functional status refers to a person’s ability to performtasks that are required for living. An older adult’s functional
status can be assessed by the Katz ADL (Activities of Daily
Living) scale (6), and the Lawton IADL (Instrumental Activities of Daily Living) scale (7).
In addition to measures of ADLs, physical performancesmight be measured by the SPPB (Short Performance Physical Battery) (8). Measures of physical performance may
identify older persons with a preclinical stage of disability
who may benefit from interventions to prevent the development of disability. The physical assessment should also
include the frequency and duration of usual exercise andphysical activities (walking, housework) in which the patientis already engaged. An assessment of fall history, fall risk,
gait or balance problem should be integrated into the history and physical examination of all frail patients and can beindicative of neurologic or rheumatologic disease.

NUTRITION

Compared to the general population the elderly are more
vulnerable to inadequate nutrition because of number ofreasons such as limited dentition, diminished appetite, depression, dementia, limited functional status to purchase or
prepare food, or lack of financial resources. Undernutrition
and weight loss are strongly associated with frailty in elderly patients, but are still under-diagnosed. Simple measures
such as protein-calorie supplementation have been associated with positive outcomes in older persons, especiallywhen associated with exercise resistance programs (1). At aminimum, a nutritional assessment involves the evaluationof the current weight and height (and the determinationof the Body Mass Index (BMI)), recent changes in bodyweight, food intake, and calculation of the MNA (Mini Nutritional Assessment) score (4). These criteria are useful todiagnose an under-nutrition or at-risk of under-nutrition.
The diagnosis of under-nutrition should lead to further investigations to understand the underlying causes but also
its consequences (such as sarcopenia or falls). If needed, adietary assessment is added.

MOOD DISORDERS

Depression in the elderly may present atypically and remained under-diagnosed and inadequately treated. It is aserious health concern, strongly associated with frailty, andleading to unnecessary suffering, impaired functional status,increase mortality and excessive use of health care resources. A variety of screen tests are available for depression.
Among them, mini-GDS (Geriatric Depression Scale) scale
or GDS scale can be easily administered (9). If the frail
person is depressed, she should be treated.
SENSORY ABILITIESCOGNITIVE STATUS

The majority of older adults will experience some changes
in their sensory abilities. These changes may lead to further complications such as falls, social isolation, medication
errors or poor quality of life. Vision and hearing testing
are essential in older frail patients. An ophthalmologic evaluation including visual acuity measurement (distance vision and near vision) and Amsler grid testing (for maculardegeneration) can be easily performed in routine. Hearing
impairment can be assessed using the Hearing Handicap
Inventory for the Elderly Screening Version (HHIE-S). In
case of hearing impairment, an otoscopic examination anda review of medications (looking for potentially ototoxic
drugs) are recommended. Vision and hearing testing are required before any cognitive assessment.
Finally, additional components may also be evaluated suchas urinary continence, sexual function, sleeping disorders,or vaccinations.

The evaluation of cognitive function includes a thoroughhistory (with the patient and his/her caregiver), a detailed
mental status examination, and neuropsychological testing.
Many instruments can be used for cognitive assessment,such as the MMSE (Mini Mental State Examination) (5), theMemory Impairment Screening (MIS) and the clock-drawing test. In case of cognitive impairment, nutritional complications, falls or behavioral complications must be investigated.
FUNCTIONAL AND PHYSICAL STATUS

A major goal in the care of older adults is maintaining
their functional and physical status (e.g walking, or bathing themselves, but also driving or cooking). Many exercise
programs have demonstrated efficacy in improving physical23

WHITE BOOK

The objective of this comprehensive geriatric assessment
is to propose and implement a personalized multi-domainintervention, to prevent disability. This intervention is de-veloped with the patient, by taking into account his goals
and preferences, and determining priority actions.

REFERENCES
1. Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R,
et al. Frailty consensus: a call to action. J Am Med Dir Assoc. 2013
Jun;14(6):392-7.
2. Resnick B, Pacala JT. 2012 Beers Criteria. J Am Geriatr Soc. 2012
Apr;60(4):612-3.
3. Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony D. STOPP(Screening Tool of Older Person’s Prescriptions) and START(Screening Tool to Alert doctors to Right Treatment). Consensus
validation. Int J Clin Pharmacol Ther. 2008 Feb;46(2):72-83.
4. Vellas B, Guigoz Y, Garry PJ, Nourhashemi F, Bennahum D, Lauque S, et al. The Mini Nutritional Assessment (MNA) and its use
in grading the nutritional state of elderly patients. Nutr Burbank
Los Angel Cty Calif. 1999 Feb;15(2):116-22.
5. Folstein MF, Robins LN, Helzer JE. The Mini-Mental State Examination. Arch Gen Psychiatry. 1983 Jul;40(7):812.

6. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of
illness in the aged. The index of ADL: a standardized measure of
biological and psychosocial function. JAMA J Am Med Assoc. 1963
Sep 21;185:914-9.
7. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. The Gerontologist. 1969;9(3):179-86.
8. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF,
Blazer DG, et al. A short physical performance battery assessing
lower extremity function: association with self-reported disability
and prediction of mortality and nursing home admission. J Gerontol. 1994 Mar;49(2):M85-94.
9. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al.
Development and validation of a geriatric depression screening
scale: a preliminary report. J Psychiatr Res. 1982 1983;17(1):37-49.

24

NUTRITION AND FRAILTY: A REVIEW OF CLINICAL INTERVENTION STUDIESNUTRITION AND FRAILTY:A REVIEW OF CLINICAL INTERVENTION STUDIES
B. MANAL1, S. SUZANA1, D.K.A. SINGH2

1 Dietetics Programme, School of Healthcare Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia;
2 Physiotherapy Program, School of Rehabilitation Sciences, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia.
Correspondence: Prof. Dr. Suzana Shahar, Dietetics program, School of Health Care Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia. Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
Tel +60 3 9289 7194, Fax +60 3 2693 8717, Email: suzana.shahar@gmail.com

Abstract: Frailty is one of the major health concerns inaging. It is considered a geriatric syndrome characterizedby muscle weakness, sarcopenia and fatigue. It is also associated with several adverse health outcomes, including
disability. Literature shows that there are a number of studies conducted to define the relationship between frailty andnutrition. The majority is from cross sectional, longitudinal,and cohort studies. Few intervention studies using micronutrients, macronutrients, nutritional supplement, or foodregimens have been found. This review examines the nutrition intervention studies targeted towards older adults withfrailty, and evaluates the effectiveness of nutrition interventions on frailty indicators. Twenty-four intervention studies from six electronic databases met the inclusion criteria.
Sixteen were randomized controlled clinical trials; one wasa quasi- experimental design, whilst the rest were controlled
trials. Participants included in the studies differed in termsof age and frailty status. The studies were inconsistent in intervention type, duration, and targeted outcomes. Most of
the studies indicated that modification of nutrition quality,
either by giving supplements or by improving diet intake,could improve strength, walking speed, and nutritional status in majority of frail or pre-frail older adults. However,there was limited evidence on the effectiveness of intervention on inflammatory status and other biomarkers related
to frailty due to limited number of studies targeting frailty
biomarkers as a major outcome.

BACKGROUND

59.9% respectively, whilst the corresponding figures were
21.6%, and 60.3% respectively in United Kingdom (3).
In Spain frailty was 8.4% and prefrailty was 41.8% in older populations (6). Similar findings were found in Asian
countries, specifically in Thailand where the prevalence was
4.9% for frailty and 40.0% for prefrailty (7). The difference
was probably due to the variability on sample, assessment
methodology, criteria and heterogeneity in pattern of diseases and lifestyles including diet.
The relationship between diet and chronic age related diseases has been reported in literature (5). However, the relationship between diet and mechanism of how nutrition
contributes to frailty is still not clear and needs further

Key words: Frailty, nutrition, supplement, randomized
controlled trials, intervention studies.

Frailty is a geriatric syndrome involving multi-system disorders, neuromuscular dysfunction, abnormalities in energy
metabolism, immune dysfunction, inflammation, and endocrine regulation (1-3). It has been associated with increased
risk of negative health outcomes including decline in quality of life (1, 2, 4) and disability (5). The concept of frailty
is multidimensional based on the relation between physical,
psychological, social and environmental factors (1, 3).
Literature has recorded a high variability in the prevalenceof frailty. The prevalence of frailty and prefrailty amongolder adults in the United States of America were 12% and25

WHITE BOOK

investigation (8). Nutritional status, dietary behavior, typeof food, and nutrients consumed are important parameters that should be thoroughly studied to determine therelationship between frailty and nutrition (8). Malnutrition
has been significantly associated with many of the frailty
components such as impairments in cognitive and physicalfunction (9, 10). The results of studies investigating the relationship between body mass index (BMI) and frailty are
more controversial (5). For example, Balum and colleagues
reported a significant association between frailty and obesity (11), Hubbard and colleagues reported a U-shape relationship between BMI and frailty (12), whereas Frisoli andcolleagues found no significant association (13).
Diet quality, healthy food choices, food sufficiency, and fooddiversity are significantly correlated with frailty (2, 14, 15).
A higher protein consumption was associated with a lower
risk of the incidence of frailty (16). Serum levels of carotenoid, vitamin D, vitamin B6, and folate levels differed
between non-frail, prefrail and frail older women (10).
However, interventional effect of related micronutrients or
dietary patterns in the experimental studies were few compared to cross sectional, longitudinal, or cohort studies.
In this review we aimed to report and evaluate the nutritional intervention studies that have been conducted on
frail older adults, and to determine which type of nutritional intervention significantly contributed to improving
frailty. As yet, there are no published reviews on nutritional
intervention studies and frailty that have been reported.

(5) intervention involved mainly nutrition alone or mixed
with others; and(6) f ull-text published in English.
Studies that did not fulfill the inclusion criteria were excluded. All the selected studies were reviewed in termsof methodology, study design, intervention type and duration, participants enrolled in the studies, targeted outcome and main findings. Figure 1 summarizes the procedures of articles selection.
Figure 1
Articles selection flow chart

METHODS

A thorough search for nutritional intervention studies onolder adults with frailty using multiple electronic bibliographic databases (Medline, CINAHL, Scopus, Science Direct and Springerlink), was conducted. Key words including frailty with nutrition, diet, supplement, macronutrients,
micronutrients and food were used to trace more studies.
The search was not limited to any time period but the oldest
studies were from the early1990s and onwards. The databases search resulted on hundreds of studies. A screening on
the title, abstract, and methodology was done to identify thestudies that met the inclusion criteria for further analysis.

RESULTS

Twenty-four nutritional intervention studies met the inclusion criteria, with 2216 older adults identified as frail andprefrail, distributed unevenly in twelve countries including
USA, Canada, Australia, Netherland, China, France, Germany, Sweden, Poland, Japan, Finland and Korea. The
majority of the study design was a randomized controlled
clinical trial, followed by controlled trial; two were placebo controlled and blinded, one was quasi experiment. The
sample size ranged from 47 to 243, one study included
women only, while the rest included both genders, mainly community dwelling older adults, except for four of thetrials that were done on institutionalized older adults. The
outcome measures reported were mainly physical functions(walking speed and strength) and nutritional status compared to frailty biomarkers. Summary of clinical trials in thepresent review included study design, intervention period,
assessment tools main findings and outcomes as listed intable 1.

Inclusion and Exclusion Criteria
The inclusion criteria included:(1) only original studies(2) study design was experimental i.e. clinical trials or quasi studies;(3) study participants were defined as “frail” or “prefrail”;(4) intervention targets had at least one of the frailty indicators: nutritional status, physical function, cognitive
function and mood, physical activity, mobility, energy,
psychology and frailty biomarkers;
26

NUTRITION AND FRAILTY:A REVIEW OF CLINICAL INTERVENTION STUDIES

clinical research, the frailty phenotype proposed by Friedand colleagues is very popular and well accepted for frailty
assessment (5, 17). The Frailty Index (based on the accumulation of deficits) has also been recommended for intervention studies (17). However, in the reviewed studies, thefrailty phenotype was used only in 2 of the studies (18, 19),
and the Frailty Index had not been used in any of the studies. Moreover, in many of the studies frailty assessment was
not defined. Participants’ selection criteria were not clear
and it was only stated as older adults with frailty were selected to participate. Nevertheless, in the study by Kim and colleagues mobility (gait speed) was used to define older adults
with frailty (20). Zak and colleagues used an operationalization of frailty based on five criteria which was different
from the original phenotype by Fried and colleagues (21).
In the study by Olin and colleagues, level of dependency was used as a tool to determine frailty status (9).
It could be concluded that frailty assessment was not consistently carried out in most of the studies. This might bedue to the fact that the frailty phenotype was published in
2001, the Frailty Index later, and a systematic review evaluating different frailty tools only in 2011 (17). Prior to thesepublications, evidence for recommendations of frailty assessment was not sufficiently available.

Types of nutrition intervention
Various types of nutritional interventions were used according to the requirements of the study. Nine studies
used a specific nutritional supplement formula, with calories ranging from 200 to 400 kcal per day. Other studies
used i) daily food fortification with protein supplement,ii) nutritional education and counseling for healthy foodand dietary habits, iii) an additional evening meal, dietary
counseling, and an educational program for healthy foodchoices and iv) micronutrients (vitamin D, omega three fatty acids, and multivitamin) supplementation as the nutritional intervention.
Effectiveness of intervention
The measures used to evaluate effectiveness of the intervention varied among the studies. Nutritional status, bodyweight, body composition, basal metabolic rate (BMR) andbiomarkers were inconsistent due to variability in participants’ nutritional status at baseline and the types of intervention used. Eleven of the sixteen studies that targetedfrailty status reported improvement in one or more of thefrailty domains, whilst the others reported improvement onother outcomes. Most of the studies that measured frailty
parameters reported significant improvement on these parameters.

The frailty indicators
Frailty has several indicators which include nutritional status, physical function, cognitive function, mood, physicalactivity, mobility, energy, psychology (9, 22) and biologicalmarkers (12). In the reviewed frailty intervention studies,
one or more of these indicators had to be included in theintervention outcomes. The most frequently studied frailty indicators in the reviewed studies were nutritional status
and physical function (18, 23, 24-30). In addition to nutritional and physical functional status, physical activity was
also added to frailty indicators assessment in some recent
studies (18, 19).
A more comprehensive assessment for frailty indicators was
performed in a study among 139 older adults with frailty
which includes, the changes in cognitive function, psychological status, physical function and physical activity (31).
Psychological status, nutritional, physical and cognitive
function has been used in the frailty assessment as early
as 1994 (30). Moreover, some of the studies limited frailty
indicators in the nutritional status to only diet intake, bodycomposition, and serum micronutrients (32, 33, 34). Generally, the rest of the studies examined two or more of thefrailty indicators namely physical activity, nutritional, cognitive and physical function.
Frailty biomarkers such as homocysteine and serum levelof vitamin B12 were studied in only two studies (20, 35).
These studies reported improvement in the oxidative stress,
immune function and inflammatory status indicating an im-

DISCUSSION

The published reviews on frailty were mainly addressing
frailty assessments and risk factors. Intervention studies inrelation to frailty are limited. Thus, in this review we focused on evaluating the effectiveness on frailty status. The
aim of this review was to answer a research question ofwhether certain types of dietary intervention, nutritional or
micronutrients supplementations have an impact on frailty status. The evaluation of the studies acknowledged thehigher level of evidence from RCT as compared to controlled trials that includes: frailty assessment tools, frailty
indicators, nutritional status assessment and the nutritionintervention itself.
The level of evidence of the reviewed studies is high as allof them are clinical trials, but sixteen studies involved randomization and this provided further strength in the level ofevidence (14). The rest of the studies are controlled studies.
A well-designed RCT is considered as a level A in evidence
based practice, however, the power of the study also need
to be considered (14). The quality of these studies’ methodology is discussed in the following paragraphs.

Frailty definition tool
Frailty assessment has been the main concern in the intervention studies and has been used to assess outcomes. In
27

WHITE BOOK

provement in frailty status. Future studies need to consider
the inclusion of biomarkers to indicate early changes in the
biological system following intervention.

ment compared to the nutrition groups, which revealed thestronger effect of exercise on frailty when compared to nutrition. The intervention period is varied according to thestudy objectives, ranging from one day to one year. However, the justification for the intervention period was not
mentioned in the published articles.
In general, nutrition intervention showed significant effects
on frailty indicators in most of the studies. Nutritional status before the intervention had an impact on the results,
with intervention appearing to be effective in older adults
with malnutrition. The comprehensive nutritional status
and the assessments are substantial constituents of any intervention study. Improvement in nutritional status might
possibly have led to improvement in frailty status. Mixed
intervention nutrition and exercise might have been more
effective than nutrition only.
Further research is recommended to include normal weightolder adults with frailty to determine the effect of the intervention of frailty status without affecting malnutrition,
which would confound the research results. Some micronutrients deficiency such as vitamin D and B12 were studied
to examine their effect on frailty in cross sectional and longitudinal studies, although the experimental studies are very
sparse. So, experimental studies with adequate dose and intervention period are needed to determine the effectivenessof vitamin D on frailty.

Nutritional status assessment
As nutrition and its related impact were the main issues infrailty, comprehensive nutritional status assessments are important to report in order to highlight the effects of theintervention on frailty. These include anthropometric measurements, biochemical data (especially micronutrients level), albumin, clinical assessments using the Mini Nutritional
Assessment tool (MNA) or Subjective Global Assessment(SGA) and dietary intake.
As shown in Table 1, nutritional assessments were conducted using several methods. Some studies reported detailed
nutritional assessments, which examined nutritional status
as the main outcome. In the study by Lammes et al. (2012),
nutritional status was assessed by using MNA, resting metabolic rate to estimate the energy intake, anthropometricmeasurements, BMI, fat mass and body density using four
skinfolds (33). On the other hand, several studies involved
limited nutritional status assessments such as BMI and diet
(18, 20, 27). MNA (a highly sensitive and accurate toolfor nutritional assessment in older adults) has repeatedly
been used as a tool for clinical nutritional status assessment(9, 19, 21, 23-25).
Type of the nutrition intervention
The nutrition intervention used in the studies included, asingle type of (n=2), multivitamins (n=4), nutritional supplement formula (n=8), adding an extra meal (n=1), meals
on wheels (MOW) (n=1), mixed with exercise (n=7) andindividualized dietary counseling (n=4). The results andoutcomes varied due to the type and duration of nutritionintervention and nutritional status before the intervention.
The studies that used energy supplements in the intervention reported significant improvements in one or more of
the frailty indicators or nutritional status, while nutritional
advice and counseling (20, 33) showed no significant improvement. However, Nykanen and colleagues reported
improvement in frailty status with individual dietary counseling (19). Probably because the study involved older adults
who were at risk of malnutrition, showed improvement infrailty status by improving their nutritional status. This may
explain that older adults who were at risk of malnutrition,
showed improvement in frailty status by improving theirnutritional status. On the other hand, adding an extra meal
to the habitual diet showed significant improvements on
dietary intake (34). But, in the study by Olin et al. (2008) nosignificant improvement was found (9), which might havebeen due to the difference in the participants ages between
the two studies. In the mixed intervention of nutritionand exercise, the exercise groups showed more improve-

Acknowledgement: We would like to acknowledge the financial
supports from the Ministry of Education in the Long Term
Research Grant Scheme (LRGS/BU/2012/UKM-UKM/K/01), and the direct and indirect input from the research team towards the study, particularly the co-supervisors Assoc. Prof. Dr. Norfadilah Rajab and Assoc. Prof. Dr.
Zahara Abdul Manaf, from the Faculty of Health Sciences,
University Kebangsaan Malaysia.
Conflict of interest: Authors have no interest of interest to
declare.
Ethical standards: Ethical approval was obtained from the
Research and Ethics Committee of Universiti Kebangsaan
Malaysia. Ref.No.: UKM1.53.5/244/NN-149-2013.

28

NUTRITION AND FRAILTY:A REVIEW OF CLINICAL INTERVENTION STUDIES

Table 1
Frailty and Nutrition intervention study
AuthorsStudy
designIntervention

Intervention
periodIntervention
arms

Subjects
characteristics

Frailtyassessment
tools

Main findings

Hutchins etal (2013)

RCT
BlindedPlaceboOmega 3(2gm of EPA,
DHA)

Six months

Two arms

126
postmenopausal
womenFried et al2001 criteria

Improvement inwalking speed

Kim et al(2013)

RCT

200 ml -400kcal
nutritional
supplement.

12 weeks

Two arms

87 community
dwelling frail
elderly

Their own
definition
Nutrition andmobility

Improvement ingait speed andtime up and go(TUG)

Lammes et al   RCT(2012)

Nutritional
advice with orwithout exercise

3 months

Four arms

96 frail elderly
aged 75 and above

Nykanen et al(2012)CT

Individual dietary 1 year
counseling

Two arms

159 community
dwelling at risk ofmalnutrition 75
years and above(frail and prefrail)

Fried criteria

Improvement in
the frailty status

Rydwik et al(2010)

RCT

Physicaltraining andindividual dietary
counseling

3 months
intervention.
9 months
follow up

4 arms96 community
dwelling frail
elderly

Weight loss
and low
physical
activity

Increase of thehabitual physicalactivity level No
significant effects
on ADLZak et al  (2009)

RCT
BlindedPlacebo

300 kcalnutritional
supplement(NUTRIDRINK) /exercise

7 weeks

4 arms

80 frail elderly(both community
dwelling andinstitutionalized)

5 points
inclusion
criteria

Improvement inmuscle strength
were found in(EG/ E+NS)

Olin et al(2008)

CT

Additional
evening meal
(530kcal)

6 months

2 arms49 service flat frail
elderly aged 75
and above

Level ofdependency

No changes onbody weight, andcognitive function

Rydwik et al(2008)

RCT

Physical andnutritional
intervention
program6  months

4 arms

96 frail community
dwelling elderly
aged 75 and above

Smoliner et al(2008)CT

Food fortification

12 weeks

2 arms65 institutionalized(malnourished orat risk)

Roy & Payette Quasi(2006)   
experimental

Meals on wheels(MOW) program

8 weeks

2 arms

51 frail elderly

Wouters et al(a) (2005)

CT
Placebo

250 ml, 300
kcal nutritional
supplement

6 months

2 arms

33 frail elderly
65 years andabove, BMI<25

Not definedSignificant
difference inproliferation,
no significant
difference in IL2  
between groups

Wouters et al(b) (2005)

CT
placebo

250 ml,300 kcalnutritional
supplement

6  months

2 arms

67 frail elderly

Not definedSignificant
changes in theserum biomarkers.
Improvement insome of cognitive
test

Bonnefoy etal (2003)

RCT

400 kcal \ dayProtein – energy
supplement with
exercise

9 months

4 arms

57 frail elderly,
from retirement
housesNot defined

Improvementof the muscle  functional test in
the supplementgroup

No effect by
the Nutritionintervention
Not defined

Improvement inprotein intake andBody composition
Increase in the
dietary intake

NUTRITIONAL INTERVENTION IN FRAILTY

29

Increase in RMR in
the exercise group
onlyWHITE BOOK

Study
designIntervention

Intervention
periodIntervention
arms

Subjects
characteristics

Frailtyassessment
tools

Main findings

Latham et al(2003)

RCT
Multicentral

Vitamin D /exerciseSingledose of
Vitamin D
10 weeks
exercise

4 arms

243 frail elderly

Winogradet al., 1991
criteria

Exercisegroup showed
increases risk ofmusculoskeletal
injuryPayette et al(2002)

RCT

400ml,
400 kcalnutritional
supplement

16 weeks

2 arms

83 frail elderly
at risk for undernutrition

Not defined

Improvement
in total energy
intake, weight,
muscle strength,
functional status,
days spent in bed

Paw et al(2002)

RCT

Micronutrient
supplement /exercise

17 weeks

4 arms139 frail elderly

Not defined

None

Kwok et al(2001)RCT

Low lactose milk
powder

7 weeks

2 arms47 institutionalized
frail elderly

Not defined

Improvement in
dietary intake only

Marijke 2001

RCT
placebo
controlled

Enriched foodand exercise

17 weeks

4 arms

157 frail elderly

Weight loss
Low physicalactivity

Significant
improvement on
physical function
and fitness in theexercise groups,
Consumption ofenriched products
did not affect performance, fitness,or disability scores

De jong et al(A) (2000)

CT

Nutrients dense
products/
exercise

17 weeks

4 arms

159 frail
communitydwelling elderly

Weight loss
Low physicalactivityNone

De jong et al(B) (2000)

RCT

Nutrients dense
products/
exercise

17 weeks

4 arms

143 frail elderly

Weight loss
Low physicalactivity

Increase in thelean body massin the exercisegroupsSingh et al(2000)

RCT

Multinutrient
liquid10 weeks

50 frailinstitutionalized
elderly

Not definedSignificant
decrease in dietintakeGray et al  
(1995)

RCT

200 kcalnutritional
supplement

12 weeks

2 arms

50 frail elderly

Not definedSignificant weightgain

Fiatrone et al(1994)

RCT

Nutritional
supplement andexercise

10 weeks

4 arms100 frail
institutionalized
elderly

Not defined

Increase in thephysical functionin the exercisegroups

NUTRITIONAL INTERVENTION IN FRAILTY

Authors

This article was published in the Journal of Frailty & Aging - Volume 4, Number 2, 2015
http://www.jfrailtyaging.com/

REFERENCES
1. Crentsil V. Mechanistic contribution of carnitine deficiency to geri- 4. Rockwood K, Mitnitski A. How might deficit accumulation give riseatric frailty. Ageing Res Rev 2010;9(3):265-8.
to frailty. J Frailty Aging 2012;1:8-12.
2. Bollwein J, Diekmann R, Kaiser MJ, Bauer JM, Uter W, Sieber CC, et 5. Guyonnet S SM, Ghisolfi A, Ritz P, Vellas B. Nutrition frailty and
al. Dietary quality is related to frailty in community-dwelling older
prevention of disabilities with aging. J Frailty Aging 2014 in press.
adults. J Gerontol A Biol Sci Med Sci 2013;68(4):483-9.
6. Garcia-Garcia FJ, Avila GG, Alfaro-Acha A, Andres MA, Aparicio
3. Bowen ME. The Relationship Between Body Weight, Frailty,
ME, Aparicio SH, et al. The prevalence of frailty syndrome in an
and the Disablement Process. J Gerontol B Psych Sci Soc Sci
older population from Spain. The Toledo study for healthy aging. J
2012;67(5):618-26.
Nutr Health Aging 2011;15(10):852-6.

30

NUTRITION AND FRAILTY:A REVIEW OF CLINICAL INTERVENTION STUDIES

7. Chen C-Y, Wu S-C, Chen L-J, Lue B-H. The prevalence of subjective
frailty and factors associated with frailty in Taiwan. Arch Gerontol
Geriatr 2010;50:S43.
8. Bischoff HA, Staehelin HB, Willett WC. The effect of undernutrition in the development of frailty in older persons. J Gerontol A
Biol Sci Med Sci 2006;61(6):585-9.
9. Olin AÖ, Koochek A, Cederholm T, Ljungqvist O. Minimal effecton energy intake by additional evening meal for frail elderly service
flat residents—a pilot study. J Nutr Health Aging 2008;12(5):295301.
10. Bartali B, Frongillo EA, Bandinelli S, Lauretani F, Semba RD, FriedLP, et al. Low nutrient intake is an essential component of frailty
in older persons. J Gerontol A Biol Sci Med Sci 2006;61(6):589-93.
11. Blaum CS, Xue QL, Michelon E, Semba RD, Fried LP. The association between obesity and the frailty syndrome in older women: the Women’s Health and Aging Studies. J Am Geriatr Soc
2005;53(6):927-34.
12. Hubbard RE, Lang IA, Llewellyn DJ, Rockwood K. Frailty, bodymass index, and abdominal obesity in older people. J Gerontol A
Biol Sci Med Sci 2010;65(4):377-81.
13. Frisoli Jr A, Chaves PH, Ingham SJM, Fried LP. Severe osteopenia and osteoporosis, sarcopenia, and frailty status in community-dwelling older women: results from the Women’s Health andAging Study (WHAS) II. Bone 2011;48(4):952-7.
14. Bernstein MA, Tucker KL, Ryan ND, O’Neill EF, Clements KM,
Nelson ME, et al. Higher dietary variety is associated with better nutritional status in frail elderly people. J Am Diet Assoc
2002;102(8):1096-104.
15. Tieland M, Borgonjen-Van den Berg KJ, van Loon LJ, de Groot
LC. Dietary protein intake in community-dwelling, frail, and institutionalized elderly people: scope for improvement. Eur J Nutr
2012;51(2):173-9.
16. Beasley JM, LaCroix AZ, Neuhouser ML, Huang Y, Tinker L, Woods
N, et al. Protein intake and incident frailty in the Women’s Health
Initiative observational study. JJ Am Geriatr Soc 2010;58(6):106371.
17. De Vries N, Staal J, Van Ravensberg C, Hobbelen J, Olde Rikkert
M, Nijhuis-Van der Sanden M. Outcome instruments to measurefrailty: a systematic review. Ageing Res Rev 2011;10(1):104-14.
18. Hutchins-Wiese H, Kleppinger A, Annis K, Liva E, Lammi-Keefe
C, Durham H, et al. The impact of supplemental n-3 long chain
polyunsaturated fatty acids and dietary antioxidants on physicalperformance in postmenopausal women. J Nutr Health Aging
2013;17(1):76-80.
19. Nykänen I, Rissanen TH, Sulkava R, Hartikainen S. Effects of individual dietary counseling as part of a comprehensive geriatric assessment (CGA) on frailty status: A population-based intervention
study. J Clin Gerontol Geriatr 2012;3(3):89-93.
20. Rydwik E, Frändin K, Akner G. Effects of a physical training andnutritional intervention program in frail elderly people regarding habitual physical activity level and activities of daily living—A randomized controlled pilot study. Arch Gerontol Geriatr
2010;51(3):283-9.
21. Zak M, Swine C, Grodzicki T. Combined effects of functionally- oriented exercise regimens and nutritional supplementation on boththe institutionalised and free-living frail elderly (double-blind, randomised clinical trial). BMC Public Health 2009;9(1):39.
22. Olin AÖ, Koochek A, Ljungqvist O, Cederholm T. Nutritional status, well-being and functional ability in frail elderly service flat residents. Eur J Clin Nutr 2005;59(2):263-70.

23. Kim C-O, Lee K-R. Preventive effect of protein-energy supplementation on the functional decline of frail older adults with low socioeconomic status: a community-based randomized controlled
study. J Gerontol A Biol Sci Med Sci 2013;68(3):309-16.
24. Smoliner C, Norman K, Scheufele R, Hartig W, Pirlich M, Lochs H.
Effects of food fortification on nutritional and functional status in
frail elderly nursing home residents at risk of malnutrition. Nutrition 2008;24(11):1139-44.
25. Bonnefoy M, Cornu C, Normand S, Boutitie F, Bugnard F, Rahmani A, et al. The effects of exercise and protein–energy supplements on body composition and muscle function in frail elderly
individuals: a long-term controlled randomised study. Br J Nutr
2003;89(05):731-8.
26. Bonnefoy M, Cornu C, Normand S, Boutitie F, Bugnard F, Rahmani A, et al. The effects of exercise and protein-energy supplements on body composition and muscle function in frail elderly
individuals: a long-term controlled randomised study. BBr J Nutr
2003;89(5):731-8.
27. Payette H, Boutier V, Coulombe C, Gray-Donald K. Benefits ofnutritional supplementation in free-living, frail, undernourishedelderly people: a prospective randomized community trial. J Am
Diet Assoc 2002;102(8):1088-95.
28. Kwok T, Woo J, Kwan M. Does low lactose milk powder improve
the nutritional intake and nutritional status of frail older Chinese
people living in nursing homes? J Nutr Health Aging 2000;5(1):1721.
29. Gray-Donald K, Payette H, Boutier V. Randomized clinical trial ofnutritional supplementation shows little effect on functional status among free-living frail elderly. J Nutr 1995;125(12):2965-71.
30. Fiatarone MA, O’Neill EF, Ryan ND, Clements KM, Solares GR,
Nelson ME, et al. Exercise training and nutritional supplementation for physical frailty in very elderly people. N Engl J Med
1994;330(25):1769-75.
31. Paw MCA, De Jong N, Schouten E, Van Staveren W, Kok F. Physical exercise or micronutrient supplementation for the wellbeingof the frail elderly? A randomised controlled trial. Br J Sports Med
2002;36(2):126- 31.
32. De Jong N, Paw MCA, De Groot LC, Hiddink GJ, Van Staveren
WA. Dietary supplements and physical exercise affecting bone
and body composition in frail elderly persons. Am J Public Health
2000;90(6):947.
33. Lammes E, Rydwik E, Akner G. Effects of nutritional intervention
and physical training on energy intake, resting metabolic rate andbody composition in frail elderly. A randomised, controlled pilot
study. J Nutr Health Aging 2012;16(2):162-7.
34. Roy M, Payette H. Meals-on-wheels improves energy and nutrient
intake in a frail free-living elderly population. J Nutr Health Aging
2005;10(6):554-60.
35. Latham NK, Anderson CS, Lee A, Bennett DA, Moseley A, Cameron ID, et al. A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty
Interventions Trial in Elderly Subjects (FITNESS). J Am Geriatr Soc
2003;51(3):291-9.
36. Rao M. Nitric oxide scavenging by curcuminoids. J Pharmacy
Pharmacol 1997;49(1):105-7.

31

WHITE BOOKREASONING ABOUT FRAILTY IN NEUROLOGY:
NEUROBIOLOGICAL CORRELATESAND CLINICAL PERSPECTIVES
M. CANEVELLI, F. TROILI, G. BRUNO

Memory Clinic, Department of Neurology and Psychiatry, University “Sapienza”, RomeCorrespondence: Marco Canevelli, Memory Clinic, Department of Neurology and Psychiatry, University “Sapienza”, Vialedell’Università 30, 00185 Rome, Italy, Tel/fax +39 06 49914604, Email: marco.canevelli@gmail.com

Abstract: To date, the frailty syndrome has surprisingly
attracted limited attention in the field of neurology andneuroscience. Nevertheless, several concepts closely related to frailty, such as vulnerability, susceptibility, and homeostatic reserves, have been increasingly investigated anddocumented at level of neuronal cells, brain networks, andfunctions. Similarly, several aspects commonly assessed in
the neurological practice, including cognitive functioning
and emotional/affective status, clearly appear to be major
determinants of the individual’s vulnerability and resiliency
to stressors. Therefore, they should be carefully consideredin the clinical approach to frail subjects. Moreover, dysfunctions of these domains, if timely detected, may be suitable
to be targeted by interventions providing beneficial effects
to the overall health status of the individual. In the present
article, we discuss the neurobiological processes potentiallycontributing to frailty. Moreover, we reason about the clinical manifestations allowing the prompt and easy recognition of frail persons in the neurological practice.
Key words: Frailty, cognitive impairment, dementia, brain
aging, emotional status.

Frailty is defined as a multidimensional conditionof increased vulnerability to stressors, posing
the subject at risk of negative health-related outcomes, including falls, hospitalization, institutionalization,and disability (1). This concept is triggering a growing scientific and clinical interest as it may allow the identification of a pre-disability state still amenable to interventions
and, thus, potentially reversible. To date, surprisingly, such
entity attracted limited attention in the field of neurology
and neurosciences. The word “frailty” has appeared onneurological and neuropsychiatric journals in only 17 outof nearly 450 articles (3.8%) published in 2013 (research
updated to August 15th, 2013). Nevertheless, several concepts closely related to frailty are extensively investigated inneurosciences.
First, as stated above, frailty may be intended as a state ofincreased vulnerability/susceptibility. Such condition has
been increasingly documented at level of neurons, brain
networks, and functions. Despite sharing several pathophys-iological pathways at different biological levels (i.e. synaptic,
glial, mitochondrial, inflammation, and protein misfolding),
each neurodegenerative disease (e.g. Alzheimer’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis) seems toprimarily affect defined neuronal subsets and populations,suggesting underlying specific cellular vulnerabilities (2).
Based on these observations, it can be hypothesized thatthese diseases may result from specific combinations of genetic predispositions and environmental stressors causing
dysfunctions in susceptible neurons. Similarly, brain aging is
considerably heterogeneous being characterized by various
degrees of involvement of specific brain systems (notably a
medial temporal lobe system and a fronto-striatal system) (3).
Accordingly, some brain functions (e.g. semantic memory)
are relatively preserved with age, while other abilities (e.g.
processing speed, working memory, and episodic memory) more consistently decline (4). The routine neurologicalpractice offers numerous clinical examples of such brain
vulnerability. Vascular lesions, though small and limited, can

32

REASONING ABOUT FRAILTY IN NEUROLOGY: NEUROBIOLOGICAL CORRELATES AND CLINICAL PERSPECTIVES

cause overt dementia syndromes when involving strategic
cerebral structures. Furthermore, individuals with impaired
cognitive performance may experience the occurrence of
psychotic disturbances and/or an abrupt worsening of cognitive abilities when subjected to general anesthesia. Taken
together, this evidence indicates that several brain components, networks, and functions are intrinsically vulnerable,potentially contributing to individual vulnerability to stressors (e.g. stressful events, neuropathological changes).
On the other hand, frailty may also be interpreted as acondition of reduced resilience/reserve. The concept ofreserve has been introduced for explaining differences
across individuals when facing similar age-related brain
modifications and pathologies. It combines both structural(e.g. number of neurons and synapses) and functional (e.g.
use of pre-existing or compensatory mechanisms) aspects
that may increase tolerance to pathology. Epidemiologicalstudies suggest that lifelong experiences and leisure activities in later life may increase such reserves. This has been
mainly documented in the field of cognition (i.e. “cognitive reserve”) (5). For example, individuals with higher educational and occupational attainment have been found tohave a reduced risk of developing Alzheimer’s disease (6-7).
Subjects with higher reserve may maintain adequate functioning of strategic networks in critical situations (i.e. neuronal knock-out related to head trauma, anesthesia, dehydration, electrolyte dysfunction, and metabolic syndromes)
and tolerate a greater amount of structural and functional
disease-specific pathology (e.g. Alzheimer’s disease). Therefore, changes in lifestyle and interventions may be useful todelay age-related cognitive decline or dementia.
In recent years, several proxies of cognitive reserve havebeen proposed including educational level, work complexity, social networks as well as engagement in cognitivelystimulating activities, leisure time activities, and physicalexercise. In parallel, the neural mechanisms potentially underlying such reserve have been increasingly investigatedand elucidated.
Beside of defining the biological basis of frailty, a great effort is also devoted to the identification of clinical parameters allowing the easy identification of the frail person. Thismay consent to promptly implement preventive interventions against disability and other negative outcomes. Several operational definitions have been developed in order
to translate into practice the theoretical concept of frailty.
So, how can we detect frailty in the neurological practice?
What clinical symptom/sign can help us identifying frail
subjects at risk of negative events that may still beneficiate from appropriate interventions? In our opinion, twodomains should be carefully considered, namely cognitive
abilities and affective/emotional status. These factors greatly influence the individual’s vulnerability and resiliency tostressors. They have been consistently found to significant-ly influence the risk towards relevant adverse outcomes.
Moreover, if promptly detected, the impairment of these
domains may be still manageable and suitable to be targetedby preventive interventions providing beneficial effects tothe overall health status of the individual.
Cognitive impairment, independently from specific clinical diagnosis (i.e. dementia, mild cognitive impairment),
is increasingly recognized as a potential contributor to theclinical vulnerability of older persons, resulting as a strong
predictor of several adverse health-related outcomes (8).
In particular, a decline of cognitive performance has beenfound to increase the risk of mortality, disability, and institutionalization, independently of potential confounders(e.g. socio-demographic characteristics, incident dementia,
depression, and comorbidities). Several hypotheses may
explain the association between cognitive impairment andfrailty. Impaired cognitive functioning may interfere in recognizing symptoms of diseases, affect adherence to therapeutic interventions, and influence the adoption of healthy
lifestyle behaviors. Similarly, cognitive deficits may limit
vocational achievements resulting in socioeconomic disadvantage and, consequently, in reduced access to health care.
Finally, the decline of each cognitive domain may result ina relevant limitation in planning and implementing adaptive behaviors and strategies in response to stressful events.
According to these considerations, there is a growing consensus proposing to include cognitive impairment as acomponent of the operational definitions of frailty (9-10).
A factor potentially limiting its adoption in the clinicaltranslation of the frailty syndrome is represented by thetimeliness of its detection. In fact, if cognitive decline isrecognized too late (when an extensive neurodegeneration
has already occurred), it may be not substantially modifiableby preventive actions and may potentially evolve toward a
condition of overt dementia. To date, we still need accurate
clinical tools allowing the prompt identification of at-risk
subjects. Moreover, the limited/controversial validity of the
proposed pre-dementia phases (e.g. mild cognitive impairment, subjective cognitive decline) still limits their implementation in the routine clinical practice (11).
Consistently, emotional and affective dimensions strongly influence the individual’s vulnerability and should thennecessarily be taken into account when addressing the multidimensional syndrome of frailty. Pathological emotional
responses (e.g. anxiety and depression) have been found to
considerably affect the onset, course over time, and severity of several medical conditions (e.g. ischemic heart disease, essential hypertension, tumors, and infectious diseases) as result of well-established interactions with nervous,
endocrine, and immune systems. Subjects with affective
disorders may more likely adopt unhealthy behavioral conducts resulting in increased risk of diseases and reduced
compliance to proposed interventions. Moreover, chronic
33

WHITE BOOK

mood disorders are frequently associated with a subsequent
impairment of specific cognitive abilities (e.g. executivefunctions), leading to further reduction of individual resiliency. Differently from cognitive disorders, emotional andaffective disturbances may be more responsive to diverse
non-pharmacological (e.g. psychotherapy) and pharmacological interventions. These strategies may positively influence the overall health status by improving the capacity tocope with stressors and dysfunctions.
In conclusion, we believe that “frailty” should represent asource of inspiration in the field of neurology. This concept
stresses the multidimensionality of aging and age-related
medical conditions, the urgent necessity to identify at-risk
subjects potentially benefiting from preventive actions, andthe possibility of significantly influence the trajectories toward the “successful” aging. In this context, cognition andemotional/affective status appear to be major determinantsof individual vulnerability and resiliency. The dysfunctionsof these domains should be therefore carefully investigatedand managed. Inspired by the process of attempting thetranslation of “physical frailty” in clinical settings, neurologists will need to develop and validate use-friendly assessment tools (necessarily encompassing cognitive and emotional aspects) in order to allow a prompt detection of frail
subjects in their practice.
This article was published in the Journal of Frailty and Aging
Volume 3, Number 1, 2014
http://www.jfrailtyaging.com/

REFERENCES
1. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381(9868):752–62.
2. Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration.
Neuron 2011;71(1):35–48.
3. Jagust W. Vulnerable neural systems and the borderland of brain
aging and neurodegeneration. Neuron 2013;77(2):219–34.
4. Park DC, Lautenschlager G, Hedden T, Davidson NS, Smith AD,
Smith PK. Models of visuospatial and verbal memory across theadult life span. Psychol Aging 2002;17(2):299–320.
5. Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 2012;11(11):1006–12.
6. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004;3(6):343–53.

7. Mangialasche F, Kivipelto M, Solomon A, Fratiglioni L. Dementia
prevention: current epidemiological evidence and future perspective. Alzh Res Ther 2012;4(1):6.
8. Houles M, Canevelli M, Abellan van Kan G, Ousset P, Cesari M,
Vellas B. Frailty and cognition. J Frailty Aging 2012;1(2):56–63.
9. Avila-Funes JA, Amieva H, Barberger-Gateau P, Le Goff M, Raoux
N, Ritchie K, et al. Cognitive impairment improves the predictive
validity of the phenotype of frailty for adverse health outcomes:
the three-city study. J Am Geriatr Soc 2009;57(3):453–61.
10. Robertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment- A review of the evidence and causal mechanisms. Ageing
Res Rev 2013;12(4):840–51.
11. Abdulrab K, Heun R. Subjective Memory Impairment. A review of
its definitions indicates the need for a comprehensive set of standardised and validated criteria. Eur Psychiatry J Assoc Eur Psychiatr
2008;23(5):321–30.

34

MOLECULAR CROSSROADS OF FRAILTY AND HIV

MOLECULAR CROSSROADS OF FRAILTYAND HIV
O. TAMEZ-RIVERA1, P. MARTINEZ-AYALA2, A.P. NAVARRETE-REYES1,
H. AMIEVA3, J.A. AVILA-FUNES1,3

1 Department of Geriatrics. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
2 Department of Infectous Diseases. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
3 Centre de recherche INSERM, U897, Bordeaux, France; Université Victor Segalen Bordeaux 2, Bordeaux, France
Correspondence: José Alberto Ávila-Funes. Department of Geriatrics. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Vasco de Quiroga 15. CP 14000; Tlalpan, Distrito Federal, México. Phone: 52 (55) 54 87 09 00, 5703.
E-mail: avilafunes@live.com.mx
Alternate Corresponding Author: Oscar Tamez-Rivera. E-mail: otr_39@hotmail.com

Abstract: An epidemiological transition is occurring regarding Human Immunodeficiency Virus (HIV) infection.
This phenomenon, explained by several mechanisms (e.g.:physiologic changes, pharmacologic advances, sexual behaviors), is demonstrated by a significant increase in thenumber of patients aged 50 years and older diagnosed
with this infection. The immunological changes observedin HIV-infected patients may prompt the appearance ofan accelerated aging process as well as that of comorbidities and other pathological entities commonly diagnosedin older adults. Frailty is a biologic syndrome characterized
by a multi-systemic decrease of the individual’s physiologic
and homeostatic reserves, leading to diminished resistanceagainst stressors and increased vulnerability. The purposeof this review is to describe the common molecular changes seen in both frailty and HIV-1 infection, offering an
in-depth analysis of their pathophysiology and specifying
common processes where their pathways meet.

INTRODUCTION

represented 10%. (2). In Mexico, according to the National
Center for Prevention and HIV/AIDS Control (CENSIDA), 19,877 cases of HIV-1 infection were reported between 1983 and 2012 in patients 50 years of age and older,
representing 12.6% of the entire affected population (3).
Consequently, it is projected that from 2015 to 2020, patients belonging to this group of age will represent morethan 50% of the infected population worldwide. One aspect that has gained importance over the last few years is
the presence of frailty.
“Frailty” has emerged as a condition associated with an increased risk of functional decline among the older persons.
Frailty can be differentiated from aging, disability, and comorbidity. It is a biologic condition in which the individual’s physiologic and homeostatic reserves are decreased and

Key words: Frailty, elderly, HIV, AIDS.

Nowadays, a significant epidemiological transition is occurring regarding Human Immunodeficiency Virus-infectedpatients around the world. This change is characterized byan increased prevalence of HIV-1 infection among patients
aged 50 and older (1). A variety of factors have influenced
this change, including the access to highly active antiretroviral therapy (HAART) and the increase in the number of
newly- diagnosed cases in this group of age. For example,
in the United States, the Centers for Disease Control (CDC)
estimates that approximately 30% of people currently living with HIV/AIDS are 50 years and older. In 2010, 1525% of new diagnoses of HIV/AIDS occurred in individuals older than 50 years, while in the year 2000 they only

35

WHITE BOOK

its resilience diminished, resulting in a state of increased
vulnerability to the adverse effects of a variety of environmental factors, expressed as an increased risk for hospitalization, institutionalization, and mortality (6). In the absenceof biological markers, various operational definitions aimed
at identifying elderly persons vulnerable to adverse healthrelated outcomes have been proposed. Fried et al. proposeda definition that conceptualizes frailty as a clinical syndrome
integrated by the combination of the following five components: weight loss, exhaustion, low physical activity, slow
gait speed, and low grip strength (6). Subjects meeting threeor more of these criteria were considered to be “frail”; thosemeeting one or two criteria were considered “pre-frail” or“intermediate” while those meeting none were “non-frail”.
However, the best way to identify frailty remains controversial. Although the Fried et al.’s definition is widely used,
inclusion of other common age-related conditions into thepreviously described phenotype has been a topic of considerable debate. For example, Rockwood et al. understandfrailty in the context of the accumulation of deficits, where
the individual’s frailty index score reflects the proportionof potential deficits present at a given time translating the
likelihood of the patient being frail (7). However that may
be, the conceptual frame of frailty implies a connection between all its components and supports the perception offrailty as a multifactorial entity.
On the other hand, unlike the typical definition of the term
‘syndrome’ used in medical literature, the term ‘geriatricsyndrome’ has a different meaning (8). A geriatric syndrome
is defined as the “accumulated effect of impairments in
multiple domains” that could lead to a variety of adverse
health-related outcomes including falls, incontinence or delirium (6, 8). It is precisely this accumulation of deficits andtheir physiologic correlations that represent frailty.
As the ever-increasing cohort of HIV-1 positive patients
aged 50 and older continues to grow, researchers aroundthe world have formulated interrogations and hypotheses regarding interconnections between frailty and HIV-1
infection in elderly patients. Several associations between
these two entities have been suggested in previous research(9, 10). From a molecular perspective, both may share similar changes that could lead to a series of inter-related multi-systemic implications. Indeed, HIV infection has been
proposed as a “premature aging model” (11), where a variety of biological systems are compromised, including themusculoskeletal, cardiovascular, neurologic, hematologic,
endocrine, and immune systems (12). Furthermore, the aging process coupled with HIV infection situates these patients at a high-risk for adverse health-related outcomes andincreased morbimortality (13). In this review, we explore
the molecular mechanisms and changes observed in bothHIV-1 infection and frailty following a system-based analysis in order to describe how each change contributes to theclinical manifestations that place these patients’ health andoutcomes at stake.
CHANGES IN THE IMMUNE SYSTEM AND
INFLAMMATION

The innate immune system, considered the organism’s firstline of defense, confers an immediate-yet-unspecific response against stressors such as infectious processes andphysical injuries. On the other hand, the adaptive immune
system offers a more specialized defense mechanism due
to its ability to mount pathogen-specific responses and develop immunological memory in case of subsequent infections (14). In order to serve their purpose, both immune
systems have under their command a variety of cellularcomponents implicated in mounting an effective response.
If a disturbance to the immune system occurs, its protective
response suffers alterations as well (15).
HIV infection is characterized by a progressive failure of
the immune system, which shares some of the characteristics seen in the immune system of elderly subjects. As theindividual ages, his ability to generate a robust and accurate
immune response deteriorates over time. The term “immunosenescence” refers to this deterioration of the immune
system also present in frailty, mimicking a state of immunosuppression that has a negative impact on the patient’s
morbimortality (15). Both HIV-1 infected patients and frail
persons share common immune cellular changes (Table 1).
Even though several immune alterations are present infrailty and HIV-1 infection, changes in lymphocyte countand function are the most prominent ones (16). Both conditions are accompanied by thymic involution, leading to
a decreased production of T-cells (17). This anatomicalalteration of the thymus is compensated by an increased
proliferation of memory T-cells at the expense of naïve
lymphocytes, which in the long run is associated with reduced T-cell function (18). Both frail and HIV-1 positive
patients show a marked increase in the production of
CD28-, CD57+ memory CD8+ T-cells with reduced ability to produce interleukin 2 (IL-2) (19). In addition to acompromised production of T-cells, the telomeric shortening evidenced in CD4+ T-lymphocytes causes premature
apoptosis that further contributes to immunosuppression.
CD4+ T-cell dysregulation has also been associated withan increased risk of developing a frailty-related phenotype(FRP) among HIV-1 infected patients who were not alreadyfrail at diagnosis (20).

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MOLECULAR CROSSROADS OF FRAILTY AND HIV

cess is caused by the activation of several genomic cellular
systems involved in the resistance to oxidative stress andapoptosis (22). T-cells also contribute to inflammation by
expressing chemokine CC receptor-5 (CCR5) and at thesame time by showing a type-1 pro-inflammatory phenotype (23, 24). These receptors are not only expressed in the
aging individual but also in HIV-1 infected patients (25).
Common inflammatory changes between frailty and HIV-1
infection, summarized in Table 1, have been strongly associated with increased all-cause mortality (16, 19).

Table 1
Common immune cellular changes between frailty and HIV

Thymic involution
 CD4+ T-cell and its repertoire Naïve CD4+ T-cellCD4+ T-cell telomeric shortening
CD4+ T-cell premature apoptosis
 Expression of CCR-5
 CD28-, CD57+ memory CD8+ T-cells
 Inflammatory cytokines (IL-6, TNF-α)
 Secretion of IL-2

CHANGES IN BONE HOMEOSTASIS

HIV: Human Immunodeficiency Virus; CCR-5: CC
chemokine receptor 5; IL: Interleukin; TNF: Tumor Necrosis Factor

The human skeletal system is responsible for major functions related to support, protection and movement, as well
as for endocrine functions such as calcium metabolism andhematopoiesis. Bone tissue goes through a continuous cycleof self-regeneration that replaces old bone with new bone,
and a cautious balance between these two phenomena must
exist in order to maintain bone integrity. This complex
process in which osteoclasts resorb bone and osteoblasts
produce and deposit new bone is called “remodeling” (26).
As the individual ages, such balance suffers alterations thatlead to less bone formation and greater bone resorption.
A variety of studies have described a considerably higher
prevalence of osteoporosis in both frail and HIV-1 infectedpatients (27).

Inflammatory changes have been widely documented inboth frailty and HIV infection, and there is strong evidence
that they play a central role in the pathogenesis of bothconditions (16). The accumulation and deposit of senescent cells in various tissues have been proposed to be strong
contributors of long- lasting secretion of proinflammatory
cytokines during the aging process (21). This chronic stateof low-grade systemic inflammation seen in the elderly iscalled “inflammaging”, and it is characterized by an elevatedamount of circulating inflammatory cytokines, particularlyinterleukin 6 (IL-6). This inflammation-related aging proFigure 1
Common molecular changes among frailty and HIV-1 infection

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The increased production of inflammatory cytokines, particularly TNF-α, plays a key role in the development ofbone homeostasis changes, especially in osteoclast activity (28-30). Both, patients with HIV-1 infection and frail
patients show an increased expression of TNF-α, which
in turn promotes bone resorption within bone metabolic
units. Due to this elevated production of proinflammatory
cytokines, the balance between bone formation and resorption is largely disrupted (31).
Another of the best-studied mechanisms related to TNF-α
and osteoclast activation is the expression of Receptor Activator of NFKB Ligand (RANK-L). In basal conditions,a member of the TNF superfamily called osteoprotegerin(OPG) binds to RANK-L inhibiting its transcription process and thus reducing the production of osteoclasts (27).
In HIV-1 infection, OPG production by lymphocytes is diminished while RANK-L remains present in a considerable
amount. This leads to an elevated RANK-L/OPG ratio,
promoting osteoclasts formation and ultimately contributing to osteoporosis. The increase in TNF-α expression also
causes a downregulation of IFN-γ expression, which has
the capacity to inhibit RANK-L. The attenuation of this inhibitory mechanism delivers the ideal scenario for RANK-L
to perpetuate the progression of osteoporosis. The verysame mechanism of bone turnover can be evidenced in the
aging individual, being one of the most important physiopathologic factors in postmenopausal osteoporosis (32, 33).
On the other hand, specific components of antiretroviral therapy have also been implicated in the pathogenesisof reduced bone mineral density (BMD) in HIV-infected
persons. Randomized controlled trials comparing BMD inprotease inhibitor (PI) versus non-PI treatment regimens
have shown mixed results. Several studies have revealed that
PI-containing regimens led to decreased spine BMD whileothers showed no difference in total body or hip BMD
between treatment groups. Despite the mixed effects on
BMD, cumulative exposure to boosted PI was found to be
associated with increased risk of fracture (HR 1.11; 95%
confidence intervals 1.05-1.18; p<0.001) (34). In particular,
treatment with lopinavir/ritonavir led to a 17% increase in
the risk of incident hip, vertebral, or wrist fracture (34).
Multiple studies have assessed the impact of ART initiation
on BMD and have generally shown a 2-6% loss after 48-96
weeks of therapy, regardless of the type of ART initiated.
This degree of bone loss is larger than what would be expected by aging alone and is comparable to the bone loss
seen in women aged 50-59 over 2 years (35, 36).

qualitative and quantitative progressive loss of muscle massis called “sarcopenia”, which in turn has a significant impact on the individuals’ mobility and strength which translates into an increased risk of adverse health-related outcomes (37). The model of frailty described by Fried et al. isstrongly influenced by the musculoskeletal system function,
whose impairment results in a decreased resting metabolic rate, decreased strength and power, and decreased VO2max (37). Even with the use of HAART, HIV-1 infected individuals are at increased risk of wasting and sarcopenia (6).
In fact, data suggest that changes in muscle mass occur at asimilar rate over 5 years in HIV- infected adults and non-infected elderly (38). Several factors have been implicated inmuscle damage, including inflammation and mitochondrial
dysfunction.
The state of chronic inflammation observed in both frail
patients and untreated HIV-1 infected patients has significant repercussions in the muscle system since myocytes arehighly responsive to cytokines (39). Furthermore, muscle
homeostasis appears to be dependent on a balanced expression of cytokines such as IL-6 and TNF-α (40). This essential balance is disrupted by catabolic stimuli, which include
low-grade chronic inflammation. Such disruption will eventually lead to sarcopenia in both frail and HIV-1 infectedindividuals, causing serious implications on their prognosis
as stated in data from the Framingham Heart Study, which
reported that IL-6 production was a significant predictor ofmortality over a 6- year period (41).
Mitochondrial dysfunction is also a part of the multifactorial etiology of sarcopenia. Mitochondria are the cellularorganelles responsible for adenosine triphosphate (ATP)production, and as such, are considered the main sourceof energy at a cellular level. Many reactions and processes
in the organism are dependent of ATP, and muscle contraction is not an exception. The pathways by which mitochondrial dysfunction is related to sarcopenia in frail andHIV-1 infected patients will be described below. As it waspreviously mentioned, sarcopenia is a highly prevalent phenomenon in older adults as well as in frail individuals. Muscle is not only responsible for movement and strength but
also works as the body’s main reservoir of protein and as an
essential site of glucose disposal (42). The process of aging
causes a reduction in mitochondrial size and DNA content,
as well as a decrease in mitochondrial protein synthesis (39).
This flawed functioning could be associated with oxidative
damage caused by the excess of free radical production (39).
Over time, the accumulation of oxidative damage reduces
ATP production in muscle, causing impaired muscle contraction and affecting the individual’s capacity for movement and strength. HAART has also been implicated inpremature and accelerated aging via direct effects on mitochondria. Antiretroviral drugs cause accumulation of damaged mitochondrial DNA, induce morphologic changes

CHANGES IN MUSCLE

Consequences of aging in the muscular system have been
extensively described in the literature. The decline in skeletal muscle mass is commonly observed in the elderly. This
38

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and increase oxidative stress (10). This mechanism of mitochondrial damage is common for both frailty and HIV-1
infection.
Growth hormone also plays a major role in the development of sarcopenia in frail older adults and HIV infectedpatients. Due to its predominant endocrine nature, it will
be discussed in the section dedicated to endocrine changes.
Another factor of great importance in the pathophysiology of sarcopenia is the decline of α-motor neuron input.
Nevertheless, there are very few reports of HIV-1 positive
patients with a documented motor neuron disorder (43).
This lack of evidence makes it difficult to associate motor
neuron disease with sarcopenia in HIV-1 infected individuals. However, neuromuscular impairment is considered acornerstone in the development of sarcopenia in the context of frailty, which is the reason why it should not be
overlooked while reviewing the different mechanisms ofmuscle damage. All these inter-related mechanisms highlight the importance of sarcopenia as a critical factor in thedevelopment of the impairment of strength, mobility, balance, and gait.

EPO is a known mechanism of anemia in frailty and HIV,
respectively (53).
CARDIOVASCULAR CHANGES

Several changes in the cardiovascular system have been described in the aging individual as well as in HIV infected patients. Previous work has shown these changes to be associated with an increased risk of cardiovascular disease, posing
a threat to health related quality of life of both groups ofpatients. More than two decades ago, Joshi et al. and Paton et al. described atherosclerotic changes in post-mortem analyses of young HIV-infected patients, setting theinitial evidence of vascular dysfunction in HIV infection(54, 55). Recent studies have also suggested a link between
HAART and acute myocardial infarction (AMI) risk among
HIV-positive patients; however, the mechanisms are not entirely known yet. History of cardiovascular disease, such as
AMI, angina, and congestive heart failure is more prevalent
among frail elderly patients, being congestive heart failure
the most strongly associated with frailty (56). Possible factors by which HIV infection contributes to these changes
have been recently postulated and include inflammation,
CD4+ T-cell depletion, altered coagulation, dyslipidemia,
impaired arterial elasticity, and endothelial dysfunction (57).
Some of these structural and functional cardiovascularchanges can also be seen in the aging individual, including increased vascular stiffness and endothelial dysfunction(58). Vascular stiffness results from calcification of the tunica media, thickening of the intima, and an increase in collagen content, which intertwines and forms a rigid matrix
that results in atherosclerotic disease (59).
Endothelial dysfunction, another core cardiovascular alteration, is present in HIV-positive patients as well as infrail elderly patients (60, 61). Individuals with both of these
conditions develop dysregulations of nitric oxide synthesis(NO). However, even though both HIV and frailty present
this endothelial change, NO synthesis behaves differently ineach condition. In the setting of HIV infection, productionof NO increases and is further enhanced by TNF-α monocyte activation (62).
The coagulation system is involved in frailty and HIV infection, and its alterations may be causative agents ofcardiovascular sequelae. It has been recognized that bothconditions feature a procoagulant state with an increase of
several biomarkers, particularly D-dimer (63, 64). Evidence
obtained from previous research demonstrates that the increase in D-dimer observed in both HIV-1 infection andfrailty correlates with adverse health-related outcomes, increasing both morbidity and mortality (65, 66). Moreover,the increase of these coagulation/fibrinolysis biomarkers
was associated with physical performance decline, specifi-

CHANGES IN THE HEMATOLOGIC SYSTEM

Anemia is the most frequently diagnosed hematologic disorder. This disorder can be found in both frail and HIV-1
infected patients and is associated with higher mortality anddiminished health-related quality of life (44-46). Anemia isa manifestation of several phenomena including hemorrhage, diminished erythropoiesis, hemolysis, and nutritional
deficiencies (i.e. iron, folic acid, vitamin B12), among others. However, in order to discuss anemia in HIV and frailty
we need to retake inflammation as the core causative mechanism. There is convincing evidence that supports a stronglink between IL-6 and anemia (47). The chronic low-grade
pro-inflammatory state characterized by increased levels of
IL-6 observed in HIV infection and frailty modifies ironmetabolism, which is essential for the homeostatic regulation of the hematologic system (48). Because of the deregulation of pro-inflammatory cytokines, iron is diverted
from the blood flow into the reticuloendothelial system
where it is no longer available for the erythrocyte (49, 50).
Iron maldistribution is the consequence of an IL-6-induced
type II acute phase response that results in the expressionof Hepcidin (Hepc) and Ceruloplasmin (Cp), contributing
to a restriction in iron availability and affecting hemoglobin
production (51).
Proinflammatory cytokines also have an inhibitory effect onerythropoietin (EPO), the glycoprotein hormone responsible for erythropoiesis (52). HIV-1 infected patients express
a myriad of circulating antibodies, including autoantibodies to endogenous erythropoietin (anti-EPO). Diminishederythropoiesis due to either inhibition or destruction of39

WHITE BOOK

cally that of lower extremities, disability for activities of thedaily living and poorer cognitive performance (67).
Due to the influence of these changes, the cardiovascularsystem is significantly compromised in both groups of patients, increasing the risk of complications such as AMI.
Further evidence is needed to describe the exact molecularchanges of the cardiovascular system in the frail individual;
however, physiological changes observed with aging may
represent strong indicators of what is observed in frailty.

CHANGES IN THE ENDOCRINE SYSTEM

The endocrine system contributes to homeostasis by secreting hormones into the blood stream. Its functions dependon connections -or axes- between several organs and glands.
The pathophysiologic processes of the two conditions discussed in this review are strongly linked with endocrine system dysfunction. As the individual ages, the somatotroph
axis is one of the hormonal pathways that demonstrates
a significant decay and thus has been implicated in several
catabolic phenomena present in older adults. The term “somatopause” was coined in order to describe the decline in
the activity of the GH-IGF-1 axis as well as its metabolic
consequences. Frailty is directly related to somatopause as
both conditions share common alterations and sequelae (75).
The decrease in GH and IGF-1, along with the abnormallyhigh levels of inflammatory mediators, contribute to thedevelopment of frailty (76). IGF-1, whose synthesis by theliver is GH-dependent, has been proposed as the most important mediator of muscle and bone growth (77). Several
studies suggest that low circulating levels of IGF-1, as well
as reduced responsiveness to its action by musculoskeletal
tissues, play an essential role in age-related osteopenia andsarcopenia, changes also observed in frail elders (78).
Individuals with HIV-1 infection experience endocrine dysregulations related to hypothalamic and pituitary dysfunction (79). Just as in frailty, the somatotroph axis is affected
in HIV-1 infection (80). Data obtained from recent studies
suggest that the development of early functional impairment
in HIV-1 infected patients is associated with low IGF-1,
which leads to the decrease of muscle mass and bone mineral density. These indicators are initial manifestations ofsomatopause (81). Another mechanism in which the somatotroph axis is involved in the setting of HIV-1 infectionis the development of lipodystrophy. Patients with HIVassociated lipodystrophy show decreased levels of GH and
IGF-1 (82). Recent investigations on the relationship between body composition and frailty in HIV-infected older
adults have concluded that infected frail subjects tend to
exhibit central obesity and characteristic fat redistribution
consistent with lipodystrophy.
Several other changes related to the decay of the somatotroph axis are worth noting. Recently, IGF-1 has been attributed a role in the pathogenesis of numerous conditions
seen during aging such as atherosclerosis, cardiovasculardisease, cognitive decline, and dementia (83). These conditions can be observed in HIV-1 infection as well. However,further research must be carried out in order to determine
the definitive mechanism by which they occur.
Sex hormones are also affected due to changes in the pituitary-gonadal axis and most notably observed in men.
As HIV progresses to AIDS, testosterone levels usually
decrease. With the arrival of HAART, the incidence of

CENTRAL NERVOUS SYSTEM CHANGES

Atherosclerosis, a key factor for the development of cardiovascular disease, also plays a major role in central nervous
system (CNS) alterations observed in frailty. The brain is
one of many end organs affected by atherosclerosis andstiffening of large and small vessels (68). The interaction
between vessel pathology and other factors associated withneurodegenerative changes may result in cognitive decline
and dementia in the aging individual. Current neurogeriatricviews consider Alzheimer’s disease (AD), small and large
vessel disease, and Lewy-body disease as the three main
conditions related to dementia and cognitive decline. Even
though they are considered to be different pathological entities, these three conditions may coexist; an example of thisinteraction is the evidence that large-vessel atherosclerosis
may contribute to AD (69, 70). Frailty is associated withlow cognitive performance and has been proposed as a risk
factor for mild cognitive impairment and AD (71, 72). Only
recently has it been proposed that frailty is an independentrisk factor for incident vascular dementia (73). These findings support the importance of cerebral blood supply andhighlight the role of vascular factors in the pathogenesis ofdementia.
Central nervous system involvement in HIV infected patients comprises a wide range of neurocognitive disorders,which are collectively known as HIV-associated neurocognitive disorders (HAND), being the HIV-associated dementia (HAD) its most severe manifestation. Vascular dysfunction may contribute to a lesser extent to the pathogenesis
of HAND; however, the main recognized developmental
mechanism of HAD/HAND is neuronal cell damage
by infected monocytes that cross the blood-brain barrier
to further differentiate into macrophages responsible forthe neuronal insult (74). Even though the mechanisms bywhich neurocognitive impairment presents and develops in
HIV-1 infection and frailty may not be exactly the same,
recognizing both entities as possible sources of CNS damage in the setting of these conditions is imperative.

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hypogonadism in HIV-infected men has declined from 40
to 20%. Hypogonadism may be accompanied by decreased
muscle and strength, generalized fatigue, reduced libido,
mood alterations, gynecomastia, normocytic anemia, anddiminished BMD (84). Hypogonadal men with HIV-associated weight loss treated with physiologic testosterone
therapy show improvement in lean body mass (LBM), muscle strength, BMD, and health-related quality of life. Hypogonadism may also be involved in the pathogenesis ofwasting syndrome, as it is present in up to 50% of men andwomen with wasting and has been directly correlated withdecreased in both LBM and fat (85).
Given the multi-systemic nature and metabolic complexityof frailty and HIV, it is unlikely that alterations of a single
axis (i.e. the somatotroph axis) can explain the entire metabolic dysregulation present in these conditions. Nevertheless, the importance of somatopause has been widely recognized as a determinant factor in aging and HIV infection.

vast commonalities between these two conditions, frailty
could escape even a well- trained clinical eye and remain
unnoticed. Failure to identify and address frailty in HIV-1
positive patients could result in the appearance of serious
adverse health-related outcomes or potentiate those alreadypresent. Even though HIV and frailty share similarities at
a molecular level, pharmacologic treatment of the first has
shown no benefit on the course of the second. No current
consensus is available on the treatment of frailty; however,prevention via identification of risk factors and protective
countermeasures (i.e. management of weight loss, physicalactivity, adequate caloric and protein intake, among others)
could theoretically improve outcomes in pre-frail and frail
individuals. In the meantime, surveillance of this ever- increasing population is required since life expectancy of an
HIV-1 infected frail patient could be even more compromised in spite of adequate HAART treatment.
Acknowledgments: Dr J. A. Ávila-Funes is supported by a
Bourse ECOS (2010-2013) from the Ministère des Affaires Étrangères in France and the Secretaría de Educación
Pública (SEP), the Asociación Nacional de Universidades
e Instituciones de Educación Superior (ANUIES), andCONACyT in Mexico.
Conflict of interest: Authors declare no conflict of interest on
this paper.

CONCLUSION

HIV infection in older adults has important medical, psychological, and socioeconomic implications. These patientsshow a higher prevalence of comorbidities and, those who
remain untreated, a more rapid progression to AIDS. The
physiopathological similarities found between HIV-1 infection and frailty could behave as synergic phenomena thatmay potentially impact these patients’ health status andtranslate into a more profound deterioration. Due to theThis article was published in the Journal of Frailty and Aging
Volume 3, Number 2, 2014
http://www.jfrailtyaging.com/

REFERENCES
1. Perez JL, Moore RD. Greater effect of Highly Active Antiretroviral
Therapy on survival in people aged > or = 50 years compared withyounger people in an urban observational cohort. Clin Infect Dis
2003;36:212-218.
2. Centers for Disease Control and Prevention. HIV/AIDS among
persons aged 50 and older: CDC HIV/AIDS facts. 20011, Washington, DC: US Department of Health and Human Services.
3. SS/DGE. National Census of AIDS Cases. Data up to April 2013.
SS/CENSIDA.
4. Kirk JB, Goetz MB. Human immunodeficiency virus in an aging population, a complication of success. J Am Geriatr Soc
2009;57:2129- 2138.
5. Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection: what is known and future research
directions. Clin Infect Dis 2008;47:542-553.
6. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults:
evidence for a phenotype. J Gerontol A Biol Sci Med Sci
2001;56:M146-M156.
7. Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol
Sci Med Sci 2007;62:738-743.
8. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm - issues and controversies. J Gerontol A Biol Sci Med Sci 2007;62:731-737.

9. Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known andfuture research directions. Clin Infect Dis 2008;47:542-553
10. Smith RL, de Boer R, Brul S, et al. Premature and accelerated
aging: HIV or HAART? Front Genet 2012;3:328. doi: 10.3389/
fgene.2012.00328. Epub 2013 Jan 28.
11. Pathai S, Lawn SD, Gilbert CE, et al. Accelerated biological aging
in HIV- infected individuals in South Africa: a case-control study.
AIDS 2013;27:2375-2384.
12. Deeks SG. HIV infection, inflammation, immunosenescence, andaging. Annu Rev Med 2011;62:141-155.
13. Önen NF, Abayomi A, Enbal S, et al. Frailty among HIV-infected
persons in an urban outpatient care setting. J Infect 2009;59:346352.
14. Kuchel GA. Aging and homeostatic regulation. In: Halter J,
Ouslander J, Tinetti M, Studenski S, High K, Asthana S (ed)Hazzard’s Geriatric Medicine and Gerontology, 6th edn. 2009.
McGraw Hill, pp 621-629.
15. Deeks SG, Verdin E, McCune J. Immunosenescence and HIV. Curr
Opin Immunol 2012;24:501-506.
16. Yao X, Li H, Leng SX. Inflammation and Immune System Alterations in Frailty. Clin Geriatr Med 2011;27:79-87.
17. Sauce D, Larsen M, Fastenackels S, et al. Evidence of premature
immune aging in patients thymectomized during early childhood.
J Clin Invest 2009;119:3070-3078.

41

WHITE BOOK

18. Akbar AN, Henson SM. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat
Rev Immunol 2011;11:289-295.
19. Aberg, JA. Aging, inflammation and HIV infection. Top Antivir
Med 2012;20:1-5.
20. Desquilbet L, Margolick JB, Fried LP, et al. Relationship between afrailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Synr
2009;50:299- 306.
21. Coppé JP, Patil CK, Rodier F, et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependenton physiological oxygen. PLoS ONE 2010;5:e9188.
22. Navarrete-Reyes, AP. Montaña-Álvarez M. Inflammaging: Aging
inflammatory origin. Rev Invest Clin 2009;61:327-336.
23. De FU, Wang GC, Fedarko NS, et al. T-lymphocytes expressing CC
chemokine receptor-5 are increased in frail old adults. J Am Geriatr
Soc 2008;56:904-908.
24. Qin S, Rottman JB, Myers P, et al. The chemokine receptors
CXCR3 and CCR5 mark subsets of T cells associated with certain
inflammatory reactions. J Clin Invet 1998;101:746-754.
25. Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor account for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996;86:367-377.
26. Guyton AC, Hall J. Parathyroid hormone, calcitonin, calcium &phosphate metabolism, vitamin D, bone & teeth. In: Guyton AC,
Hall J. (ed). Guyton and Hull textbook of medical physiology. 11thedn. 2001. Philadelphia, Pensylvania., pp 978-995.
27. Saccomanno MF, Ammassari A. Bone disease in HIV infection.
Clin Cases Miner Bone Metab 2011;8:33-36.
28. Stone B, Dockrell D, Bowman C, et al. HIV and bone disease. Arch
Biochem Biophys 2010;503:66-77.
29. Ofotokun I, Weitzmann MN. HIV-1 infection and antiretroviraltherapies: risk factors for osteoporosis and bone fracture. Curr
Opin Endocrinol Diabetes Obes. 2010;17:523-529.
30. Yin MT, Shane E. Low bone-mineral density in patients with HIV:
pathogenesis and clinical significance. Curr Opin Endocrinol Diabetes 2006;13:497-502.
31. McComsey GA, Tebas P, Shane E, et al. Bone disease in HIV infection: A practical review and recommendations for HIV care providers. Clin Infect Dis 2010;51:937–946.
32. Yun TJ, Chaudhary PM, Shu GL, et al. OPG/FDCR-1, a TNF receptor family members, is expressed in lymphoid cells and is up-regulated by ligating CD40. J Immunol 1998;161:6113-6121.
33. Li Y, Toraldo G, Li A, et al. B cells and T cells are critical for thepreservation of bone homeostasis and attainment of peak bonemass in vivo. Blood 2007;109:3839-3848.
34. Bedimo R, Zhang S, Dreschler H, et al. Risk of osteoporotic fractures associated with cumulative exposure to tenofovir and otherantiretroviral agents. AIDS 2012;26:825-831
35. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da
Silva BA. Loss of bone mineral density after antiretroviral therapy
initiation, independent of antiretroviral régimen. J Acquir Immune
Defic Syndr 2009; 51:554-61.
36. Warming L, Hassager C, Christiansen C. Changes in bone mineraldensity with age in men and women: a longitudinal study. Osteoporos Int 2002; 13:105-112.
37. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European
consensus on definition and diagnosis: report of the European
working group on sarcopenia in older people. Age Ageing 39:412–
423.

38. Tang AM, Jacobson DL, Spiegelman D, et al. Increasing risk of 5%
or greater unintentional weight loss in a cohort of HIV-infected patients, 1995 to 2003. J Acquir Immune Defic Syndr 2005;40:70–76.
39. Yarasheski, K. Age-related skeletal muscle decline is similar inHIV- infected and uninfected individuals. J Gerontol A Biol Sci
Med Sci. 2011;66:332–340.
40. Drey, M. Sarcopenia-pathophysiology and clinical relevance. Wien
Med Wochenschr 2011;161:402–408.
41. Cannon JG. Intrinsic and extrinsic factors in muscle aging. Ann NY
Acad Sci 1998;854:72–77.
42. Roubenoff R, Parise H, Payette H, et al. Cytokines, insulin-likegrowth factor 1, sarcopenia, and mortality in very old community dwelling men and women: the Framingham Heart Study. Am J
Med 2003;115:429–435.
43. Cooper C, Dere W, Evans W, et al. Frailty and sarcopenia: definitions and outcome parameters. Osteoporos Int 2012;23:1839–
1848.
44. Roubenoff R, Hughes VA. Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci 2000;55:716-724.
45. Belperio PS, Rhew DC. Prevalence and outcomes of anemia in
individuals with human immunodeficiency virus: a systematic review of the literature. Am J Med 2004;116:27-43.
46. Volberding PA, Levine AM, Dieterich D, et al. Anemia in HIV infection: clinical impact and evidence-based management strategies.
Clin Infect Dis 2004;38:1454-1463.
47. Dong X, Mendes de Leon C, Artz A, et al. A population-based
study of hemoglobin, race, and mortality in elderly persons. J Gerontol A Biol Sci Med Sci 2008;63:873–878.
48. Boelaert JR, Weinberg GA, Weinberg ED. Altered iron metabolism
in HIV infection: mechanisms, possible consequences, and proposals for management. Infect Agents Dis 1996;5:36-46.
49. Wisaksana R, Sumantri R, Indrati AR, et al. Anemia and iron homeostasis in a cohort of HIV-infected patients in Indonesia. BMC
Infect Dis 2011;11:213. doi: 10.1186/1471-2334-11-213.
50. Ganz T. The role of hepcidin in iron sequestration during infections and in the pathogenesis of anemia of chronic disease. Isr
Med Assoc J 2002;4:1043-1045.
51. Vyoral D, Petrak J. Hepcidin: a direct link between iron metabolism and immunity. Int J Biochem Cell Biol 2005;37:1768-1773.
52. William B. Biological Interactions of Aging and Anemia: A Focus
on Cytokines. J Am Geriatr Soc 2003;51:18-21.
53. Tsiakalos A, Kordossis T, Ziakas PD, et al. Circulating antibodies
to endogenous erythropoietin and risk for HIV-1-related anemia. J
Infect 2010;60:238-243.
54. Joshi VV, Pawel B, Connor E, et al. Arteriopathy in children withacquired immune deficiency syndrome. Pediatr Pathol 1987;7:261275.
55. Paton P, Tabib A, Loire R, et al. Coronary artery lesions and humanimmunodeficiency virus infection. Res Virol 1993;144:225-231.
56. Freiberg M, Chang CC, Kuller LH, et al. HIV infection and the riskof acute myocardial infarction. JAMA Intern Med 2013;173:614622.
57. Newman AB, Gottdiener JS, McBurnie MA, et al. Association of
subclinical cardiovascular disease with frailty. J Gerontol A Biol Sci
Med Sci 2001;56:158-166.
58. Lakkata EG, Schulman S. Age-associated cardiovascular changes
are the substrate for poor prognosis with myocardial infarction. J
Am Coll Cardiol 2004;44:1097-1104.
59. Lakatta EG. Cardiovascular regulatory mechanisms in advanced
age. Physiol Rev 1993;73:413–467.

42

MOLECULAR CROSSROADS OF FRAILTY AND HIV

60. Kline ER, Sutliff RL. The roles of HIV-1 proteins and antiretroviraldrug therapy in HIV-1-associated endothelial dysfunction. J Investig Med 2008;56:752-769.
61. Taddei S, Virdis A, Mattei P, et al. Aging and endothelial function
in normotensive subjects and patients with essential hypertension. Circulation 1995;91:1981–1987.
62. Bukrinksy M, Schmidtmayerova H, Zybarth G, et al. A criticalrole of nitric oxide in human immunodeficiency virus type 1-induced hyperresponsiveness of cultured monocytes. Mol Med
1996;2:460-468.
63. Pontrelli G, Martino AM, Tchidjou HK, et al. HIV is associatedwith thrombophilia and high D-dimer in children and adolescents.
AIDS 2010;24:1145-1151.
64. Kanapuru B, Ershler W. Inflammation, coagulation and the pathway to frailty. Am J Med 2009;122:605-613.
65. Pieper CF, Rao KM, Currie MS, et al. Age, functional status, andracial differences in plasma D-dimer levels in community-dwellingelderly persons. J Gerontol A Biol Sci Med Sci 2000;55:649-657.
66. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS
Med 2008;5:203.
67. McDermott MM, Greenland P, Green D, et al. D-dimer, inflammatory markers, and lower extremity functioning in patients with andwithout peripheral arterial disease. Circulation. 2003;107:31913198.
68. O’ Rourke MF, Hashimoto J. Mechanical factors in arterial aging.
J Amer Coll Cardiol. 2007;50:1–3.
69. Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction andthe clinical expression of Alzheimer disease. The Nun Study. JAMA
1997;277:813–817.
70. Black S, Gao F, Bilbao J. Understanding white matter disease: imaging pathological correlations in vascular cognitive impairment.
Stroke 2009;40:48-52.
71. Avila-Funes JA, Amieva H, Barberger-Gateau P, et al. Cognitive
impairment improves the predictive validity of the phenotype offrailty for adverse health outcomes: The Three-City Study. J Am
Geriatr Soc 2009;57:453-461.
72. Rothman MD, Leo-Summers L, Gill TM. Prognostic significance ofpotential frailty criteria. J Am Geriatr Soc 2008;56:2211–2216.

73. Avila-Funes JA, Carcaillon L, Helmer C, et al. Is frailty a prodromal
stage of vascular dementia? Results from the Three-City Study. J
Am Geriatr Soc 2012; 60:1708-1712.
74. Lindl KA, Marks DR, Kolson DL, et al. HIV-associated neurocognitive disorder: Pathogenesis and Therapeutic Opportunities. J
Neuroimmune Pharmacol 2010;5:294-309.
75. Perrini S, Laviola L, Carreira MC, et al. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying
age-related skeletal muscle wasting and osteoporosis. J Endocrinol 2010;205:201-210.
76. Joseph C, Kenny AM, Taxel P, et al. Role of endocrine-immune
dysregulation in osteoporosis, sarcopenia, frailty and fracture risk.
Mol Aspects Med 2005;26:181-201.
77. Goldspink G. Loss of muscle strength during aging studied at thegene level. Rejuvenation Res 2007;10:397-405.
78. Kveiborg M, Flyvbjerg A, Rattan SI, et al. Changes in the insulin-like growth factor-system may contribute to in vitro age-related
impaired osteoblast functions. Exp Gerontol 2000;5:1061–1074.
79. Bhasin S, Singh AB, Javanbakht M. Neuroendocrine abnormalities
associated with HIV infection. Endocrinol Metab Clin North Am
2000;30:749-764.
80. Jain S, Desai N, Bhangoo A. Pathophysiology of GHRH-growth
hormone- IGF1 axis in HIV/AIDS. Rev Endocr Metab Disord
2013;14:113-118.
81. Erlandson KM, Allshousee AA, Jankowski CM, et al. Functional
impairment is associated with low bone and muscle mass among
persons aging with HIV infection. J Acquir Immune Defic Syndr
2013;63:209- 215.
82. Koutkia P, Canavan B, Breu J, et al. Growth hormone releasing
hormone in HIV-infected men with lipodystrophy: a randomized
controlled trial. JAMA 2004;292:210.
83. Ceda GP, Dall’Aglio E, Maggio M. Clinical implications of the reduced activity of the GH-IGF-I axis in older men. J Endocrinol Invest 2005;28:96-100.
84. Salehian B, Jacobson D, Swerdloff RS, et al. Testicular pathologicchanges and the pituitary-testicular axis during human immunodeficiency virus infection. Endocr Pract 1999;5:1-9.
85. Dobs A. Role of testosterone in maintaining lean body mass andbone density in HIV infected patients. Int J Impot Res 2003;15:21-25.

43

WHITE BOOKCOGNITIVE FRAILTY:FRONTIERS AND CHALLENGES
A.J. WOODS, R.A. COHEN, M. PAHOR

Department of Aging and Geriatric Research, Institute on Aging, Cognitive Aging and Memory Clinical Translational Research
Program, University of Florida, Gainesville, FL, USA.
Correspondence: Adam J. Woods, PhD, Institute on Aging CTRB, Department of Aging and Geriatric Research, 2004 Mowry
Road, University of Florida, Gainesville, FL 32611, Phone: 352-294-5842, Email: ajwoods@ufl.edu

An international consensus group comprised ofinvestigators from the International Academy of
Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG)
recently convened in Toulouse, France to establish a definition for cognitive frailty in older adults. This effort was
motivated by growing awareness that many people withphysical frailty are also prone to cognitive problems. In“Cognitive Frailty: Rationale and Definition” (1), an initial
working definition was developed, and a framework proposed for future studies of cognitive frailty.
This group should be commended for addressing the construct of cognitive frailty and an obvious gap in the clinicalgerontology literature. Physical frailty is a widely recognizedproblem in the elderly. While age-associated cognitive dysfunction has been studied for many years, for the most partit was not conceptualized in a manner that is consistent withcurrent definitions of physical frailty. In fact, cognition has
typically not been conceptualized in this manner, and only
recently has the term cognitive frailty been employed. Rockwood et al published one of the first studies to examine
factors associated with frailty in the elderly (2). Frailty wasconceptualized as a multidimensional construct with both
physical and cognitive origins. Panza et al. used the term
cognitive frailty in the title of their review of pre-dementia
syndrome vascular risk factors (3). In a subsequent paper,
Panza et al, attempted to specify different models of frailty
in pre-dementia and dementia syndrome (4). The prognostic accuracy of frailty assessment inventories for mortality among hospitalized elderly people was examined subsequently, with results suggesting that both cognitive andphysical factors were important in predicting outcome (5).
We reviewed 199 manuscripts cited in PubMed in which
cognitive frailty was mentioned in either the title or as a
keyword. In the vast majority of these manuscripts, frailty
was examined as a manifestation of cognitive dysfunction.
Only recently has cognitive frailty itself become the focus
of inquiry.
The term cognitive frailty is attractive as it suggests a parallelwith physical frailty. The concept of physical frailty is relatively well understood in the context of aging, and has been
operationalized in studies conducted over the past two decades (6-8). However, as Kelaiditi et al. point out, the operational definition of physical frailty remains unresolved (1).
The situation is even more problematic for cognitive frailty,
as past investigators have focused on a variety of different
phenomena.
The term has often been used as a general descriptor forcognitive impairment occurring as people reach advanced
age. Sometimes cognitive frailty refers to cognitive disturbances or pre-dementia occurring in association with othermedical conditions (9). However, Kelaiditi et al. state thatcognitive frailty must be considered as being independentof dementia or pre-existing brain disorders (1). Accordingly, there seems to be several different perspectives on
the nature of cognitive frailty. The fact that the construct
is ambiguous and lacking a precise operational definition
clearly reinforces the authors’ effort to establish a common
language for future studies of cognitive frailty.
An obvious question emerges: How is cognitive frailty
different from cognitive reserve? Cognitive reserve refers
to the capacity of a given individual to resist cognitive im44

COGNITIVE FRAILTY: FRONTIERS AND CHALLENGES

pairment or decline. Educational level and prior cognitive
abilities have been shown to be important determinantsof cognitive reserve (10-12). Cognitive reserve has been
linked with resilience of brain function and structure in
the presence of disease, injury, or other factors that alter
physiological functioning (13). While cognitive and brain
reserve undoubtedly have some common underpinnings,
the relationship between these types of reserve is still not
fully understood.
Kelaiditi et al maintain that “cognitive frailty is characterized by reduced cognitive reserve”. Accordingly, cognitive
frailty could be viewed as simply the inverse of cognitive
reserve. The authors indicate that while cognitive reserveis an important element of cognitive frailty, it is also dependent on the existence of physical frailty; i.e., “the simultaneous presence of both physical frailty and cognitive
impairment”. They distinguish this category of older nondemented adults from cognitive impairment in the absenceof physical frailty. The importance of this categorizationis that it emphasizes an important and often under- recognized relationship between systemic physical illness, brain
dysfunction, and cognitive impairment. It is now well established that cognitive disturbances occur secondary tovarious medical conditions, such as cardiovascular disease,diabetes and HIV (14-19).
The value of excluding brain disorders from cognitive
frailty may be less well justified. By limiting cognitive frailty to people with physical frailty, Kelaiditi et al create four
discrete categories of older non-demented adults, which
may have some clinical value. However, with respect to theconcept of cognitive frailty, there are many examples ofpeople who are vulnerable to subsequent functional decline
based on the existence of subtle cognitive and/or brain abnormalities below the threshold for clinical detection. In
fact, a major thrust of current research on neurodegenerative disease focuses on the discovery of vulnerability andearly markers of future functional decline. While physicaldisorders such as diabetes and cardiovascular risk factors
contribute to this vulnerability, a variety of neurobiologicaland behavioral risk factors also exist that create functional
vulnerability (20-22), and ultimately cognitive frailty. In fact,
excluding people with brain disturbances from the definition of cognitive frailty fails to account for the fact that theeffects of physical illnesses are exacerbated by the existence of a neural predisposition to cognitive decline or priorbrain disturbances that reduce cognitive reserve. Furthermore, people with physical frailty who develop cognitive
frailty presumably do so as their brain begins to develop
neuropathological changes. Accordingly, there is value in dichotomizing cognitive frailty between people with or without pre-existing brain dysfunction, or alternatively treating
brain vulnerability as a mediator of the effects of physicalillness on cognitive frailty.

Defining cognitive frailty depends on determining its diagnostic criteria. Other than physical frailty, the primary criteria proposed by Kelaiditi et al. is the presence of mild cognitive impairment as defined by a clinical dementia rating(CDR) score of 0.5, without Alzheimer’s disease or anotherprogressive brain disturbance that would lead to dementia. Using these criteria, it is not clear whether people withcerebrovascular disturbances would meet these criteria ornot. The authors make a point of also noting that “under
different circumstances cognitive frailty may also represent
a precursor of neurodegenerative processes”. This is a critical point that reinforces the need to go beyond the definition of cognitive frailty as occurring in the absence of brain
dysfunction. It is also likely that a CDR = 0.5 is too narrow
to fully capture the heterogeneity of cognitive frailty. For
example, people without cognitive impairment that rises tothe level of a CDR=0.5 may still be vulnerable to functional decline under certain conditions. This occurs commonly
during hospitalization, in response to extreme stress, or tochanges in the physical environment in the elderly.
In fact, it is the vulnerability to alterations in cognitive
function under such conditions that may be the essential
determinant of cognitive frailty. There are many people insociety with cognitive limitations who would not be considered to be frail, unless they exhibit a tendency to functionally decompensate when their resources are challenged.
The key to operationalizing cognitive frailty may ultimately
depend of developing diagnostic challenges that would enable clinicians to determine this tendency. This will dependon determining which neurocognitive measures are mostuseful for detecting this vulnerability and for assessing theseverity of cognitive frailty.
In sum, “Cognitive Frailty: Rationale and Definition” (1)provides a valuable starting point for the development ofa coherent operational definition and for future studies ofcognitive frailty. While closely linked to cognitive reserve,
the construct of cognitive frailty goes beyond cognitive reserve, particularly because of its association with physicalfrailty and the fact that it often becomes evident in the context of acute physical illness. There seems to be considerable value in distinguishing vulnerability to cognitive functional decline among people with or without physical frailty,
though there is evidence that both cognitive and physicalfrailty share several common pathophysiologic mechanisms
and risk factors. Growing and consistent epidemiologic evidence shows that impaired physical performance, which is acomponent of physical frailty, measured with walking speedor the Short Physical Performance Battery (SPPB) (23),is independently associated with cognitive decline (24-36).
The SPPB tests, including walking, balance and chairstands, require the complex interplay of sensory, cognitive,
and motor functions. These systems may be altered early inthe path to cognitive decline (36, 37), and possibly to cogni45

WHITE BOOK

tive frailty. Low walking speed and low SPPB score are also
associated with elevated inflammatory cytokines and low
Brain-Derived Natirurectic Factor (BDNF) (38-40), all ofwhich are predictors of cognitive decline (41, 42).
Future research is needed to determine how phenotypic
differences among people and the existence of a wide variety of preexisting manifestations of brain structure andfunction affect this vulnerability. Following the expert consensus, prospective studies will be needed to assess the reli-ability and predictive validity of the operational measure ofcognitive frailty. We laud the efforts of the IANA/IAGG
consensus group in laying the foundation for the emerging
concept of cognitive frailty and strongly encourage futurestudies aimed at advancing this clinical domain.
This article was published in the Journal of Nutrition, Health and Aging
Volume 17, Number 9, 2013
http://www.springer.com/medicine/internal/journal/12603

REFERENCES
1. Kelaiditi E, Cesari M, Canevelli M, van Kan GA, Ouset P, Gillette-Guyonnet S, Ritz P, Duveau F, Soto ME, Provencher V, Nourhashemi F, Salva A, Robert P, Andrieu S, Rolland Y, Touchon
J, Fitten, Vellas B (2013) Cognitive Frailty: Rational and definition
from an (I.A.N.A./I.A.G.G.) International Consensus Group. J
Nutr Health Aging 2013;9:726-734.
2. Rockwood K, Stolee P, McDowell I (1996) Factors associated withinstitutionalization of older people in Canada: testing a multifactorial definition of frailty. J Am Geriatr Soc 44(5):578-582.
3. Panza F, D’Introno A, Colacicco AM, et al (2006) Cognitive frailty:
Predementia syndrome and vascular risk factors. Neurobiol Aging
27(7):933-940.
4. Panza F, Solfrizzi V, Frisardi V, et al (2011) Different models of frailty in predementia and dementia syndromes. J Nutr Health Aging
15(8):711-719.
5. Pilotto A, Rengo F, Marchionni N, et al (2012) Comparing the
prognostic accuracy for all-cause mortality of frailty instruments:
a multicentre 1-year follow-up in hospitalized older patients. PLoS
One. 7(1):e29090.
6. Abellan van Kan G, Rolland Y, Houles M, Gillette-Guyonnet S,
Soto M, Vellas B (2010) The assessment of frailty in older adults.
Clin Geriatr Med 26(2):275-286.
7. Abellan van Kan G, Rolland Y, Andrieu S, et al (2009) Gait speed
at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition
and Aging (IANA) Task Force. J Nutr Health Aging 13(10):881-889.
8. Abellan van Kan G, Rolland Y, Bergman H, Morley JE, Kritchevsky
SB, Vellas B (2008) The I.A.N.A Task Force on frailty assessment ofolder people in clinical practice. J Nutr Health Aging 12(1):29-37.
9. Chouliara Z, Kearney N, Stott D, Molassiotis A, Miller M (2004)
Perceptions of older people with cancer of information, decision
making and treatment: a systematic review of selected literature.
Ann Oncol 15(11):1596-1602.
10. Satz P, Morgenstern H, Miller EN, et al (1993) Low education as
a possible risk factor for cognitive abnormalities in HIV-1: findings from the multicenter AIDS Cohort Study (MACS). J Acquir
Immune Defic Syndr 6(5):503-511.
11. Stern Y (2002) What is cognitive reserve? Theory and research application of the reserve concept. J Int Neuropsychol Soc 8(3):448460.
12. Stern Y, Albert S, Tang MX, Tsai WY (1999) Rate of memory decline
in AD is related to education and occupation: cognitive reserve?
Neurology 53(9):1942-1947.
13. Satz P, Cole MA, Hardy DJ, Rassovsky Y (2011) Brain and cognitive
reserve: mediator(s) and construct validity, a critique. J Clin Exp
Neuropsychol 33(1):121- 130.
14. Okonkwo OC, Cohen RA, Gunstad J, Tremont G, Alosco ML,
Poppas A (2010) Longitudinal trajectories of cognitive decline

among older adults with cardiovascular disease. Cerebrovasc Dis
30(4):362-373.
15. Cohen RA, Poppas A, Forman DE, et al (2009) Vascular and cognitive functions associated with cardiovascular disease in the elderly. J Clin Exp Neuropsychol 31(1):96-110.
16. Gunstad J, Cohen RA, Paul RH, Tate DF, Hoth KF, Poppas A (2006)
Understanding reported cognitive dysfunction in older adults withcardiovascular disease. Neuropsychiatr Dis Treat 2(2):213-218.
17. Devlin KN, Gongvatana A, Clark US, et al (2012) Neurocognitiveeffects of HIV, hepatitis C, and substance use history. J Int Neuropsychol Soc 18(1):68-78.
18. Cohen RA, de la Monte S, Gongvatana A, et al (2011) Plasma cytokine concentrations associated with HIV/hepatitis C coinfection
are related to attention, executive and psychomotor functioning.
J Neuroimmunol 233(1-2):204-210.
19. Cohen RA, Harezlak J, Schifitto G, et al (2010) Effects of nadir CD4
count and duration of human immunodeficiency virus infection
on brain volumes in the highly active antiretroviral therapy era.
J Neurovirol 16(1):25-32.
20. Elie M, Cole MG, Primeau FJ, Bellavance F (1998) Delirium
risk factors in elderly hospitalized patients. J Gen Intern Med
13(3):204-212.
21. Robertsson B, Blennow K, Gottfries CG, Wallin A (1998) Delirium
in dementia. Int J Geriatr Psychiatry 13(1):49-56.
22. Woods AJ, Mark VW, Pitts AC, Mennemeier M (2011) Pervasive
cognitive impairment in acute rehabilitation inpatients without
brain injury. PM R 3(5):426- 432.
23. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace
RB (1995) Lower- extremity function in persons over the age of
70 years as a predictor of subsequent disability. N Engl J Med
332(9):556-561.
24. Camargo EC, Beiser A, Tan ZS et al (2012) Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham
Offspring Study. American Academy of Neurology, 64th Annual
Meeting, New Orleans, April 21-28, 2012.
25. Dodge HH, Mattek NC, Austin D, Hayes TL, Kaye JA (2012) Inhome walking speeds and variability trajectories associated withmild cognitive impairment. Neurology 78(24):1946-1952.
26. McGough EL, Kelly VE, Logsdon RG, McCurry SM, Cochrane BB,
Engel JM, Teri L (2011) Associations between physical performance and executive function in older adults with mild cognitive
impairment: gait speed and the timed «up & go» test. Phys Ther
91(8):1198-1207.
27. Fitzpatrick AL, Buchanan CK, Nahin RL, DeKosky ST, Atkinson
HH, Carlson MC, Williamson JD (2007) Associations of gait
speed and other measures of physical function with cognition ina healthy cohort of elderly persons. J Gerontol A Biol Sci Med Sci
62(11):1244-1251.

46

COGNITIVE FRAILTY: FRONTIERS AND CHALLENGES

28. Deshpande N, Metter EJ, Bandinelli S, Guralnik J, Ferrucci L. Gait
speed under varied challenges and cognitive decline in older persons: a prospective study. Age Ageing 2009; 38(5):509-514.
29. Rosano C, Simonsick EM, Harris TB, Kritchevsky SB, Brach J, Visser
M, Yaffe K, Newman AB (2005) Association between physical andcognitive function in healthy elderly: the health, aging and bodycomposition study. Neuroepidemiology 24(1-2):8- 14.
30. Soumare A, Tavernier B, Alperovitch A, Tzourio C, Elbaz A (2009)
A cross- sectional and longitudinal study of the relationship between walking speed and cognitive function in community-dwelling elderly people. J Gerontol A Biol Sci Med Sci 64(10):1058-1065.
31. Abellan Van KG, Rolland Y, Andrieu S, Bauer J, Beauchet O, et al(2009) Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 13(10):881-889.
32. Wang L, Larson EB, Bowen JD, van BG (2006) Performance-based
physical function and future dementia in older people. Arch Intern
Med 166(10):1115-1120.
33. Hajjar I, Yang F, Sorond F, Jones RN, Milberg W, Cupples LA,
Lipsitz LA (2009) A novel aging phenotype of slow gait, impaired
executive function, and depressive symptoms: relationship toblood pressure and other cardiovascular risks. J Gerontol A Biol
Sci Med Sci 64(9):994-1001.
34. Zimmermann LJ, Ferrucci L, Kiang L, Lu T, Guralnik JM, Criqui
MH, Yihua L, McDermott MM (2011) Poorer clock draw testscores are associated with greater functional impairment in peripheral artery disease: the Walking and Leg Circulation Study II.
Vasc Med 16(3):173-181.

35. Verghese J, Robbins M, Holtzer R, Zimmerman M, Wang C, Xue X,
Lipton RB (2008) Gait dysfunction in mild cognitive impairment
syndromes. J Am Geriatr Soc 56(7):1244-1251.
36. Verghese J, Wang C, Lipton RB, Holtzer R, Xue X (2007) Quantitative gait dysfunction and risk of cognitive decline and dementia. J
Neurol Neurosurg Psychiatry 78(9):929-935.
37. Buchman AS, Boyle PA, Wilson RS, Tang Y, Bennett DA (2007)
Frailty is associated with incident Alzheimer’s disease and cognitive decline in the elderly. Psychosom Med 69(5):483-489.
38. Brinkley TE, Leng X, Miller ME, Kitzman DW, Pahor M, Berry MJ,
Marsh AP, Kritchevsky SB, Nicklas BJ (2009) Chronic inflammation
is associated with low physical function in older adults across multiple comorbidities. J Gerontol A Biol Sci Med Sci 64(4):455-461.
39. Hsu FC, Kritchevsky SB, Liu Y, Kanaya A, Newman AB, Perry SE, Visser M, Pahor M, Harris TB, Nicklas BJ (2009) Association Between
Inflammatory Components and Physical Function in the Health, Aging, and Body Composition Study: A Principal Component Analysis
Approach. J Gerontol A Biol Sci Med Sci 64(5):581- 589.
40. Scalzo P, Kummer A, Bretas TL, Cardoso F, Teixeira AL (2010) Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J Neurol 257(4):540-545.
41. Erickson KI, Prakash RS, Voss MW, Chaddock L, Heo S, McLaren M, Pence BD, Martin SA, Vieira VJ, Woods JA, McAuley E,
Kramer AF (2010) Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume. J Neurosci
30(15):5368-5375.
42. Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M,
Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in well- functioning African-American and white elders. Neurology 61(1):76-80.

47

WHITE BOOKFRAILTY AND CHRONICRESPIRATORY DISEASESJean BOUSQUET, MD, PhD1, Joao MALVA, PhD2, Jacques MERCIER, PhD3,
Michel NOGUES, PhD4, Carlos ROBALO-CORDEIRO, MD, PhD5,
Leocadio RODRIGUEZ-MANANS, MD, PhD6, Bruno VELLAS, MD, PhD7

1 University Hospital, Montpellier, MACVIA-LR - Contre les Maladies Chroniques pour un Vieillissement Actif en Languedoc
Roussillon, European Innovation Partnership on Active & Healthy Ageing Reference Site, INSERM, VIMA: Ageing & chronic
diseases epidemiological & public health approaches, U1168, Paris, & UVSQ, UMR-S 1168, Université Versailles St-Quentinen-Yvelines, France
2 Neuroscience Department, Coimbra University, Portugal
3 Vice President Research, University Montpellier, France
4 Caisse d'Assurance Retraite et de la Santé Au Travail (CARSAT)
5 Pneumology Department, Coimbra University, Portugal
6 Jefe de Servicio de Geriatría, Hospital Universitario de Getafe, Spain
7 Department of Internal Medicine and Geriatrics, Toulouse University Hospital, Toulouse France
Correspondence: Prof. Jean Bousquet, CHRU Montpellier, 34295 Montpellier Cedex 5, France
E-mail: jean.bousquet@orange.fr

Abbreviations
AIRWAYS ICPs: Integrated Care for Airway Diseases (EIP-AHA)
CRD: Chronic Respiratory Diseases
EIP on AHA: European Innovation Partnership on Active and Healthy Ageing
EU: European Union
COPD: Chronic Obstructive Pulmonary Disease
GARD: WHO Global Alliance against Chronic Respiratory Diseases
NCD: Non-communicable Chronic Disease
UN: United Nations
WHO: World Health Organization
6MWD: Six-Minute Walking Distance

AHA allows people to realize their potential for physical,
social (economic, cultural, spiritual and civic affairs) andmental wellbeing throughout the life course (3). AHA needs
to be promoted very early in life to be successful, contributing to general wellbeing of citizens and sustainability ofsocial support systems.
Frailty is a common threaten to both physical and psychological/mental wellbeing in the elderly and is a major determinant of adverse outcomes including functional decline.

INTRODUCTION

As populations continue to grow older, efforts to support
the process of ageing well are important goals (1). Ageing isintertwined with socioeconomic inequalities, providing an
under-appreciated cause of poverty and hinders economic
development, particularly of underserved populations andwomen. Active and Healthy Ageing (AHA) is a major societal
challenge common to all countries and to all populations (2)48Frailty and chronic respiratory diseases

Frailty is increasingly seen as a multidimensional processthat may include disruption in the health status, mental
wellbeing or impact the equilibrium of the person with its
surrounding physical environment and social networks.
Chronic respiratory diseases (CRD) represent a model ofchronic diseases across the life course. As any non-communicable disease (NCD), they can be associated to frailty.
Both conditions, CRD and frailty, are key targets of goodpractices emerging from the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). In orderto foster discussion about key determinants of CRD andfrailty and to highlight good practices for replicability andscaling-up, a meeting EIP on AHA was organized by the
Région Languedoc-Roussillon and Region Centro Portugal,
Lisbon July 1-2, 2015.

COPD is a heterogeneous disease with various clinicalpresentations. It is a characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response (neutrophilic) in the
airways and the lungs to noxious particles and gazes. Worldwide, the most common risk factor is tobacco smoking. In
many countries, outdoor, occupational and indoor air pollution (mainly biomass fuel combustion) are major risk factors. In addition, any factor that affects lung growth during
pregnancy and early childhood (infection) may increase therisk for COPD (6). COPD is a major public health problem
in subjects over 40 years of age and will remain a challenge
for the future. COPD has an estimated annual death rateof over 4 million people globally. COPD is a major sourceof disability. Physical disability stemming from exercise-induced dyspnea, muscular deconditioning, and other factors
has a major impact on the quality of life of the patients.
The six-minute walking distance (6MWD) is a patient-important outcome in research and clinical practice to evaluate
exercise capacity in COPD and cardiovascular disorders (7).
Many individuals with COPD have low body weight associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity and higher mortality thanthose who are adequately nourished (8). COPD is associated with social disability (9).
Asthma is defined as an airflow obstruction that is reversible spontaneously or after treatment. Inflammation(eosinophilic) of the airways and non-specific bronchial
hyper-reactivity are features of asthma (10). Asthma andallergic diseases occur along the life cycle from early childhood (11). Asthma is a global health problem. Patients fromall countries, all ethnic groups, all ages suffer from asthma.
The prevalence of asthma can be higher than 20% of the
population in some age groups. Asthma affects social life,
sleep, school and work. Long-standing asthma can cause
disability and COPD. Various social and economic effects
are associated with asthma including absenteeism and presenteeism (12).

CHRONIC RESPIRATORY DISEASESCRDs are chronic diseases of the airways and the otherstructures of the lungs. Major preventable CRD include
asthma and respiratory allergies, chronic obstructive pulmonary disease (COPD), occupational lung diseases, sleep apnea syndrome and pulmonary hypertension. CRDs are major NCDs and affect over one billion people in the world (4)(Table 1). The burden of preventable CRD has major adverse effects on the quality of life and disability of affectedindividuals; they cause premature death and create large adverse and underappreciated economic effects on families,
communities and societies in general. Among the EU member states, asthma accounted for an average of 53 hospital
admissions per 100 000 population in 2009 and the average
COPD-related admission rate was 184(5). The annual direct
and indirect costs in the 28 EU countries due to COPD or
asthma are estimated at €48 billion and €34 billion respectively (5).
Table 1: Prevalence of chronic respiratory diseases (WHO estimates)from (2)DiseaseYear of estimate

Prevalence

Asthma2004

300 million

COPD

2007

210 million

Allergic rhinitis

1996-2006

400 million

Sleep apnea

1986-2002>100 million

2006>50 million

OthersFRAILTY IN CHRONIC RESPIRATORY DISEASES

Frailty is a progressive physiological decline in multiple organ systems marked by loss of function, loss of physiological reserve and increased vulnerability to disease (13).
It is considered as an early stage in the pathway towards
disability characterised by a progressive functional decline
which, differently from disability, is still amenable for preventive interventions and is reversible. Frailty appears to besecondary to multiple conditions using multiple pathways
leading to a vulnerability to a low-power stressor. Biological(inflammation, loss of hormones), and clinical (e.g. sarcopenia, osteoporosis) factors are involved in the mechanisms
leading to frailty and social factors (isolation, financial sit-

Chronic respiratory diseases negatively impact active andhealthy ageing (AHA). Breath difficulties and poor bloodgas exchange are key determinants of metabolic health,leading to physiological inefficiencies, susceptibility to theonset or fast progression of diseases and poor physical andmental performance.
49

WHITE BOOK

uation) play a significant role in modulating both the timeof its clinical onset and its evolution and prognosis (14, 15).
Many chronic diseases are associated with increasing frailty
and functional decline in older people, with concomitant
personal, social, and public health implications (16). Prefrail participants have more comorbidity and are at higher risk for disability than non-frail participants (17). Older people suffering from frailty often receive fragmented
chronic care from multiple professionals. There is an urgent need for coordination of care and a multidimensional approach in developing interventions aimed at reducing
frailty, especially in lower educated groups (18, 19). Patientswith CRDs are ageing and it is therefore of importance toconsider frailty as an important outcome in order to reverseit (Figure 1).

indicator (22). The usual gait speed is correlated with the
6MWD (23). In community-dwelling elderly people, hasbeen demonstrated in patients with COPD that usual gait
speed is a consistent predictor of adverse outcomes (24).
The changes in usual gait speed and 6MWD were associatedwith increased 12-month mortality in patients with severe
COPD suggesting that gait speed may inform clinicians
when to initiate end-of-life communications and palliative
care (25). The increasing evidence on gait speed is promising as a simple test that can inform the clinician about many
important functional aspects of the COPD patient (26).
CRDs are associated with social life and work impairment and the social component of frailty may be of
relevant importance in some patients with asthma and/or
COPD, especially in old age adults.
It remains to be proven, however, whether optimizing treatment of frail COPD patients with multi-morbidities andpolypharmacy improves health outcomes. Integrated careservices in frail community-dwelling COPD patients improved clinical outcomes such as survival and decreased theED visits, but it did not reduce hospital admissions (27).

Figure 1: The vicious circle between chronic respiratory diseases andfrailty

Frailty may be common in asthma in the elderly (28)but no studies have demonstrated it.
CRDs may represent a model of frailty across the life
course. CRDs are diseases often occurring early in life
and they represent a model of chronic diseases across thelife course. They impact social life and are inducing frailty
across the life course. Understanding how frailty can occur
and be prevented across the life course is likely to have amajor impact on the prevention of frailty in old age adults
with chronic diseases with a major impact in health and social care as well as costs.
THE EUROPEAN INNOVATION PARTNERSHIP ON ACTIVE
AND HEALTHY AGEING

Unrecognized CRDs can be detected in frail elderly
patients (20).

To tackle the potential of ageing in the EU, the European
Commission -within its Innovation Union policy- launched
the EIP on AHA (DG Santé, DG Connect) (29). It pursues
a triple win for Europe (https://webgate.ec.europa.eu/eipaha/):• Enabling EU citizens to lead healthy, active and independent lives while ageing.
• Improving the sustainability and efficiency of social andhealth care systems.
•
Boosting and improving the competitiveness of themarkets for innovative products and services, responding to the ageing challenge at both EU and global levels,
thus creating new opportunities for businesses.

COPD may be associated with frailty. Sarcopenia affects
up to 15% of patients with stable COPD and impairs function and health status (21).
Gait speed in Impact of COPD treatment: Gait speed,a key marker of frailty is a consistent predictor of adverse
outcomes. Gait speed is mainly determined by exercise
capacity but reflects global well-being as it captures manyof the multi-systemic effects of disease severity in COPD
rather than pulmonary impairment alone. Gait speed slows
down with increasing COPD severity. It correlates with age,clinical symptoms, pulmonary functions, and quality of lifescores. Gait speed may be used as a functional capacity
50

Frailty and chronic respiratory diseases

The Action Plan A3 of the EIP on AHA is helping to prevent
functional decline and frailty, targeting multi-dimensions
including the physical and mental/cognition components,
as well as environment-related determinants, like malnutrition. The Action Plan B3 of the EIP on AHA is promoting integrated care models for chronic diseases, including
the use of remote monitoring. The objective of Integrated
Care Pathways for Airway Diseases (AIRWAYS-ICPs) (30)
is to launch a collaboration to develop multi-sectoralcare pathways for CRDs in European countries and regions as part of the EIP on AHA (Area 5 of the Action
Plan B3) and to scale up globally with WHO GARD (4)in order to (i) reduce the burden of the CRDs and (ii) promote AHA. AIRWAYS ICPs does not duplicate existing
EU prevention programmes in CRDs (e.g. anti-smoking)but will strengthen them where appropriate.

THE MEETING ON AIRWAYS ICPS AND FRAILTY,
LISBON, JULY 1-2, 2015

On behalf of the EIP on AHA Reference Site Network,
the Languedoc Roussillon (31) and Centro Portugal regions
have organised a meeting on CRDs and frailty in collaboration with the Directorate General of Health of Portugal
and WHO GARD (4). This meeting reviewed the achievements of AIRWAYS ICPs and link the EIP on AHA Action
Plan B3 initiative and the Action Plan A3 (frailty). Moreover, this meeting initiated a proposal attempting to link
frailty across the life course in patients with CRDs. In particular, it followed a previous EIP on AHA Reference Site
Network meeting in Montpellier (October 24, 2014) (32)
on an operational definition of AHA.

REFERENCES
1. Depp CA, Jeste DV. Definitions and predictors of successful aging:a comprehensive review of larger quantitative studies. Am J Geriatr Psychiatry. 2006;14(1):6-20.
2. Rechel B, Grundy E, Robine JM, Cylus J, Mackenbach JP, Knai C, etal. Ageing in the European Union. Lancet. 2013;381(9874):1312-22.
3. Kuh D, Cooper R, Hardy R, Richards M, Ben-Shlomo Y. A life
course approach to healthy ageing. Oxford: Oxford; 2014.
4. Bousquet J, Khaltaev N. Global surveillance, prevention and control of Chronic Respiratory Diseases. A comprehensive approach.
Global Alliance against Chronic Respiratory Diseases. World
Health Organization. ISBN 978 92 4 156346 8. 2007:148 pages.
5. Gibson G, Loddenkemper R, Lundback B, Sibille Y. The new European Lung White Book: Respiratory health and disease in Europe:
ERS Publications; 2013.
6. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A,
et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive
Summary. Am J Respir Crit Care Med. 2013;187(4):347-65.
7. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The
six-minute walk test: a useful metric for the cardiopulmonary patient. Int Med J. 2009;39(8):495-501.
8. Ferreira IM, Brooks D, White J, Goldstein R. Nutritional supplementation for stable chronic obstructive pulmonary disease.
Cochrane database Syst Rev. 2012;12:CD000998.
9. Liu Y, Croft JB, Anderson LA, Wheaton AG, Presley-Cantrell LR,
Ford ES. The association of chronic obstructive pulmonary disease, disability, engagement in social activities, and mortality
among US adults aged 70 years or older, 1994-2006. Int J COPD.
2014;9:75-83.
10. Boulet LP, FitzGerald JM, Reddel HK. The revised 2014 GINA
strategy report: opportunities for change. Curr Opin Pulm Med.
2015;21(1):1-7.
11. Samolinski B, Fronczak A, Kuna P, Akdis CA, Anto JM, Bialoszewski AZ, et al. Prevention and control of childhood asthma andallergy in the EU from the public health point of view: Polish Presidency of the European Union. Allergy. 2012;67(6):726-31.
12. Fletcher M, Jha A, Dunlop W, Heron L, Wolfram V, Van der Molen T,
et al. Patient reported burden of asthma on resource use and productivity across 11 countries in Europe. Adv Ther. 2015;32(4):370-80.

13. Rodriguez-Manas L, Fried LP. Frailty in the clinical scenario. Lancet. 2015;385(9968):e7-9.
14. Berrut G, Andrieu S, Araujo de Carvalho I, Baeyens JP, Bergman
H, Cassim B, et al. Promoting access to innovation for frail old
persons. IAGG (International Association of Gerontology andGeriatrics), WHO (World Health Organization) and SFGG (Societe Francaise de Geriatrie et de Gerontologie) Workshop--Athens
January 20-21, 2012. J Nutr Health Aging. 2013;17(8):688-93.
15. Gobbens RJ, van Assen MA, Luijkx KG, Wijnen-Sponselee
MT, Schols JM. Determinants of frailty. J Am Med Dir Assoc.
2010;11(5):356-64.
16. Sinclair A, Morley JE, Rodriguez-Manas L, Paolisso G, Bayer T,
Zeyfang A, et al. Diabetes mellitus in older people: position statement on behalf of the International Association of Gerontology
and Geriatrics (IAGG), the European Diabetes Working Party for
Older People (EDWPOP), and the International Task Force of Experts in Diabetes. J Am Med Dir Assoc. 2012;13(6):497-502.
17. Danon-Hersch N, Rodondi N, Spagnoli J, Santos-Eggimann B. Prefrailty and chronic morbidity in the youngest old: an insight fromthe Lausanne cohort Lc65+. J Am Geriatr Soc. 2012;60(9):1687-94.
18. Hoogendijk EO, van Hout HP, Heymans MW, van der Horst HE,
Frijters DH, Broese van Groenou MI, et al. Explaining the association between educational level and frailty in older adults: resultsfrom a 13-year longitudinal study in the Netherlands. Ann Epidemiol. 2014;24(7):538-44 e2.
19. Tavassoli N, Guyonnet S, Abellan Van Kan G, Sourdet S, Krams T,
Soto ME, et al. Description of 1,108 older patients referred by their
physician to the "Geriatric Frailty Clinic (G.F.C) for Assessmentof Frailty and Prevention of Disability" at the gerontopole. J Nutr
Health Aging. 2014;18(5):457-64.
20. Bertens LC, Reitsma JB, van Mourik Y, Lammers JW, Moons KG,
Hoes AW, et al. COPD detected with screening: impact on patientmanagement and prognosis. Eur Respir J. 2014;44(6):1571-8.
21. Jones SE, Maddocks M, Kon SS, Canavan JL, Nolan CM, Clark AL,
et al. Sarcopenia in COPD: prevalence, clinical correlates and response to pulmonary rehabilitation. Thorax. 2015;70(3):213-8.
22. Ilgin D, Ozalevli S, Kilinc O, Sevinc C, Cimrin AH, Ucan ES. Gait
speed as a functional capacity indicator in patients with chronic
obstructive pulmonary disease. Ann Thorac Med. 2011;6(3):141-6.

51

WHITE BOOK

23. DePew ZS, Karpman C, Novotny PJ, Benzo RP. Correlations between gait speed, 6-minute walk distance, physical activity, andself-efficacy in patients with severe chronic lung disease. Respir
Care. 2013;58(12):2113-9.
24. Kon SS, Patel MS, Canavan JL, Clark AL, Jones SE, Nolan CM, et al.
Reliability and validity of 4-metre gait speed in COPD. Eur Respir J.
2013;42(2):333-40.
25. Benzo R, Siemion W, Novotny P, Sternberg A, Kaplan RM, Ries
A, et al. Factors to inform clinicians about the end of life in severe chronic obstructive pulmonary disease. J Pain Sympt Manag.
2013;46(4):491-9e4.
26. Karpman C, Benzo R. Gait speed as a measure of functional status
in COPD patients. Int J COPD. 2014;9:1315-20.
27. Hernandez C, Alonso A, Garcia-Aymerich J, Grimsmo A, Vontetsianos T, Garcia Cuyas F, et al. Integrated care services: lessons
learned from the deployment of the NEXES project. Int J Integr
Care. 2015;15:e006.
28. Hanania NA, King MJ, Braman SS, Saltoun C, Wise RA, EnrightP, et al. Asthma in the elderly: Current understanding and future

research needs--a report of a National Institute on Aging (NIA)
workshop. The J Allergy Clin Immunol. 2011;128(3 Suppl):S4-24.
29. Bousquet J, Michel J, Standberg T, Crooks G, Iakovidis I, Gomez
M. The European Innovation Partnership on Active and Healthy
Ageing: the European Geriatric Medicine introduces the EIP on
AHA Column. Eur Geriatr Med. 2014;5(6):361-2.
30. Bousquet J, Addis A, Adcock I, Agache I, Agusti A, Alonso A, etal. Integrated care pathways for airway diseases (AIRWAYS-ICPs).
Eur Respir J. 2014;44(2):304-23.
31. Bousquet J, Bourquin C, Augé P, Domy P, Bringer J, Camuzat
T, et al. MACVIA-LR Reference Site of the European Innovation
Partnership on Active and Healthy Ageing. Eur Geriatr Med.
2014;5(6):406-15.
32. Bousquet J, Kuh D, Bewick M, Strandberg T, Farrell J, Pengelly R,
et al. Operational definition of active and healthy ageing (AHA):
Report of the meeting held in Montpellier October 21,22-2012. Eur
Geriatr Med. 2015;7:in press.

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Diabetes and frailty: an up to date synopsis

DIABETES AND FRAILTY:AN UP TO DATE SYNOPSIS
Alan SINCLAIR, MSc, MD, FRCP2, Harriet SINCLAIR, MD1

1 Foundation for Diabetes Research in Older People, Diabetes Frail Ltd, Hampton Lovett, Droitwich, Worcestershire, United
Kingdom
2 University of Aston, United Kingdom
Correspondence: Prof. Alan J. Sinclair, Director, Diabetes Frail Ltd, Oakmoore Court, Kingswood Road, Droitwich WR9 0QH, UK,
Tel: + 44 (0) 74 69 17 82 32, E-mail: sinclair.5@btinternet.com

Abstract
Diabetes mellitus (DM) is a disabling chronic condition
with a tremendous health, social, and economic burden
within our ageing communities. The main impact of diabetes in older adults stems from its effect on function, both
physical and cognitive, that finally impairs their quality oflife, although the impact on survival is modest.

Frailty is a powerful predictor of disability and other adverse outcomes including mortality, disability, and institutionalization in older adults.
We explore the intimate relationship between diabetes andfrailty and recognise their huge societal and personal healthburden.
Key words: diabetes, sarcopaenia, frailty, older people

INTRODUCTION  

physiological pathway leading to frailty and its effects areexacerbated by diabetes which is known to accelerate lossof muscle mass.
This review explores these interrelationships.

Diabetes mellitus (DM) is a highly prevalent metabolic
condition (up to 30%) that is associated with disability andreduced life expectancy in older people (1-4). As many as
40% of people with DM remain undiagnosed (5).

DIABETES MELLITUS

Frailty has emerged during the last two decades as themost powerful predictor of disability and other adverse
outcomes including mortality, disability, and institutionalization in older adults (6). Frailty can be described as a stateof increased vulnerability to stressors, which results fromdecreased physiological reserve in multiple systems thatcauses limited capacity to maintain homeostasis (7). The
prevalence of frailty in older adults has been described tobe between 7-30% depending on the nature of the populations and the criteria used (8).

DM is a syndrome characterised by chronic hyperglycaemia
and disturbances of carbohydrate, fat, and protein metabolism, associated with an absolute or relative deficiency ininsulin secretion and/or insulin action. The developmentof type 2 diabetes in older adults represents the progressive
worsening of multiple age-related metabolic disturbances
plus a contribution from environmental, genetic, and behavioural factors (9).
Older people with diabetes have higher rates of premature
death and coexisting medical conditions than those without diabetes (10). They are also at a greater risk of several common geriatric syndromes such as polypharmacy,

Sarcopaenia, the loss of muscle mass associated with ageing, appears to be an important contributor to the patho53

WHITE BOOK

depression, cognitive impairment, urinary incontinence,
injurious falls, and persistent pain (11). Diabetes is a risk
factor for the development of frailty, more than doubling
the risk (OR: 2.18) after 3.5 years of follow-up. Overall, it isassociated with a decline in quality of life and a decrease inleisure activities (12,13).

Other factors can also contribute to poor nutrition in older
people such as renal impairment and vitamin deficiencies.

Hormone imbalance:
Age-related alterations in hypothalamic-pituitary-testicular, hypothalamic—pituitary-adrenal and GH-IGF-1 axes
are known to be associated with frailty via influences on
muscle strength, bone strength and mobilit (16). There isaccumulating evidence that several factors that have beenshown to play a key role in the protein synthesis of muscle
mass, such as IGF-1 and testosterone, are decreased in diabetes (20,21).

SARCOPAENIA

Sarcopaenia, the progressive decline in muscle mass andconsequently strength and function may be due to progressive atrophy, loss of muscle fibres (14), and a reduction
in “muscle quality” due to the infiltration of fat and othernon-contractile material alongside changes in muscle metabolism and insulin resistance (15). The main effect of aloss of muscle mass is reduced muscle strength and power, which are important factors to maintain stability andgait, and necessary to perform ADLs (16). Impaired muscle strength is highly predictive of incident disability andall-cause mortality in this population, and sarcopaenia has
been considered to be an integral component of frailty (17).

Vitamin D levels are lower in diabetes which may contribute to
B cell dysfunction, insulin resistance and inflammation (22).
Also, studies suggest that vitamin D levels correlate withmuscle mass and strength and low levels of vitamin D areassociated with falls and functional decline (23), and thefrailty syndrome (24).

Insulin and insulin resistance:
Insulin resistance may lead to impairment of muscle
strength, and during ageing, insulin resistance appears to be
involved in muscle protein loss. Loss of control of the anabolic action of insulin on ageing muscle may be a key factor favouring sarcopaenia (16). Handgrip muscle strengthis also significantly associated with fasting insulin level orinsulin resistance. Other relevant observations include insulin-induced inhibition of protein degradation, an increasein protein synthesis and inhibition of proteolysis and a rolein other key steps in protein regulation (25-27).

FRAILTY

Frailty is a complex clinical condition lacking consensus
on a standardised definition, however Fried and colleagues
have put forward a definition of a clinical phenotype offrailty which has been widely used (18) and is based on
three main questions relating to weight loss, exhaustion,and physical activity levels supported by two practical tests
involving hand grip strength and gait speed determinations.

Inflammation and anti-inflammatory response:
An increase in proinflammatory cytokines may be associated with sarcopaenia and frailty (28,29). Diabetes is also
associated with elevated cytokine levels, and higher level ofcytokines can induce insulin resistance.

A biological model, the “cycle of frailty”, that included
sarcopaenia, neuroendocrine and inmune dysfunction as
potential causes has been proposed. Frailty is not an inevitable consequence of the ageing process, but appears to bea dynamic process and also potentially reversible. Early recognition of frailty and early intervention should therefore
be a major focus for care of older people.

Obesity:
Obesity is a causative factor for the development of type 2
diabetes and frailty; with higher fat mass and lower muscle
mass, physical activity becomes progressively more difficult,promoting further muscle mass loss. This cycle potentiallyleads to “sarcopaenic obesity”, a major risk factor for the
onset of physical disability (30).

SARCOPAENIA IS AN INTERMEDIARY

The maintenance of skeletal mass and function is a due tomultiple factors including hormonal, inflammatory, neurological, nutritional, and activity components (16). The development of sarcopaenia can be a result of alterations in
multiple physiological systems, as well as from decline inactivity and specific diseases. Briefly these are:Nutritional factors:
Older people with diabetes may be at increased risk ofmalnutrition, and there is probably a causal relationship between malnutrition and functional decline in this group (19).

54

Diabetes and frailty: an up to date synopsis

Advanced glycation end products (AGEs):
AGEs formation accompanies diabetes mellitus and may
play a role in the pathogenesis of sarcopaenia, throughAGE-mediated increases in inflammation, endothelial dysfunction in the microcirculation of skeletal muscle andthrough cross-linking of collagen in skeletal muscle (31).
Mitochondrial dysfunction:
Defects in mitochondrial oxidation and phosporylation
have been demonstrated both in older adults without diabetes, and in young obese and non-diabetic offspring ofpeople with type 2 diabetes (32,33). These abnormalities
could lead to a vicious cycle in which mitochondrial dysfunction, elevation of intramyocellular lipids, impaired lipidoxidation and insulin resistance amplify each other, leading
to sarcopaenia.

Cognitive decline:
Both frailty and diabetes is associated with an increased riskof mild cognitive impairment (MCI) and diabetes increases the risk of dementia; repeated hypoglycaemic episodes
are also more likely to develop dementia (36). Multiple
mechanisms such as the formation of AGEs, cerebrovascular disease which may exacerbate β amyloid neurotoxicity
and decreased cholinergic transport across the blood-brain
barrier (37-38) may explain part of this linkage. The term
“type 3 diabetes” has also been used to suggest that AD is aform of diabetes based on findings such as hyperinsulinaemia linked to recent onset Alzheimer’s in subjects without
diabetes (39). Vascular risk factors such as hyperglycaemia
interact with ApoE4 to increase the risk of cognitive decline above and beyond the effect of ApoE4 alone, and thisassociation has been supported by recent data (40).

OTHER FACTORSCONCLUSIONS

Microvascular Complications of Diabetes:
Alterations in neurotransmission and motor unit remodelling seen in diabetic polyneuropathy may provide a basis
for changes in motor performance (34). Diabetes-related
renal impairment and may increase the risk of frailty due
to inactivity, loss of muscle mass, comorbid conditions anddecline in physical and cognitive function.

Diabetes, sarcopaenia and frailty are associated with disability, morbidity and mortality. Diabetes accelerates the ageing
process and could provide a pathophysiological environment for the development of frailty, with the close relationship between diabetes and sarcopaenia as a common factor(Figure 1). Diabetes can contribute to frailty by increasing
the incidence of the core components of frailty: weakness,exhaustion, slowness and low physical activity level. Diabetes can also contribute to frailty through its associatedcomplications; atherosclerosis, microvascular disease, neuropathy and dementia/cognitive impairment.
We believe that early recognition of frailty and sarcopaenia
in older adults with diabetes should be a mandatory process
in order to promote early multi-modal interventions basedon physical exercise, nutritional education and which arealigned to glycaemic and other metabolic targets essential
to proper functioning.

Atherosclerosis and Diabetes:
Diabetes-related macrovascular disease can increase morbidity and mortality and also exacerbate physical inactivity (13).
Atherosclerotic change and endothelial dysfunction are key
underlying features involved in this process.
Peripheral vascular disease may also affect muscular performance, and tends to be more diffuse in individuals with diabetes. The effect of impaired oxygen supply on striated muscle may be direct, or indirect via the peripheral nerves (35).

Figure 1: Schematic representation - combined effects of ageing, diabetes and sarcopaenia on lower limb dysfunction: moving towards Frailty(Marley J. Sinclair AJ et al, 2014)

Reproduced with permission from: Morley JE, Malmstrom TK, Rodriguez-Mañas L, Sinclair AJ. Frailty, sarcopenia and diabetes. J Am Med Dir
Assoc. 2014 Dec;15(12):853-9

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Acknowledgement: This mini-review is based on a recent manuscript (lead author: Professor A J Sinclair) published in the
Canadian Journal of Diabetes 2015.

REFERENCES
1. Wilson PNF. Epidemiology of diabetes in the elderly. Am J Med 80:(suppl, 15A):3-15, 1982
2. Harris MI, Hadden WC, Knowler WC, Bennett PH. Prevalence ofdiabetes and impaired glucose tolerance and plasma glucose levels in US population aged 20-74 years. Diabetes 36:523-34, 1987
3. Manton Kg, Stallard ES, Liu K. Forecasts of active life expectancy:
policy and fiscal implications. J Gerontol 48 (special Issue): 11-26,
1993
4. Resnick HE, Harris MI, Brock DB, Harris TB. American Diabetes
Association diabetes diagnostic criteria, advancing age, and cardiovascular disease risk profiles: results from the Third National
Health and Nutrition Examination Survey. Diabetes Care. 2000
Feb;23(2):176-80.
5. Halter JB 2003. Diabetes mellitus in older adults: underdiagnosis
and undertreatment. J Am Geriatr Soc. 2000 Mar; 48 (3): 340-1.
6. Fried LP, Ferruci L, Darer J, Williamson JD, Anderson G: Understanding the concepts of disability, frailty and comorbidity: implications for improved targeting and care. J Gerontol Biol Sci Med
Sci 2004; 59: 255-263.
7. Fried LP, Kronmal RA, Newman AB, Bild DE, Mitelmark MB, PolakJF et al. Risk factors for 5-years mortality in older adults: the Cardiovascular Health Study. JAMA 1998; 279: 585-92.
8. Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalenceof frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc. 2012;60(8):1487-1492.
9. Meneilly, G.S. and Elahi, D. (2005) Metabolic alterations in middle-aged and elderly lean patients with Type 2 diabetes. Diabetes
Care, 28, 1498–9.
10. Mac Leod KM, Tooke JE: Direct and indirect costs of cardiovascular and cerebrovascular complications of type II diabetes. Pharmacoeconomics 8 (Suppl. 1):46-51, 1995
11. Standards of medical care in diabetes-2015. American Diabetes
Association. Diabetes Care, January 2015; Vol 38 (Suppl 1).
12. García-Esquinas E, Graciani A, Guallar-Castillón P, López-García
E, Rodríguez-Mañas L, Rodríguez-Artalejo F. Diabetes and Risk of
Frailty and Its Potential Mechanisms: A Prospective Cohort Studyof Older Adults. J Am Med Dir Assoc. 2015 May 16. pii: S15258610(15)00296-0. doi: 10.1016/j.jamda.2015.04.008. [Epub aheadof print]
13. Sinclair A, Dunning T, Rodriguez-Mañas L. Diabetes in older people: new insights and remaining challenges. Lancet Diabetes Endocrinol. 2015 Apr;3(4):275-85.
14. McNeil CJ, Doherty TJ, Stashuk DW, Rice CL (2005). Motor unit
number estimates in the tibialis anterior muscle of young, old,and very old men. Muscle Nerve 31: 461-467.
15. Cree MG, Newcomer BR, Katsanos CS, Sheffield-Moore M, Chinkes D, Aarsland A, Urban R, Wolfe RR (2004). Intramuscular andliver triglycerides are increased in the elderly. J Clin Endocrinol Metab 89: 3864-3871.
16. Rolland Y, CzerwinskiI S, Abellan Van Kan G, et al. Sarcopenia:
its assessment, etiology, pathogenesis, consequences and future
perspectives. J Nutr Health Aging. 2008 Aug-Sep; 12(7): 433–450.
17. Cesari M, Leeuenburgh c, Lauretani F, Onder G, Bandinelli S, Maraldi C et al. Frailty syndrome and skeletal muscle-Result from the
InCHIANTI study. Am J Clin Nutr 2006; 83(5): 11421148.

18. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J
Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56.
19. Turnbull PJ, Sinclair AJ. Evaluation of nutritional status and its relationship with functional status in older citizens with diabetes
mellitus using the mini nutritional assessment (MNA) tool-a preliminary investigation. J Nutr Health Aging. 2002 May;6(3):185-9.
20. Kalyani RR, Corriere M, Ferrucci L. Age-related and disease-related
muscle loss: the effect of diabetes, obesity, and other diseases.
Lancet Diabetes Endocrinol. 2014 Oct;2(10):819-29.
21 Kitty Kit Ting Cheung, Andrea On Yan Luk, Wing Yee So, Ronald
Ching Wan Ma, Alice Pik Shan Kong, Francis Chun Chung Chow,
Juliana Chung Ngor Chan. Testosterone level in men with type 2
diabetes mellitus and related metabolic effects: A review of current evidence. Diabetes Investig. 2015 March; 6(2): 112–123.
22. Ozfirat Z, Tahseen AC. Vitamin D deficiency and type 2 diabetes.
Postgrad Med J 2010; 86: 18-25
23. Latham NK, Anderson CS, Reid IR. Effects of vitamin D supplementation on strength, physical performance, and falls in older
persons: a systematic review. J Am Geriatr Soc. 2003 Sep; 51 (9):1219-26.
24. Shardell M, Hicks GE, Miller RR, et al. Association of low vitaminD levels with the frailty syndrome in men and women. J Gerontol
A Biol Sci Med Sci 2009. vol 64 A, Nº 1, 69-75.
25. Louard RJ, Fryburg DA, Gelfand RA, Barrett EJ. Insulin sensitivity of protein and glucose metabolism in human forearm skeletal
muscle. J Clin Invest. 1992 Dec;90(6):2348-54.
26. Newman E, Heslin MJ, Wolf RF, et al. The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal
muscle protein turnover in the human forearm. Metabolism. 1994
Jan; 43 (1): 70-8.
27. Guttridge DC. Signaling pathways weigth on decisions to makeor break skeletal muscle. Curr Opin Clin Nutr Metab Care
2004;7:443-50
28. Payette H, Roubenoff R, Jacques PF, et al. Insulin-like growth factor-1 and interleukin 6 predict sarcopaenia in very old community-living men and women: the Framingham Heart Study. J am
Geriatr Soc 2003; 51:1237-43.
29. Visser M, Pahor M, Taeffe DR, et al. Relationship of interleukin-6 and tumor necrosis factor-α with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J
Gerontol A Biol Sci Med Sci. 2002; 57(5):M326-M332.
30. Baumgartner RN. Body composition in healthy aging. Ann N Y
Acad Sci. 2000 May; 904:437-48.
31. Payne GW. Effect of inflammation on the aging microcirculation:
impact on skeletal muscle blood flow control. Microcirculation.
2006 Jun; 13 (4): 343-52.
32. Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL,
DiPietro L, Cline GW, Shulman GI. Mitochondrial dysfunction in
the elderly: possible role in insulin resistance. Science. 2003 May
16;300(5622):1140-2.
33. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired
mitochondrial activity in the insulin-resistant offspring of patientswith type 2 diabetes. N Engl J Med. 2004 Feb 12;350(7):664-71.

56

Diabetes and frailty: an up to date synopsis

34. Allen MD, Stashuk DW, Kimpinski K, Doherty TJ, Hourigan ML,
Rice CL. Increased neuromuscular transmission instability andmotor unit remodelling with diabetic neuropathy as assessed using novel near fibre motor unit potential parameters. Clin Neurophysiol. 2015 Apr;126(4):794-802.
35. Rodríguez-Mañas L, Bouzon CA, Castro M. Peripheral arterial
disease in old people with diabetes. In: Diabetes in Old Age, 3rdedition (Ed: AJ Sinclair), Wiley 2009.
36. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type2 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1565-72

37. Roriz-Filho JS, Sá-Rodriguez TM, Rosset I, et al. (Pre)diabetes,brain aging, and cognition. Biochimica et Biophysica Acta 1792
(2009) 432-443.
38. Pasquier F, Boulogne A, Leys D , Fontaine P. Diabetes mellitus
and Dementia. Diabetes Metab 2006;32:403-414.
39. Kuusisto J, Koivisto K, Mykkanen L, et al. Association between features of the insulin resistance syndrome and Alzheimer´s disease
independently of apolipoprotein E4 phenotype: cross sectional
population based study. BMJ. 1997 Oct 25; 315 (7115): 1045-9.
40. Hsiung GY, Sadovnik AD, Feldman H. Apolipoprotein E epsilon4
genotype as a risk factor for cognitive decline and dementia: datafrom the Canadian Study of Health and Aging. Can Med Assoc J
2004;171: 863-7.

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WHITE BOOKFRAILTY FROM AN ORALHEALTH POINT OF VIEW
R.C. CASTREJÓN-PÉREZ1, S.A. BORGES-YÁÑEZ2

1 Research Department, National Institute of Geriatrics, Mexico City, Mexico;
2 Public Oral Health Department, Postgraduate and Research Division, Dental School, National Autonomous University of
Mexico, Mexico City, Mexico.
Correspondence: Castrejón-Pérez RC, Research Department, National Institute of Geriatrics, Periférico Sur No.2767, Col. San
Jerónimo Lídice, Del. Magdalena Contreras, México City, México C.P. 10200. Phone: +52 55 5573 8686;
E-mail: roberto.castrejon@salud.gob.mc, rc.castrejon.perez@gmail.com

Abstract: Frailty commonly affects older persons, increasing their risk for adverse outcomes. Oral health is affectedby those conditions related to the mouth and teeth, including caries, periodontal diseases, dysgeusia, presbyphagia andoral cancer among others. Oral health problems can be classified as development defects and acquired problems. Theselatter are related to infection or trauma, have a cumulative
effect throughout life and their consequences are lifelong.
Such acquired problems can be classified as primary or secondary, both interacting in a complex manner. Recovery toa previous state of tissue integrity is often impossible fromthese conditions. These complex interactions have negative
impacts on the individual’s general health and quality of life.
Oral status is an important contributor to general health,and has been linked to several chronic conditions such as
cognitive impairment, diabetes, cardiovascular diseases,
strokes, and cancer. An individual’s oral health is mostly stable throughout life. Tooth loss may be considered as the final outcome, resulting as a consequence of history of caries
and periodontitis, as well as failure of prevention and treatment. The loss of a tooth may thus represent the first stepof a vicious cycle. In fact, without intervention, one missing tooth may lead to further teeth loss, thus reducing thecapability to chew and consume nutrients (essential for life
and adequate physiological function), and finally contributing to the development of age-related chronic diseases.

INTRODUCTION

Frailty is a state of diminished physiologic reserve and is associated with enhanced susceptibility to adverse outcomesin older persons (1-4). The prevalence of this condition increases with age (5-7). Oral health has been related to several chronic conditions, demonstrating its important role as
major contributor to general health. Oral health problems
have a cumulative effect throughout life (8-11). They may
onset at young age (8), subsequently affecting the nutritional status at older age (12-14). Oral health problems areindeed often underestimated in youth with consequences
becoming clinically evident at more advanced ages. Oral
health conditions often anticipate the clinical manifestationof chronic diseases, contributing to their development.
FRAILTY

The concept of frailty has been studied for over 30 years (1- 4).
Sometimes, it has been wrongly used as synonymous of comorbidity, disability, and/or aging (4, 15, 16). Frailty exposes the individual at the risk of adverse outcomes, including
falls, institutionalization, and death (17, 18). Frailty consequences are considered as the result of excessive demands
in an individual with diminished physiologic reserves (3, 19).
Frailty may simulate a phase of accelerated aging.
Frailty has been identified in elders, with a prevalence ofabout 20% in community-dwelling older persons (15, 20). It
often occurs in conjunction with other chronic conditions,

Key words: Oral health, frailty, oral health problems, periodontal diseases, periodontitis.

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indicating a possible relationship between frailty and comorbidities as well as an eventual interaction among them.

can lead to changes in pressure and thermic sensibility, as
well as in taste (i.e. dysgeusia; Figure 1). Another majorchange occurring at older age is the yellowing of the teeth
due to the protective response of dentinoblasts (24).
The acquired (cumulative) modifications negatively affecting oral health may frequently be due to infections (e.g. caries and periodontal diseases) as well as to trauma. The onsetof such changes may begin at very young age (e.g. even
before one year of age with caries in primary dentition andpremature tooth loss) (8, 9). The consequences may thenbe lifelong (e.g. tooth loss and need of dental prostheses;
Figure 1) (8, 10, 24). With aging, new conditions (e.g. periodontitis after 18 years of age or xerostomia after 30 yearsof age) may be acquired (25, 26), exposing the individual atdifferent and heterogeneous outcomes, such as tooth loss,
caries or root caries, need of dental prostheses, and presbyphagia. Interestingly, specific oral disorders (e.g. xerostomia and hyposialia) are closely related to the use of certain
drugs (e.g. anticholinergics, antidepressants and antihistamines) as well as to polypharmacy, conditions particularly
frequent among elders (25-28).

ORAL HEALTH

Oral health refers to a cluster of conditions related to themouth and teeth, the most common of which are dental
caries (21-23). It also includes periodontal diseases (e.g.
gingivitis and periodontitis), xerostomia, presbyphagia, dysphagia and oral cancer, among others (Table 1).
There are two basic types of oral health problems, those related to development defects and those acquired during thecourse of life (or cumulative changes; Table 1), sometimes
simultaneously occurring with specific physiologic mechanisms (Figure 1).
Such physiologic modifications can be divided into twogroups according to the affected period of life. During thefirst 12 years of life, the changes are associated with theeruption of teeth (both primary and permanent dentition).
After the sixth decade of life (24), these changes are related
to a lower
Figure1 cellular replacement rate in the mucosa, which

Physiologic and cumulative oral modifications occurring during the life course
Figure 1
Physiologic and cumulative oral modifications occurring during the life course

The acquired changes occurring in oral health can be classified as primary (or affecting intact tissues [e.g. caries andperiodontal diseases]), and secondary (in which they are
the consequence of primary acquired problems; Table 1).
Primary and secondary changes interact in a complex manner (Figure 2), and recovery to a previous state of tissue
integrity is often impossible after their onset. Instead, rehabilitation is required. The complex interaction between

primary and secondary changes has a negative impact on
the individual’s general health and quality of life (Table 2),
potentially leading to the generation of a vicious cycle thatcan only be halted by the adoption of hygiene and lifestylemodifications. For example, in the context of periodontal
diseases, recovery from gingivitis is possible, but periodontitis will always leave sequels.

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individuals with fewer teeth (29-31) and edentate persons
who are not wearing dentures (32) present a higher risk ofbeing frail. In a longitudinal study of older persons aged 70
years and older (follow-up: 3 years), the number of residual
teeth was strongly associated with a lower risk of developing frailty (29).

ORAL HEALTH AND FRAILTY

Limited evidence is available about the possible relationship between oral health and frailty. Despite differences in
the adopted methodology, the findings of existing studies
are quite consistent. In particular, it is well established that

Table 1
Oral health conditions• Genetic and Development Oral Health Problems
Amelogenesis imperfecta
Dentinogenesis imperfecta
Cleft lipCleft palate• Acquired Oral Health Problems
Primary (onset on intact tissues)- Caries- Periodontal diseases
Gingivitis
Periodontitis
Secondary (onset as sequel of primary acquired problems)- Dental fracture- Tooth loss
- Root remains- Edentulism- Non-functional dental prostheses- Halitosis- Oral cancer• Others
Xerostomia
Hiposialia
Presbyfagia
Dysgeusia
Temporo-Mandibular Disorders

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Table 2
Consequences of oral health problems and associated chronic conditions
Oral healthproblem

Consequences

Chronic condition associatedComponent of the proposed model
linking  oral health and frailty

CariesDental fracture
Pain
Tooth loss
Root remains
Edentulism

Cognitive impairment
Arthritis

Utilization of Dental Services
Functional
Psychosocial

Gingivitis

Bleeding gums
Progression to periodontitis
Halitosis

Cognitive impairment
Arthritis

Utilization of Dental Services
Functional
Psychosocial

Periodontitis

Bleeding gums
Acute and chronic infections
Acute and chronic inflammation
Halitosis
Dental mobility
Tooth loss
Edentulism
Chewing problems
Speaking problems

Diabetes
Cardiovascular diseases
Arthritis Embolism
Cognitive impairment

Utilization of Dental Services
Psychosocial
Physiologic/biologic

Tooth loss

Chewing problems
Speaking problems
Need for dental prostheses (partial
dentures)
Loss of support for facial muscles

Diabetes
Cognitive impairment
Arthritis
Nutritional implications (changes
in food selection)
Frailty
CancerUtilization of Dental Services
Psychosocial
Functional

Root remains

Acute and chronic infections
Chewing problems
Halitosis

Chronic inflammation
Nutritional implications (changes
in food selection)
Cognitive impairment

Utilization of Dental Services
Psychosocial
Functional
Physiologic/biologic

Edentulism

Chewing problems
Speaking problems
Need for dental prostheses(complete dentures)
Dysgeusia
Thermic and pressure sensibilitychanges

Diabetes
Cardiovascular diseases
Nutritional implications (changes
in food selection)
Arthritis
Frailty
CancerUtilization of Dental Services
Psychosocial
Functional

Non-functional
dentalprostheses

Chewing problems
Speaking problems
Dysgeusia
Dysphagia
Thermic and pressure sensibilitychangesCariesPeriodontal diseases
Mucosal lesions

Nutritional implications (changes
in food selection)
Frailty
Cognitive impairment

Utilization of Dental Prostheses
Psychosocial
Functional

Xerostomia andhiposialia

CariesPeriodontal diseases
Opportunistic infections
Chewing problems
Speaking problems

Cardiovascular diseases(hypertension)
Depression
Polypharmacy
Arthritis

Functional
Physiologic/Biologic

Mucosal lesions

Pain
Chewing problems
Oral cancer

Cognitive impairment

Functional
Physiologic/Biologic

Dysphagia

Chewing problems
Malnutrition
Bronchoaspiration

Cognitive impairment(Parkinson disease)
Neurological impairment
Depression
StrokeFunctional
Psychosocial

Respiratory infections
Obesity
Osteoporosis

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Figure 2Complex interactions between primary and secondary cumulative oral changes
Figure 2Complex interactions between primary and secondary cumulative oral changes

These findings support the hypothetical model here proposed linking oral health and frailty, in which four components are identified: functional, psychosocial, physiologic/
biologic, and utilisation of dental services (33). The oral
health (acquired) problems, either primary or secondary,contribute to each component to different degrees (Table 2)with tooth loss seeming to be the major contributor tohealth deterioration. This pattern has been observed in several studies showing that the number of teeth has not only
nutritional implications (12, 13, 34-36), but is also associated with atherosclerosis (37), chronic obstructive pulmonary
disease (38), fatigue (30), reduced quality of life (39), andhigher risk of head and neck cancer (40) and cognitive impairment (41).
It must be emphasised that tooth loss is the final outcome
frequently resulting after a natural history of caries andperiodontitis. As such, missing teeth represent the failureof prevention and treatment and reflect the necessity fordental prostheses, which, in cases of failure, will then leadto a new chain of adverse outcomes (e.g. mucosal lesions).
In Figure 2, we can observe that caries, periodontal diseases, and trauma all converge to tooth loss. Tooth loss is responsible for speaking and chewing problems, as well as
for low quality of life. The utilisation of non-functional
dental prostheses may also affect the individual’s capacity
to comfortably speak and chew. Chewing problems are themain reason for changes in food choices (14, 34, 36, 42, 43),
potentially resulting in impaired nutritional status (14, 36, 44)(Figure 3).

ORAL HEALTH AND GENERAL HEALTH

Oral health is an important constituent of the overall healthstatus (22, 45, 46). Oral conditions have been related to cognitive impairment (41, 47-49), diabetes (50), cardiovasculardisease (51-55), stroke (56), respiratory infections (53),obesity (55), osteoporosis (56), and arthritis (58-62). Additionally, they have shown to exert a negative impact on
the individual’s quality of life (63-66), and are associated topolypharmacy (25, 27, 28) (Table 2).
Several pathways may be described to explain the associations between oral and non-oral health conditions. As an
example, in Figure 3, we present the mechanisms linking
oral health problems and malnutrition, probably the moststraightforward and direct relationship. This model begins
with a healthy mouth in which the presence of caries or
periodontal diseases leads to tooth loss. Consequently, theindividual may develop chewing problems and modifications in food preferences, finally resulting in lower nutrient and caloric intake. Some individuals cope with chewing
limitations by switching to unhealthier food, which maylead to obesity or weight loss. In cases where an individual’s energy intake becomes insufficient, detrimental effects
may become evident on his/her capacity to conduct daily
activities (67-71).

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Figure 3

Possible
pathway from oral health problems to malnutrition
Figure3
Possible pathway from oral health problems to malnutrition

selection (12, 34, 35, 43, 72). Finally, oral health may act
as outcome. For example, in adults taking multiple medications causing xerostomia (e.g. anticholinergic and antihypertensives) the risk of caries and periodontal diseases
might be increased (25, 26, 28).

FRAILTY FROM AN ORAL HEALTH VIEW

As mentioned above, an individual’s oral health is quite
stable throughout life, and acquired changes (in particular,
tooth loss; Figure 1) are often related to infections or traumas. The loss of a tooth may then represent the first evident sign of a starting decline; one missing tooth can leadto the loss of additional teeth, especially if no intervention(or an inadequate one) is implemented.
Most missing teeth require dental prostheses, which mustbe functional. If they are not functional, they will promote
the development of mucosal lesions and further tooth loss
and may result in chewing problems. The process of progressive loss of teeth not only puts the individual at higher
risk for malnutrition, but also exposes to the risk of inadequately respond to stressors. This scenario is very similar towhat happening in the context of frailty.
In summary, oral health problems have a cumulative effect throughout life (Figures 1 and 2) and can be of such a
low intensity that early in life, their effects may be ignored.
However, if these problems are not promptly addressed,
they may progress until the treatment becomes very complex (Figure 2). Some of the consequences will contributeat the development of additional chronic conditions, generating a network of interacting and self-feeding mechanisms
progressively and rapidly deteriorating the individual’s
health status. As such, oral health could possibly represent
an indicator, a risk factor, or even an outcome of general
health at the same time. For example, oral health could be amarker of cognitive impairment as there are reports showing that persons with cognitive impairment are more likely
to present caries (either coronal or root caries), periodontal diseases and have more missing teeth (47, 49), probably
due to poor personal hygiene. Oral health may be used as arisk factor for malnutrition, as discussed above. This meansthat in a person with poor nutrition, it is important to explore oral health and identify possible issues in his/her food

CONCLUSION

Dental loss may represent the initial point for decline ingeneral health. It is a major outcome requiring immediate
counteractions before the detrimental process becomes irreversible. Such preliminary step in a vicious cycle mining
the maintenance of adequate health status strongly resembles the concept of frailty commonly adopted in geriatrics.
It is noteworthy that the pathway we have described is not
monofactorial, but results from the interaction of several
other domains (e.g. genetics, economics, lifestyle habits…).
At the same time and in the same way, the oral health assessment becomes crucial for the understanding and correct framing of any chronic condition.
As oral health is a part of an individual’s general health status, multidisciplinary studies are needed to assess the contribution of oral health measures to specific conditions (e.g.
diabetes, cardiovascular disease, cognitive impairment). The
number of teeth may serve as a good marker for general
health, as it reflects the net accumulation of several experiences over time, from poor hygiene habits to the occurrence of caries, periodontal diseases, and trauma. Furthermore, teeth count is a clinical-friendly information that canbe easily retrieved during the comprehensive assessmentof the older person, providing useful insights (e.g. possible
nutritional issues) for the design of the most appropriate
intervention.
This article was published in the Journal of Frailty and Aging
Volume 3, Number 3, 2014
http://www.jfrailtyaging.com/

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REFERENCES
1. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm - isues and controversies. J Gerontol
A Biol Sci Med Sci. 2007;67A(7):731-7.
2. Bortz WM, 2nd. The physics of frailty. Journal of the American
Geriatrics Society. 1993;41(9):1004-8.
3. Rockwood K, Fox RA, Stolee P, Robertson D, Beattie BL. Frailty inelderly people: an evolving concept. CMAJ 1994;150(4):489-95.
4. Topinkova E. Aging, disability and frailty. Ann Nutr Metab. 2008;52
Suppl 1:6-11.
5. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty: characterization in the women's health and aging studies. J
Gerontol A Biol Sci Med Sci 2006;61(3):262-6.
6. Lipsitz LA. Physiological complexity, aging, and the path to frailty.
Sci Aging Knowledge Environ. 2004;2004(16):pe16.
7. Walston J, McBurnie MA, Newman A, et al. Frailty and activationof the inflammation and coagulation systems with and withoutclinical comorbidities. Arch Intern Med. 2002;162(20):2333-41.
8. Holst D, Schuller AA. Oral health in a life-course: birth-cohorts from 1929 to 2006 in Norway. Community Dent Health.
2012;29(2):134-43.
9. Isaksson H, Alm A, Koch G, Birkhed D, Wendt LK. Caries prevalence in Swedish 20-year-olds in relation to their previous caries
experience. Caries Res. 2013;47(3):234-42.
10. Lu HX, Wong MC, Lo EC, McGrath C. Trends in oral health fromchildhood to early adulthood: a life course approach. Community
Dent Oral Epidemiol. 2011;39(4):352-60.
11. Steele JG, Sanders AE, Slade GD, et al. How do age and tooth
loss affect oral health impacts and quality of life? A study comparing two national samples. Community Dent Oral Epidemiol.
2004;32(2):107-14.
12. Nowjack-Raymer RE, Sheiham A. Numbers of natural teeth, diet,and nutritional status in US adults. J Dent Res. 2007;86(12):1171-5.
13. Sahyoun NR, Lin CL, Krall E. Nutritional status of the older adult is
associated with dentition status. J Am Diet Assoc. 2003;103(1):61-6.
14. Sheiham A, Steele J. Does the condition of the mouth and teeth
affect the ability to eat certain foods, nutrient and dietary intake
and nutritional status amongst older people? Public Health Nutr.
2001;4(3):797-803.
15. Fried LP, Tangen CM, Waltson J. Frailty in older adults: evidence
for a phenotype. J Gerontol. 2002;56(A):M146-M56.
16. Walston J. Frailty--the search for underlying causes. Sci Aging
Knowledge Environ. 2004;2004(4):pe4.
17. Espinoza S, Walston JD. Frailty in older adults: insights and interventions. Cleve Clin J Med. 2005;72(12):1105-12.
18. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med
Sci. 2004;59(3):255-63.
19. Powell C. Frailty: help or hindrance? J Royal Soc Med. 1997;90
Suppl 32:23-6.
20. Ahmed N, Mandel R, Fain M. Frailty: An emerging geriatric syndrome. Am J Med. 2007;120(9):748-53.
21. Petersen PE. The World Oral Health Report 2003: continuous improvement of oral health in the 21st century--the approach of the
WHO Global Oral Health Programme. Community Dent Oral Epidemiol. 2003;31 Suppl 1:3-23.
22. Petersen PE, Ueda H. Oral Health in Ageing Societies. Integrationof oral health and general health report of a meeting convened at
the WHO, Centre for Health Development in Kobe, Japan 1-3 June
2005. Geneva: World Health Organization, 2006

23. Beaglehole R, Editions M. The oral health atlas: Mapping a neglected global health issue: FDI World Dental Federation; 2009.
24. McKenna G, Burke FM. Age-related oral changes. Dent Update.
2010;37(8):519-23.
25. Hopcraft MS, Tan C. Xerostomia: an update for clinicians. Aust
Dent J. 2010;55(3):238-44; quiz 353.
26. Nederfors T. Xerostomia and hyposalivation. Adv Dent Res.
2000;14:48- 56.
27. Locker D. Xerostomia in older adults: a longitudinal study. Gerodontology. 1995;12(1):18-25.
28. Thomson WM, Chalmers JM, Spencer AJ, Slade GD. Medicationand dry mouth: findings from a cohort study of older people. J
Public Health Dent. 2000;60(1):12-20.
29. Castrejón-Pérez RC. [Estudio longitudinal sobre condiciones desalud bucal y calidad de vida como predictores de fragildiad en
personas de 70 años y más]. Distrito Federal, México: Universidad
Nacional Autónoma de México; 2012.
30. Avlund K, Schultz-Larsen K, Christiansen N, Holm-Pedersen P.
Number of teeth and fatigue in older adults. J Am Geriatr Soc.
2011;59(8):1459-64.
31. de Andrade FB, Lebrao ML, Santos JL, Duarte YA. Relationshipbetween oral health and frailty in community-dwelling elderly individuals in Brazil. J Am Geriatr Soc. 2013;61(5):809-14.
32. Castrejón-Pérez RC, Borges-Yáñez SA. Association between theuse of complete dentures and frailty in edentuolous Mexican elders. J Frailty Aging. 2012;1(4):183-8.
33. Castrejón-Pérez RC, Borges-Yáñez SA, Gutierrez-Robledo LM, Avila- Funes JA. Oral health conditions and frailty in Mexican community-dwelling elderly: a cross sectional analysis. BMC Public
Health. 2012;12:773
34. Touger-Decker R, Mobley CC. Position of the American Dietetic Association: oral health and nutrition. J Am Diet Assoc.
2007;107(8):1418-28.
35. Brennan DS, Spencer AJ, Roberts-Thomson KF. Tooth loss, chewing ability and quality of life. Qual Life Res. 2008;17(2):227-35.
36. Sheiham A, Steele JG, Marcenes W, et al. The relationship among
dental status, nutrient intake, and nutritional status in older people. J Dent Res. 2001;80(2):408-13.
37. Shaboodien G, Uyar IS, Akpinar MB, et al. Carotid and popliteal
artery intima-media thickness in patients with poor oral hygiene
and the association with acute-phase reactants. Cardiovasc J Afr.
2013 12;23:1-5.
38. Barros SP, Suruki R, Loewy ZG, Beck JD, Offenbacher S. A cohort
study of the impact of tooth loss and periodontal disease on respiratory events among COPD subjects: modulatory role of systemic
biomarkers of inflammation. PloS One. 2013;8(8):e68592.
39. Jain M, Kaira LS, Sikka G, et al. How do age and tooth loss affect oral health impacts and quality of life? A study comparing
two state samples of gujarat and rajasthan. J Dent (Tehran).
2012;9(2):135-44.
40. Wang RS, Hu XY, Gu WJ, Hu Z, Wei B. Tooth loss and risk of headand neck cancer: a meta-analysis. PloS One. 2013;8(8):e71122.
41. Kaye EK, Valencia A, Baba N, Spiro A, 3rd, Dietrich T, Garcia RI.
Tooth loss and periodontal disease predict poor cognitive function in older men. J Am Geriatr Soc. 2010;58(4):713-8.
42. Locker D. Changes in chewing ability with ageing: a 7-year study ofolder adults. J Oral Rehabil. 2002;29(11):1021-9.
43. Koehler J, Leonhaeuser I-U. Changes in Food Preferences during
Aging. Ann Nutr Metab. 2008;52(1):15-9.

64

FRAILTY FROM AN ORAL HEALTH POINT OF VIEW

44. Walls AW, Steele JG, Sheiham A, Marcenes W, Moynihan PJ.
Oral health and nutrition in older people. J Public Health Dent.
2000;60(4):304-7.
45. Petersen PE, Kandelman D, Arpin S, Ogawa H. Global oral healthof older people--call for public health action. Community Dent
Health. 2010;27(4 Suppl 2):257-67.
46. Petersen PE, Yamamoto T. Improving the oral health of older people: the approach of the WHO Global Oral Health Programme.
Community Dent Oral Epidemiol. 2005;33(2):81-92.
47. Noble J, Borrell L, Papapanou P, Elkind M, Scarmeas N, Wright C.
Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol Neurosurg Psychiatry.
2009;80(11):1206-11.
48. Chalmers JM, Carter KD, Spencer AJ. Oral diseases and conditions
in community-living older adults with and without dementia. Spec
Care Dentist. 2003;23(1):7-17.
49. Syrjala AM, Ylostalo P, Ruoppi P, et al. Dementia and oral
health among subjects aged 75 years or older. Gerodontology.
2012;29(1):36-42.
50. Drumond-Santana T, Costa FO, Zenobio EG, Soares RV, Santana
TD. [Impact of periodontal disease on quality of life for dentate
diabetics]. Cad Saude Publica. 2007;23(3):637-44.
51. Arbes SJ, Jr., Slade GD, Beck JD. Association between extent of periodontal attachment loss and self-reported history of heart attack:an analysis of NHANES III data. J Dent Res. 1999;78(12):1777-82.
52. Karnoutsos K, Papastergiou P, Stefanidis S, Vakaloudi A. Periodontitis as a risk factor for cardiovascular disease: the role of anti-phosphorylcholine and anti-cardiolipin antibodies. Hippokratia.
2008;12(3):144-9.
53. Scannapieco FA. Position paper of The American Academy of
Periodontology: periodontal disease as a potential risk factor forsystemic diseases. J Periodontol. 1998;69(7):841-50.
54. Syrjala AM, Ylostalo P, Hartikainen S, Sulkava R, Knuuttila M.
Number of teeth and selected cardiovascular risk factors among
elderly people. Gerodontology. 2010;27(3):189-92.
55. Borges-Yanez SA, Irigoyen-Camacho ME, Maupome G. Risk factors and prevalence of periodontitis in community-dwelling elders
in Mexico. J Clin Periodontol. 2006;33(3):184-94.
56. Boehm TK, Scannapieco FA. The epidemiology, consequences
and management of periodontal disease in older adults. J Am
Dent Assoc. 2007;138 Suppl:26S-33S.
57. Moedano DE, Irigoyen ME, Borges-Yanez A, Flores-Sanchez I,
Rotter RC. Osteoporosis, the risk of vertebral fracture, and periodontal disease in an elderly group in Mexico City. Gerodontology.
2011;28(1):19-27.

58. Felton DA. Edentulism and comorbid factors. J Prosthodont.
2009;18(2):88-96.
59. Blaizot A, Monsarrat P, Constantin A, et al. Oral health-related
quality of life among outpatients with rheumatoid arthritis. Int Dent
J. 2013;63(3):145-53.
60. Agnihotri R, Gaur S. Rheumatoid arthritis in the elderly and its relationship with periodontitis: A review. Geriatr Gerontol Int. 2013 doi:
10.1111/ggi.12062.
61. Rajkarnikar J, Thomas BS, Rao SK. Inter-relationship between rheumatoid arthritis and periodontitis. Kathmandu Univ Med J (KUMJ).
2013;11(41):22-6.
62. Yokoyama T, Kobayashi T, Ito S, et al. Comparative Analysis of Serum
Proteins in Relation to Rheumatoid Arthritis and Chronic Periodontitis. J Periodontol. 2013 May 7.
63. Locker D, Matear D, Stephens M, Jokovic A. Oral health-related
quality of life of a population of medically compromised elderly people. Community Dent Health. 2002;19(2):90-7.
64. Locker D, Quinonez C. Functional and psychosocial impacts of oral
disorders in Canadian adults: a national population survey. J Can
Dent Assoc. 2009;75(7):521.
65. Locker D, Quinonez C. To what extent do oral disorders compromise
the quality of life? Community Dent Oral Epidemiol. 2011;39(1):3-11.
66. Sheiham A. Oral health, general health and quality of life. Bull World
Health Organ. 2005;83(9):644.
67. Borges-Yanez SA, Maupome G, Martinez-Gonzalez M, CervantezTurrubiante L, Gutierrez-Robledo LM. Dietary fiber intake and dental
health status in urban-marginal, and rural communities in central
Mexico. J Nutr Health Aging. 2004;8(5):333-9.
68. Cervantes L, Montoya M, Núñez L, Borges A, Gutiérrez L, Llaca C.
Aporte dietético de energía y nutrimentos en adultos mayores deMéxico. Nutrición Clínica. 2003;6(1):2-8.
69. Sahyoun NR, Krall E. Low dietary quality among older adults with selfperceived ill-fitting dentures. J Am Diet Assoc. 2003;103(11):1494-9.
70. Furuta M, Komiya-Nonaka M, Akifusa S, et al. Interrelationship oforal health status, swallowing function, nutritional status, and cognitive ability with activities of daily living in Japanese elderly people
receiving home care services due to physical disabilities. Community Dent Oral Epidemiol. 2013;41(2):173-81.
71. Makhija SK, Gilbert GH, Clay OJ, Matthews JC, Sawyer P, Allman
RM. Oral health-related quality of life and life-space mobility in community- dwelling older adults. J Am Geriatr Soc. 2011;59(3):512-8.
72. N'Gom P I, Woda A. Influence of impaired mastication on nutrition.
J Prosthet Dent. 2002;87(6):667-73.

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WHITE BOOK

THINKING ABOUT COGNITIVE FRAILTY
L.J. FITTEN

University of California, Los Angeles, David Geffen School of Medicine, USA
Correspondence: L.J. Fitten, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA, E-mail: jfitten@
ucla.eduOver recent years a number of concepts havearisen to describe the cognitive decline, beyond
healthy aging, that has been observed in substantial numbers of older persons whose impairments fall shortof meeting of the criteria for dementia. This decline may
or may not be linked to an early dementing process. Amongthese well-known entities are Age Associated Memory Impairment (AAMI), Cognitive Impairment, Not Demented(CIND), Mild Cognitive Impairment (MCI of various types
such as amnestic, with executive dysfunction, multi-domain,etc.) and more recently, with the emergence of Psychiatry’s
Diagnostic and Statistical Manual 5th Edition (DSM 5), Minor Neurocognitive Impairment (MNCI). Each entity uses
similar but distinct clinical diagnostic criteria and may belinked to underlying specific brain diseases.
A new concept, Cognitive Frailty (CF), has recently emergedin the Geriatrics literature (1, 2). Most recently Keleiditi andcolleagues (11) have proposed the elements that comprise
this clinical construct, and suggest a basic operational definition of the condition. Raising interesting points they indicate that cognitive frailty should be:1) linked to a reduction in cognitive ‘reserve’,2) independent of specific brain diseases but at the sametime co-exist with the presence of physical frailty (in thisconcept, cognitive frailty is to be distinguished from thepresence cognitive impairment found in non- physicallyfrail individuals such as physically robust mild Alzheimer’s Disease [AD] patients).
3) represented by a score of 0.5 on the well-established
Clinical Dementia Rating Scale (CDR), a score that often
is associated with a pre-dementia state, but is not withfrank dementia.
Appearing in the geriatrics literature, the term Cognitive
Frailty (CF) evokes a parallel or link to physical frailty, amajor geriatric syndrome with negative health outcomes.
Some studies now suggest that cognitive impairment (presumably of non-specific etiologies) provides added value
for the prediction of negative health outcomes in physicallyfrail elders (3, 4). Thus CF may be unlike the previously
noted mild cognitive impairment entities whose principal
goal appears to be to reveal the earliest clinical stages ofdementing illnesses. Rather than foreshadowing or predicting underlying, specific brain diseases, CF may be a concept
which identifies a proclivity toward cognitive functional decline, a loss of resiliency and adaptability to challenge, that
could lead to negative health outcomes such as diminishedexecutive abilities and increased dependency, both of which
could exacerbate other negative physical health outcomes
associated with frailty. However, while this is of interest,at this point we know little about the pathophysiology underpinning this condition, which Keleiditi et al. suggest canbe independent of specific brain disease; nor do we knowmuch about how it might be remediated. Thus the proposed Keleiditi el al. criteria that define the concept of CF
deserve further consideration and some additional suggestions for clarification and eventual clinical application.
First let us consider the basic mechanism underpinning CF
which has been suggested as a reduction of cognitive reserve. This point could benefit from further development.
It is clear that brain diseases, particularly the dementias, candramatically alter cognitive reserve as can severe systemic
illness. Yet a majority of elders do not develop these conditions, so let us first consider the case of usual aging, nonbrain diseased individuals. As employed by Keleiditi andcolleagues, cognitive reserve implies a passive process similar to the concept of ‘brain reserve capacity’ first proposedby Katzman (5), and Satz (6) who define reserve in termsof the amount of brain damage (e.g. aging changes, micro66

Thinking about Cognitive Frailty

vascular changes, white matter loss) that can be sustained
before reaching a threshold of detectable clinical expression. Analogously, according to Keleiditi et al., the appearance of CF would be established with the slightly abnormal
CDR score of 0.5. In contrast, a possibly more attractivemodel of cognitive reserve, one that is more ‘active’ could
be used. Such a model would suggest that the brain actively
attempts to manage damage or age-related changes by either using pre-existing cognitive processing approaches orby using compensatory mechanisms (7, 8). Thus, an activemodel of cognitive reserve implies that underlying it areneural networks and neuronal connectivity that are more
efficient, have a greater capacity or are more flexible in individuals with greater reserve than those with less. Consequently, high brain reserve persons may be more capableof coping with challenges imposed by age-related brainchanges or systemic or brain disease. Significant variability
exists in cognitive reserve among individuals and epidemiologic studies have suggested that good proxies for amountof cognitive reserve include measures of economic attainment, level of education, IQ, and degree of literacy (9).
This type of information might be useful to clinicians trying to estimate cognitive reserve and find ways of augmenting it even in the later years.

begin to engage additional neural circuitry, whereas older
adults plateau and then begin to decline, probably because
they are no longer able to engage task-related circuitry, thatis, they can no longer compensate for the challenge of theadded cognitive load.
One could consider then, as a more neurologically based
marker of CF, the inability to exhibit a minimal level ofcompensation for a cognitive task that had been previously
established to produce a compensating response in mosthealthy older persons. In translating such experimental
findings to the clinic, an office proxy for the imaging evidence could be employed such as the successful completionof the cognitive task in a specified amount of time. An approach of this type would have a markedly improved validity over the more arbitrary selection of a particular CDR
score as a cut off point for CF, and would likely be easier
to administer by primary care practitioners and their assistants than the CDR. Its prognostic value would need to be
determined by subsequent longitudinal studies but it could
have the advantage of providing a longer lead time before
negative health outcomes became imminent.
It is foreseeable that through the future use of state of theart cognitive testing and imaging techniques, improved understanding of the neural mediation of various aspects ofcognitive reserve can be attained. The imaging approach
to measuring cognitive reserve could be important for understanding an aged individual’s true clinical status which
would reflect a combination of underlying, age-related
brain changes and that individual’s cognitive reserve in thecontext of those changes. Individuals with similar clinicalappearances could differ substantially in their neural measures of reserve and this could have significant implications
for a timely prognosis and intervention.
Next we should consider if CF can exist independently ofbrain disease and if it must co-occur with physical frailty. A
major question in the study of brain aging has concerned
the boundary between age-related change and disease. Morerecently the questions of what distinguishes ‘normal’ or‘usual’ aging from CF and how frailty is different from disease have arisen. Our ability to answer these questions has
improved as a consequence of the development of better
imaging techniques and cognitive characterizations of patients, but it is certainly not complete. Many gerontologists
and geriatricians suggest that aging is not just the aggregation of disease but that other time-related factors and subtle but pervasive accumulation of damage to homeostaticmechanisms can account for aging changes and that somebrain structures are more vulnerable to them than others.
In making the distinction between age-related brain changes and age-related brain disease, Small and colleagues (14)have been able to demonstrate, using human and non-human primate species, that memory decline is different inaging than in Alzheimer’s disease (AD) and is mediated by

To better understand the possible neurological mechanisms
underlying diminished cognitive reserve and increased CF,
studies using the latest neuroimaging techniques need tobe employed. With the advent of more sophisticated brain
imaging techniques such as functional MRI, diffusion tensor imaging (DTI), optical imaging, among others, and incombination with the use of new, highly sensitive cognitive
tasks during imaging, activity in the functional imaging of
cognitive reserve and compensatory cognitive operations inhealthy younger and older persons has been rapidly growing (10). Functional neuroimaging is providing many useful insights into the field of cognitive aging in addition to
improving information on localization of particular cognitive operations. Functional neuroimaging of aging subjects
has provided evidence for increased recruitment of theprefrontal cortex in diverse cognitive tasks. The prefrontal
cortex is probably the area with most plastic capacity in thebrain (11). It has also revealed that functional interactions
between prefrontal cortex and other brain regions such as
the mesial temporal lobe, important in encoding new information, are associated with better memory performance inolder adults (12). These changes are likely compensatory innature. Reuter- Lorenz et al. (13) have provided data supporting the observation that older adults display regions ofgreater prefrontal activity than younger adults when cognitive task demand is low, suggesting that older adults recruit
more neural circuits than younger adults at lower levels oftask demand. As demand increases, younger adults also67

WHITE BOOK

damage to different hippocampal structures in each condition, e.g., the entorhinal cortex in AD and the dentate
gyrus in normal aging. Their work supports the proposition
that aging per se and AD are distinct but possibly related
processes since sporadic AD appears to be age-dependent
with the risk of it increasing exponentially after age 65 until
about age 95, yet there are very old individuals who do notdevelop AD.
Locating CF in relationship to ‘normal’ or ‘usual’ aging cognition and to disease is a more complicated theme and has
been viewed differently by clinicians from different disciplines. Employment of new imaging and cognitive testing
techniques should bring forth more evidence for and clarity
to subtle brain dysfunctions. If we assume that a CF process can develop intrinsically in the brain, perhaps from aloss of protective factors still operative in healthy aging, andas a result of non-disease specific, age-related physiologic
degradation of neural network communications evidenced
by a reduction of cognitive reserve and an inadequate compensatory response to a challenge, we can affirm that in atleast some cases CF can be dissociated from an identifiabledisease processes such as, for example, pre-dementia AD.
As imaging of occult brain disease (e.g. tau and amyloid
imaging in asymptomatic AD) improves and we can clinically confirm the presence of pre-clinical disease with clinically reliable biomarkers (e.g. aβ42, p-Tau), we will be able
to separate those individuals who are developing intrinsic
CF as evidenced by challenge test results, from those who
harbor occult disease and may also underperform during achallenge paradigm. This would have important intervention implications for the healthier individual as the absenceof disease would permit the frail but non-diseased brain torespond with greater resilience to cognitive and behavioral
stimulation of its inherent plasticity.
CF will be worsened by the presence of brain and systemic
disease, pre-clinical or not, as cognitive reserve and compensatory mechanisms by cognitive circuitry would be additionally challenged by disease-specific neurodegenerative,
vascular or metabolic/hormonal processes with a predilection for particular brain circuits and areas beyond thosethat are likely to be affected in non-disease aging. Examplesof these are the early damage to the entorhinal cortex andposterior cingulate in AD, and in systemic hypertension by
the deep white and deep grey matter lesions due to damageof the thin, deep, penetrating arteries of the posterior andanterior circulation. Consequently, disease-specific damage
would add to the physiologic degradation of age-vulnerable
areas such as the pre-frontal cortex, a structure likely to be
involved in reduced reserve and compensatory capacity inbasic CF.
Finally, the relationship between the state of CF and disease
needs to be considered. As with much of the preceding
discussion, little is factually known at present about this

topic and many of the ensuing comments will necessarily
be conjectural, yet eventually testable. It is appealing to hypothesize that cognitive frailty is an intermediary between“usual aging” and brain disease. For example, the molecular changes in neurons, glial cells and white matter thatcharacterize the subtle loss of functionality from “usual”
aging to CF are but part of a continuum of change thatas further degradation takes place may permit pathogenic
mechanisms of a particular disease to become more fully
activated and expressed. The additional burden of systemic
disease and physical frailty may actually hasten the process.
This could at least partially explain why the emergence ofsporadic, late onset AD seems to accelerate exponentiallywith age as individuals become more frail and ill. If thiswere the case, then it would be important to identify basic
CF in its beginnings and develop interventions to retard or
attenuate it in order to help diminish the risk of acquiring
age-related brain diseases in older age.
Lastly, we should consider the fact that CF may indicate
higher risk for adverse long term health outcomes. Basedon the assumption that frailty is driven by the same basic
age-related processes in all organs and systems in the body,its presence in the brain is bound to have functional consequences as it develops and these can lead to undesirable health outcomes short of dementia such as diminishedexecutive ability, limited concentration, reduction in decision-making capacity, attenuated motivation, and a moreprecocious lowered autonomy which can alter the qualityof life of older persons. However, it is important to notethat all organs or systems in the body will not have developed the same degree of frailty at the same point in theindividual’s history. A number of recent studies have shownlinks between cognitive deficits and physical frailty (3, 4).
The pattern emerging from these studies suggests that gait
speed and grip strength are the components of frailty moststrongly associated with cognitive function. Executive dysfunction and impaired attention are the cognitive domains
most consistently linked to frailty. This may be best understood by the strong relationship of gait to the functioningof prefrontal executive and motor circuits. More subtle
brain dysfunction such as reduction in cognitive compensation mechanisms under challenge conditions has not been
examined as a predictor of gait speed or strength or longitudinally as a possible indicator of future negative healthoutcomes.
In conclusion, CF is a new clinical concept recently put
forth in the Geriatrics literature and appears linked to physical frailty, a major geriatric syndrome with negative healthoutcomes. In contrast to other established clinical entities
describing minor cognitively impaired states, whose main
purpose appears to be to reveal the earliest clinical stages of
specific dementing illnesses, CF seems more functionallyoriented intending to identify an aging syndrome that can
68Thinking about Cognitive Frailty

be linked to functional cognitive and physical decline andpossibly to preventable negative health outcomes. As it currently stands CF is in need of further development as several authors have recently noted (15-17). Whereas cognitive
impairment per se appears to have some prognostic value
for worse health outcomes in frail elders (3, 4), CF presently has no clearly identified supporting brain theory or
demonstrated pathogenic mechanisms that differentiate itfrom healthier aging or specific brain disease, at least at the
network or circuit level. It also lacks proven valid, sensitiveand specific methods of detection at the clinical level. Studies will have to be conducted to confirm that identified CF
actually leads to specific negative cognitive outcomes as described here earlier as well as contributes to the worseningof physical frailty. Further development of the construct
could lead to a useful clinical entity that due to its possible
reversibility, based on the non- diseased brain’s potential forplastic response, might engender useful and timely interventions. This, however, will require substantial effort andadequate resources.
The present review offers some suggestions on how thatdevelopment might proceed.
Conflict of interest: None.
This article was published in the Journal of Prevention of Alzheimer's
DiseaseVolume 2, Number 1, 2015
http://www.jpreventionalzheimer.com/

REFERENCES
1. Panza F, Solfrizzi V, Frisardi V. Different models of frailty in pre-dementia and dementia syndromes. J Nutr Health Aging 2011;15:711-719.
2. Keleiditi, E, Cesari M, Canevelli M, et al. Cognitive frailty: Rationaland definition from an (I.A.N.A./I.A.G.G.) International Consensus Group. J Nutr Health Aging 2013; 9:726-734.
3. Robertson DA, Savva GM, Kenny RA. Frailty and cognitive impairment: A review of the evidence and causal mechanisms.» Aging
Res Rev 2013; 12:840- 51.
4. Avila-Funes JA, Amieva H, Barberger-Gateau P, et al. Cognitive impairment improves the predictive validity of the phenotype of frailty for adverse health outcomes: the three city study. J. AM Geriatr
Soc 2009;57:453-61.
5. Katzman R. Education and the prevalence of dementia and
Alzheimer’s disease. Neurology 1993; 43:13-20.
6. Satz P. Brain reserve capacity on symptom onset after brain injury.
Neuropsychology 1993; 7:273-295.
7. Stern, Y, Habek C, Moeller J, et al. Brain networks associated withcognitive reserve in healthy young and old adults. Cereb Cortex
2005; 15:394-402.
8. Stern Y, Moeller J, Anderson K, et al. Different brain networks mediate task performance in normal aging and AD: Defining compensation. Neurology 2000; 55:1291-97.

9. Valenzuela MJ, Sachdev P. Brain reserve and dementia: A systematic review. Psychological Medicine 2005; 35:1-14.
10. Cabeza R, Anderson ND, Locantore JK, et al. Aging gracefully:
Compensatory brain activity in high-performing older adults. Neuroimage 2002; 17;(3):1394-1402.
11. Grady CL, Maisog, JM, Horwitz B. Age-related changes in cortical
blood flow activation during visual processing of faces and location. J Neurosci 1994;14:1450-1462.
12. Fernandes MA, Pacurar A, Moscovitch M. Neural correlates of auditory recognition under full and divided attention in young andold adults. Neuropsychologia 2006; 44:2452-64.
13. Reuter-Lorenz PA and Cappell KA. Neurocognitive aging and thecompensation hypothesis. Current Directions in Psychological
Science 2008; 17:177-82.
14. Small SA, Tsai, WY, DeLaPaz R, et al. Imaging hippocampal function across the human life span: Is memory decline normal or not?
Ann Neurol 2002; 51:290-295.
15. Woods AJ, Cohen M, Pahor M. Commentary, Cognitive Frailty:
Frontiers and Challenges. J Nutr. Health Aging, 2013; 17; 9:741-3.
16. Buchman AS, Bennett DA. Commentary, Cognitive Frailty. J Nutr
Health Aging, 2013; 17;9:738-9.
17. Dartigues JF, Amieva H. Letter to the Editor, Cognitive Frailty:
Rational and definition from an (I.A.N.A./I.A.G.G.) international
consensus group. J Nutr Health Aging 2014; 18;1:95.

69

WHITE BOOKFRAILTY AND PAIN:TWO RELATED CONDITIONS
H. NESSIGHAOUI1,2, M. LILAMAND3, K.V. PATEL4, B. VELLAS5,6,
M.L. LAROCHE2,7, T. DANTOINE1,2, M. CESARI5,6

1 Geriatric Medicine Department, Centre Hospitalier Universitaire, Limoges, France;
2 Handicap Activité, Vieillissement, Autonomie, Environnement (HAVAE), Université de Limoges, Limoges, France;
3 Geriatric Medicine Department, Centre Hospitalier de Bichat-Claude Bernard (AP-HP), Paris, France;
4 Center of Pain Research on Impact, Measurement and Effectiveness, Department of Anesthesiology and Pain Medicine, University of Washigton, Seattle, WA, USA;
5 Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France;
6 Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France;
7 Service de pharmacologie, toxicologie et pharmacovigilance, centre Hospitalier Universitaire, Limoges, France
Correspondence: Hichem Nessighaoui, MD. Geriatric Medicine, Centre Hospitalier Universitaire de Limoges,
2 avenue Martin Luther King, 87042 Limoges, France. Tel: +33 (0)5 55 05 65 63.
Email: hnessighaoui@gmail.com

Abstract: Frailty is a multidimensional syndrome, involving
functional, nutritional, biological and psychological aspects.
This condition, defined as a decreased resistance to internal and external stressors, is predictive of adverse healthoutcomes, including disability and mortality. Importantly,
the frailty syndrome is usually considered a reversible condition, thus amenable of specific preventive interventions.
Persistent pain in older adults is very common and has multiple determinants. This symptom represents a determinantof accelerated aging. In the present paper, we discuss available evidence examining the association between these two

conditions. Despite the high prevalence of these two conditions and their shared underlying mechanisms, our search
only retrieved few relevant studies. Most of them reported
a relationship between pain (or analgesics consumption)and different operational definitions of frailty. Pain may
represent a relevant risk factor as well as a potential target
for interventions against the frailty syndrome, but further
studies are needed.

INTRODUCTION

nants of frailty is of major interest for improving its early
detection and structuring a proper management (4). In thisperspective, poor outcomes such as disability (which is often irreversible at old age) may be delayed or avoided.
Pain is a very common symptom in older persons (2, 5), witha substantial impact on health status, functional prognosis,
and extra costs for public health administrations (3, 6-8).
Persistent pain may be related to and determine the acceleration of the aging process. In other words, it might indeed represent the primum movens of the natural historyof frailty. Assuming that pain is a risk factor of frailty, thisKey words: Frailty, pain, elderly, preventive medicine, comorbidity.

Improving the burden of disability and the quality of lifeof elders is a key challenge in our aging societies. Frailty isan age-related multidimensional syndrome associated withpoor health outcomes such as institutionalization and mortality (1). For some older adults, frailty represents a pre-disability phase potentially amenable for targeted intervention
so as to delay the onset or prevent functional decline. Furthermore, frailty is a dynamic and time-related syndrome(2, 3). Thus, assessing the natural history and the determi70

FRAILTY AND PAIN: TWO RELATED CONDITIONS

symptom would represent a primary target for interventions aimed at reversing the frailty condition.
In the present review, we provided a brief presentation of
the frailty syndrome, followed by an overview of the theoretical relationship between frailty and pain, to end with
future perspectives in the field.

mechanisms. Yet, several aspects of the heterogeneous andcomplex frailty syndrome are still imperfectly understood,
limiting its implementation in clinical practice. Further, theimportance of the comprehensive geriatric assessment for
describing the risk profile of the individual is well established and crucial for preventing the onset of disability(1, 11-15). In fact, personalized interventions (primarily
aimed at correcting nutritional, physical and/or medical issues) have been indicated as potentially capable of restoringrobustness in frail elders (15). Interestingly, the frailty issue
has gone well beyond the geriatrics boundaries, and several
other medical specialties are today interested on this topic.
Nevertheless, despite its crucial importance, early detectionof frailty remains particularly challenging. Several instruments have been designed and validated to translate thetheory of frailty into clinical practice. To date, the Frailty Phenotype (1) and the Frailty Index (13) are probably
the most known and widely used. The Frailty Phenotype
was proposed by Fried and colleagues and validated in
the Cardiovascular Health Study. It consists of 5 criteria

FRAILTY

The frailty syndrome, as a theoretical concept, is well established in the literature and universally accepted by researchers and clinicians (9). One of the most common definitionsof frailty describes it as a state of enhanced vulnerability
with insufficient homeostatic reserves to efficiently cope
against stressors (10). Most notably, frailty is a multidimensional syndrome that paves the way for adverse healthoutcomes, such as mortality and disability (1). The frailty
syndrome may be delineated as a functional and biologicalpattern of decline accumulating across various physiological systems, because of impaired regulations and repairing
Table 1

DesignStudies exploring the relationship between frailty and pain
Study

Pain assessment

Frailtyassessment

Settingn

Main objective

Main results

Koponen et al.
(26)

CS

Musculoskeletal pain
severity

Frailty phenotype

Community

605

Analgesic useFrailty

Frail subjects used moreanalgesics

Shega et al.
(34)

CS

Pain severity, pain
duration

Frailty index

Community

4,694

Pain severityMortality

No significant
relationship between
frailty and pain

Shega et al.
(27)

CS

Persistent body pain,
pain severity

Frailty index

Community

4,968

Persistent painFrailty

More severe pain in prefrail and frail subjects

Miguel et al.
(28)

CS

No direct pain
assessment; diagnosisof osteoarthritis

Frailty phenotype

Community

58

Analgesic useFrailty

Frail elders use moreanalgesics

Chang et al.
(29)

CS

History of pain

Frailty phenotype
Edmonton Frail Scale

Community

275

Pain-Frailty

Pain more frequent infrail subjects

Lin et al. (30)

CS

SF-36

Frailty phenotype

Community

933

Disabilities-Frailty More disabling
conditions (includingpain) in frail elders

Saxton et al.
(31)

CS

SF-36

Frailty index

Surgicalpatients

226

Post-surgery
complicationsFrailty

Inverse relationshipbetween pain andpostsurgical complications

Chen et al. (35)CS

Analgesic use

Frailty phenotype

Community

2,238

Analgesic useFrailty

Higher use of analgesics
in frail subjects

Weauver et al.
(32)

CS

SF-36, pain duration,
pain severity

Frailty index

Community

744

Pain-Frailty

More severe pain in frail
eldersBlyth et al. (33)CS

SF-12, pain severity,
analgesic use

Frailty phenotype

Community

1,705

Pain-Frailty

More severe pain in frail
subjects

Misra et al. (36)CS

Symptomatic knee
osteoarthritis

SOF scaleCommunity

3,707

Knee osteoarthritisFrailty

More osteoarthritis
symptoms in frail subjects

Wise et al. (37)CS

No direct pain assessment; Frailty phenotype
radiographic evaluation of
osteoarthritis

Community

4,130

OsteoarthritisFrailty

More severe osteoarthritis in frail subjects

CS: cross-sectional study; SF-36, SF-12: Health Related Quality of Life Short Form scale (36 or 12 items, respectively); SOF: Study of Osteoporotic
Fracture index.

71

WHITE BOOK

measuring the risk-profile of the older subject. Differently, the Frailty Index proposed by Rockwood and colleagues estimates the age-related accumulation of deficits
through the arithmetical evaluation of signs, symptoms,
clinical conditions, and disabilities. These two instruments should not be considered as equivalent but rather
as complementary in the clinical geriatric assessment (9).
From these two main instruments, some additional tools
have been elaborated over the last decade. For example, theStudy of Osteoporotic Fractures (SOF) index (16) has simplified the frailty phenotype, reducing the key criteria fromfive to three. Additionally, the Groningen Frailty Indicator(GFI) (17) is a validated, 15-item questionnaire that with its
multidimensional (i.e. physical, cognitive, social, and psychological) assessment of the older person may resemble
the Frailty Index approach.
Xue and colleagues have highlighted the role of precursor signs of frailty (4). Treating these symptoms is surely apromising catalyst for breaking the vicious circle of frailty
and preventing adverse health outcomes like disability. The
evaluation and management of persistent pain have been
given a growing interest among clinicians and researchers
dealing with age-related conditions. However, although pain
may represent a potential cause of frailty, it still remains anunderstudied and undertreated symptom, especially at oldage. Instead, it indeed is a key symptom negatively affecting
quality of life and potentially triggering the disabling cascade of frail elders.

pain (regardless of the etiological factors) has a systemic
impact, also with cognitive, cardiovascular or behaviouralconsequences (22).
The multidimensional consequences of pain may actually
overlap the consequences of the frailty status triggered bypain. For example, pain is closely associated with each of
the the five frailty criteria included by Fried and colleagues
in the Frailty Phenotype. Persistent pain may result in incapacitating exhaustion (23) and decreased physical activity(24, 25). Patel et al. (8) recently showed that pain is associated with decreased physical performance (i.e., handgrip
strength and usual gait speed) in a nationally representative
study of older adults in the United States. Furthermore,
pain-induced anorexia and loss of appetite is common inolder persons. Furthermore, cognitive, behavioural and social limitations caused by the pain symptom should not be
underestimated as frequently acknowledged in the operationalization of the frailty condition.
FRAILTY AND PAIN: CURRENT EVIDENCE
AND FUTURE PERSPECTIVES

Although the relationship between frailty and pain is supported by credible shared mechanisms, evidence in the field
is still sparse and scarce. In order to provide an overview ofsuch still partially explored field (i.e., relationship between
frailty and pain), we conducted a Medline search, using the
keywords “frailty” and “pain” from 1989 to 2014 (last update: 21/10/2014). In Figure 1, the flow chart describing
the selection of studies of interest is presented.
One hundred and twenty studies were retrieved. Of thesearticles, thirteen were excluded because out of the topic(e.g., dealing with pain in children, dental health, chronic
kidney disease, general biology, chemotherapy in prostateand breast cancer). Among the 107 remaining papers, 35
review articles were then excluded. Then, three non-English language papers, one with no available abstract, three
qualitative articles, 55 papers did not take into consideration the frailty status, and one paper that only marginallyexplored frailty and joint pain were also excluded. Finally,
9 cross-sectional studies were retained (Table 1) (26-34).
Other three studies were subsequently obtained after
searching through the references of the selected articles(35-37).

PAIN

Chronic pain has been estimated to affect 100 million people in the United States (18), and is particularly prevalent in
the older adults. A recent study (8) estimated that over halfof community-dwelling older adults in the United States(18.7 million) reported bothersome pain in the last month.
Moreover, pain has been reported as one of the most common symptoms among frail older persons (1, 19), especially in specific settings like nursing homes where estimatedprevalence may be even higher than 70% (5). The increased
prevalence of age- related degenerative diseases may at least
partially explain such alarming figures. For example, the increased incidence of specific conditions such as diabetes,
herpes zoster and lumbar radiculalgia with aging can beassociated with higher rates of neuropathic pain (due toboth central or peripheral nerve injuries). Unlike nociceptive pain, neuropathic pain may be triggered by non-painfulstimuli (i.e., allodynia). The medical management of these
symptoms is often poor and the quality of life of elders
with neuropathic pain has shown to be significantly impaired (20). For these reasons, neuropathic pain often results in anxiety, mood and sleep disorders (21). Persistent72

H. NESSIGHAOUI1,2, M. LILAMAND3, K.V. PATEL4, B. VELLAS5,6, M.L. LAROCHE2,7, T.
DANTOINE1,2, M. CESARI5,6
1. Geriatric Medicine Department, Centre Hospitalier Universitaire, Limoges, France; 2. Handicap Activité, Vieillissement, Autonomie, Environnement(HAVAE), Université de Limoges, Limoges, France; 3. Geriatric Medicine Department, Centre Hospitalier de Bichat-Claude Bernard (AP-HP), Paris, France; 4.
Center of Pain Research on Impact, Measurement and Effectiveness, Department of Anesthesiology and Pain Medicine, University of Washigton, Seattle, WA,
USA; 5. Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France; 6. Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France; 7.
Service de pharmacologie, toxicologie et pharmacovigilance, centre Hospitalier Universitaire, Limoges, France
Corresponding author: Hichem Nessighaoui, MD. Geriatric Medicine, Centre Hospitalier Universitaire de Limoges, 2 avenue Martin Luther King, 87042
Limoges, France. Tel: +33 (0)5 55 05 65 63, Email: hnessighaoui@gmail.com

FRAILTY AND PAIN: TWO RELATED CONDITIONS


Figure 1   elders were found to more likely present history of pain
than robust elders (p=0.03 using the Frailty Phenotype and
p=0.006 according to the Edmonton Frail Scale) (39).
In 933 Taiwanese community-dwelling elders, Lin et al. (30)
found very similar results. The prevalence of pain assessedwith the Health Related Quality of Life short form-36
questionnaire (http://www.sf-36.org/demos/SF-36.html)
was 47.7%, 56.6%, and 70.8% in robust, pre-frail, and frail
elders, respectively (p<0.001).
Among Mexican Americans aged 65 years and older, Weaver et al. (32). studied the relationship between self- reported
pain interference and severity with the Frailty Index. Again,
frailty was associated with both pain interference (p<0.01)
and severity (p<0.001).
Two other cross-sectional studies that examined the crosssectional association between frailty and analgesic intake
were also retained from our search (26, 35). Both indirectlysuggested a relationship between frailty and pain, considering that frail elders tend to present a higher consumptionof analgesic medications. Koponen et al. (26) reported ahigher prevalence of analgesic drugs prescription in frail individuals (OR 2.96; 95%CI 1.38-6.36, p<0.001), among 605
community-dwelling elderly subjects (aged 75 years and older). It is noteworthy that in this population, musculoskeletal
pain was found to be the most common complaint in frail
people and acetaminophen the most prescribed drug. Chenet al. (35) reported a statistically significant higher preva
lence of pain in frail (87.9%) vs. prefrail (65.2%) or robust(40.7%) community dwelling subjects (n=1,085). They also
highlighted greater analgesics consumption in frail elders,distinguishing analgesics for osteoarthritis from other pain
drugs (p<0.001 for both).
Miguel et al. (28) conducted a cross sectional study of 58 elderly subjects with osteoarthritis. Higher drug consumption
was found in frail elders (compared with robust subjects),
but no information was available regarding the used analgesics. However, pain and stiffness were not significantly
overrepresented in frail or prefrail elders.
Saxton and Velanovitch (31) investigated the role of preoperative frailty (assessed with the Frailty Index) on postoperative complications after general surgery interventions,in 226 older adults. Frailty was associated with a higher riskof complications (OR 1.48, 95%CI 1.10-1.99; p=0.02). No
difference in body pain was reported in frail patients according to the onset of postoperative complications.

        

Flow chart describing the selection process of the articles of interest.

Five cross-sectional studies specifically examined the relationship between frailty and pain. Blyth et al. in the Concord
Health and Ageing in Men Project (CHAMP) study (33)
investigated the association between intrusive pain andfrailty in 1,705 community-dwelling Australian older men(mean age 77 years). Frailty was defined according to the
Frailty Phenotype criteria. Intrusive pain was assessed using
one item from the SF-12 quality of life questionnaire (38).
Frailty status was significantly and incrementally associatedwith reporting intrusive pain, with unadjusted odds ratios(OR) for pain of 3.9 (95% Confidence Interval [95%CI]
2.7-5.6; p<0.0001) in frail men, compared to robust men.
The results were consistent even after adjusting for multiple
potential confounders including depression.
Shega et al. (27) explored the association between pain andfrailty in the Canadian Study of Health and Aging. Frailty
was defined according to a modified version of the Frailty Index (33 self-reported items). Pain was evaluated using five questions. Among 4,968 participants (mean age 80
years) self-reported “moderate or severe” pain was significantly associated with a higher frailty score than “no or verymild” pain.
Chang et al. (29) reported a cross-sectional association between frailty and history pain in a sample of 275 community- dwelling residents in Taiwan (65 years and older). Frail

CONCLUSIONSTo date, only twelve cross-sectional studies have more orless directly examined the relationship between frailty andpain. Overall, the results of our search support the existenceof a cross-sectional relationship between these two conditions. Growing evidence has highlighted the importance of73

WHITE BOOK

early detection of frailty with appropriate screening tools
in many clinical specialties. On the other hand, persistent
pain, especially in older adults, has to be considered as amultidimensional condition with systemic consequences.
Pain and frailty might share common mechanisms and appear to be associated in various populations of elders.
The importance of pain assessment in elders is still underappreciated. We do not know whether a better managementof persistent pain in elders might impact the course of frailty syndrome. It is also unclear whether the improvementof frailty may also provide positive effects on pain. Further

research is surely needed in such promising field for better understanding the inner foundations of the relationshipbetween pain and frailty in the elderly. Results from suchinitiatives may indeed pave the way of future interventions
against age-related and disabling conditions.
Conflict of interest: The authors declare no conflict of interest
This article was published in the Journal of Frailty and Aging
Volume 4, Number 3, 2015
http://www.jfrailtyaging.com/

REFERENCES
1. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults,
evidence for a phenotype. J Gerontol A Biol Sci Med Sci
2001;56(3):M146-56.
2. Gill TM, Gahbauer EA, Han L, et al. Trajectories of disability in thelast year of life. New Engl J Med 2010;362:1173–1180.
3. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targetingand care. J Gerontol A Biol Sci Med Sci 2004;59:255–263.
4. Xue QL. The Frailty Syndrome: Definition and Natural History. Clin
Geriatr Med 2011;27(1):1–15.
5. Abdulla A, Adams N, Bone M, et.al, Guidance on the managementof pain in older people. Age Ageing 2013;42 Suppl 1:i1-57.
6. Thomas E, Mottram S, Peat G, et al. The effect of age on the onsetof pain interference in a general population of the older adults:
prospective findings from the North Staffordshire Osteoarthritis
Project (NorstOP). Pain 2007;129:21-7.
7. Cavalieri TA. Pain management in the elderly. J Am Osteopath Assoc 2002;102(9):481-485.
8. Patel KV, Guralnik JM, Dansie EJ, Turk DC. Prevalence and impact of pain among older adults in the United States: findings
from the 2011 National Health and Aging Trends Study. Pain
2013;154(12):2649-57.
9. Cesari M, Gambassi G, Abellan van Kan G, Vellas B. The frailty
phenotype and the frailty index: different instruments for different
purposes. Age Ageing 2013;43(1):10-2.
10. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381(9868):752-62.
11. Hubbard RE, Fallah N Searle SD, Mitniski A, Rockwood K. Impact of exercise in community-dwelling older adults. PloS One
2009;4(7):e6174.
12. Strawbridge WJ, Shema SJ, Balfour JL, Higby HR, Kaplan GA. Antecedents of frailty over three decades in an older cohort. J Gerontol
B Psychol Sci Soc Sci 1998;53:9–16.
13. Rockwood K, Fox RA, Stolee P, Robertson D, Beattie BL. Frailty inelderly people: an evolving concept. CMAJ 1994;150:489–495.
14. Jones D, Song X, Mitnitski A, Rockwood K. Evaluation of a frailty
index based on a comprehensive geriatric assessment in a population based study of elderly Canadians. Aging Clin Exp Res 2005;17:465–471.
15. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as
a proxy measure of aging. ScientificWorldJournal 2001;1:323–336.
16. Kiely DK, Cupples LA, Lipsitz LA, Validation and comparison of
two frailty indexes: the mobilize Boston study. J Am Geriatr Soc
2009;57:1532–1539.

17. Schuurmans H, Steverink N, Lindenberg S, Frieswijk N, Slaets JP.
Old or frail: what tells us more? J Gerontol A Biol Sci Med Sci
2004;59:962–965.
18. Institute of Medicine. Relieving pain in America: a blueprint fortransforming prevention, care, education, and research. Washington, DC: The National Academies Press, 2011.
19. Rastogi R, Meek BD. Management of chronic pain in elderly, frail
patients: finding a suitable, personalized method of control. Clin
Interv Aging 2013;8:37.
20. O’Connor AB. Neuropathic pain: quality-of-life impact, costs and costeffectiveness of therapy. Pharmacoeconomics 2009;27(2):95-112.
21. Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B.
Pain severity in diabetic peripheral neuropathy is associated withpatient functioning, symptom levels of anxiety and depression,and sleep. J Pain Symptom Manage 2005;30(4):374-85.
22. Fine PG. Long-term consequences of chronic pain: mounting evidence for pain as a neurological disease and parallels with otherchronic disease states. Pain Med 2011;12(7):996-1004.
23. Whitson HE, Thielke SM, Diehr P, et al. Patterns and predictorsof recovery from exhaustion in older adults: the cardiovascular
health study. J Am Geriatr Soc 2011; 59(2): 207–213.
24. Patel KV, Dansie EJ, Turk DC. Impact of chronic musculoskeletal
pain on objectively measured daily physical activity: a review ofcurrent findings. Pain Manag 2013;3(6):467-74.
25. Dansie EJ, Turk DC, Martin KR, Van Domelen DR, Patel KV. Association of Chronic Widespread Pain with Objectively Measured
Physical Activity in Adults: Findings from the National Health andNutrition Examination Survey. J Pain. 2014;15(5):507-15.
26. Koponen MP, Bell JS, Karttunen NM, et.al. Analgesic Use andFrailty among Community-Dwelling Older People. Drugs Aging.
2013;30:129– 136.
27. Shega JW, Dale W, Andrew M, Paice J, Rockwood K, Weiner DK.
Persistent pain and frailty: a case for homeostenosis. J Am Geriatr
Soc 2012;60(1):113-7.
28. Miguel Rde C, Dias RC, Dias JM, da Silva SL, Menicucci Filho PR,
Ribeiro TM. Frailty syndrome in the community-dwelling elderlywith osteoarthritis. Rev Bras Reumatol 2012;52(3):331-347.
29. Chang CI, Chan DC, Kuo KN, Hsiung CA, Chen CY. Prevalence andCorrelates of Geriatric Frailty in a Northern Taiwan Community. J
Formos Med Assoc 2011;110(4):247–257.
30. Lin CC1, Li CI, Chang CK, et al. Reduced Health-Related Quality ofLife in Elders with Frailty: A Cross-Sectional Study of Community-Dwelling Elders in Taiwan. PLoS One 2011;6(7):e21841.
31. Saxton A, Velanovich V. Preoperative Frailty and Quality ofLife as Predictors of Postoperative Complications. Ann Surg
2011;253:1223–1229.

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32. Weaver GD, Kuo YF, Raji MA, et.al. Pain and disability in older
Mexican-American adults. J Am Geriatr Soc 2009;57(6):992-9.
33. Blyth FM, Rochat S, Cumming RG, et al. Pain, frailty and comorbidity on older men: the CHAMP study. Pain 2008;140(1):224-30.
34. Shega JW, Andrew M, Kotwal A, et al. Relationship between persistent pain and 5-year mortality: a population-based prospective
cohort study. J Am Geriatr Soc 2013;61(12):2135-41.
35. Chen CY, Wu SC, Chen LJ, et al. The prevalence of subjective frailty
and factors associated with frailty in Taiwan. Arch Gerontol Geriatr
2010;50(Suppl. 1):S43–7.

36. Misra D, Felson DT, Silliman RA, et al. Knee osteoarthritis andfrailty: findings from the multicenter osteoarthritis study and osteoarthritis initiative. J Gerontol A Biol Sci Med Sci 2014;10:1093;102.
37. Wise BL, Parimi N, Zhang Y, et al. Frailty and hip osteoarthritis in men in the MrOS cohort. J Gerontol A Biol Sci Med Sci
2014;69(5):602-8.
38. Ware JE, Kosinski M, Keller SD. A 12-items short-form health survey: construction of scales and preliminary tests of reliability andvalidity. Med Care 1996;34:220-33.
39. Rolfson DB1, Majumdar SR, Tsuyuki RT, Tahir A, Rockwood K.
Validity and reliability of the Edmonton Frail Scale. Age Ageing
2006;35(5):526-9.

75

WHITE BOOKUSE OF BIOMARKERS
L. RODRÍGUEZ-MAÑAS

Getafe University Hospital, Spain.
Correspondence: Prof. Leocadio Rodríguez Mañas, Jefe de Servicio de Geriatría, Hospital Universitario de Getafe,
Ctra. de Toledo, Km. 12,5, 28905-Getafe, Spain, Phone: 00 34 916839360 (ext. 6412), Fax: 00 34 916839210,
e-mail: leocadio.rodriguez@salud.madrid.org

Abstract: Expanding the concept of frailty to the clinical settings has raised the concern about the accuracy ofthe current definitions for identifying frail individuals (notpopulations). The usual tools to assess frailty show, among
other characteristics, a low sensitivity and a low Positive
Predictive Value. One approach to overcome this challenge
is using biological biomarkers to improve those characteristics, making feasible and accurate the assessment of frailty
in clinical settings. Many biomarkers of frailty have been
identified but few of them have been assessed as clinicalmarkers with controversial results. Taking into accountthat frailty is caused by the failure in different systems, itis worthy to check if the combination of several of thesebiomarkers could be of help. In this effort, the EU-funded
project FRAILOMIC is trying to assess the ability of different sets of biomarkers for improving the accuracy ofclassical definitions in determining the risk, the diagnosis
and the prognosis of frailty.
Key words: Frailty, aging, elderly, screening, assessment.

T

he traditional way of assessing frailty has been
based until now in using several instruments thatmeasure performance- based tasks jointly to theassessment of indicators of nutrition and physical activity.
This approach has been rather successful in the epidemiological settings, allowing the demonstration of frailty as animportant population-based risk factor for several adverse
outcomes. But it looks insufficient in clinical settings, where
the individual risk is the matter and where the characteristicsof the instruments as diagnostic tools must be refined (1).
From a clinical point of view, to detect frailty is of outstanding importance in preventing disability. When thefrailty threshold has been surpassed and the disability has
emerged, recovery from disability is unlikely (2), especiallyas the age of the patient, the degree of disability or its duration increase (3). Although the usual spontaneous evolution
is to progress from non-frail to frail and disabled, a significant percentage of people improves in terms of functional
status (4), with no clearly identified predictive factors of
this evolution. However, some results from the Women´s
Health and Aging Study II (WHAS II) suggest that some

ill-defined characteristics could predict a differential risk (5).
But to make accurate diagnosis of frailty is not only an issue
of interest for risk prediction purposes, targeting those patients who will benefit from a specific approach comparedto others who are not going to benefit from it, becoming
frailty one of the cornerstones of decision-making in elderly patients. To know which patients will respond to thedifferent treatments now available, mainly exercise and nutrition (6-8), is also of interest. Mainly when it looks that
we are now in the border of an era where multimodal andpharmacological interventions targeting frailty will be available (9, 10).
Although it is well known that the evolution from frailty todisability and its clinical consequences depends on several
factors, including genetic and other biological factors, theirutility as biological biomarkers (BMs) of frailty and of therisk to become frail, to develop disability and to respondto treatment, remains far from desirable for the day to day
clinical practice. In fact, there are no studies addressingthese issues.
76

USE OF BIOMARKERS

allowing a comprehensive approach from the genome tothe metabolome (Fig. 1).

BIOLOGICAL BIOMARKERS OF FRAILTY

The most accepted physiological framework to explain
frailty and its consequences was proposed by Walston andFried (1999). Its fundamentals are sarcopenia and the energetic misbalance. They also established a feed-back between
them: the so-called “frailty cycle”. This cycle stems fromthe physiological changes associated with ageing, producing
an imbalance between anabolism and catabolism. This stateembraces multiple systems and especially those related tohormonal changes and the development of a pro-inflammatory state: the changes in sexual hormones (low testosterone in males but also high estradiol in women), thedysfunction of GH-IGF-1 axis, the increase in the ratio
cortisol/DHEA-s, the combination of several hormonal
deficits, and the increase in IL-6, IL-1 and TNF alpha circulating levels (Penninx et al., 2004), CRP and D-Dimer (Walston et al., 2002) and pro- inflammatory cytokines (Leng etal., 2002). These findings suggest that changes associatedwith sarcopenia and with the balance between production
and use of energy may be among the most relevant factors
associated with frailty: dysregulation of inflammatory cytokines and hormones, oxidative stress, nutrition, physicalinactivity and mithochondrial dysfunction. In addition, therole of vascular disease (atherosclerosis) has been underscored by several authors (Strandberg & Pitkäla, 2007). The
presence of clinical cardiovascular disease, but also subclinical cardiovascular disease has been shown to be associatedto frailty. The possibility of detecting early biomarkers ofvascular (endothelial) dysfunction rises as an important clue
to the detection of early stages of frailty as to an improved
diagnoses and/or prognostic capacity.
In addition to these classical BMs, more recently other BMs
have come to the field of frailty. As an example, the rolefor Hypoxia Inducible Factors proteins-HIF (and mainly α
subunits of HIF) and their signaling pathway has emerged
as a main control of key pathways that are essential for cell
physiology, in a variety of processes related with humanageing. The relevance of HIFα resides in the pivotal role
played by their target genes in several of the above mentioned physiological systems involved in frailty: the cell metabolism and energy balance (e.g., NOS2, PHD3, GLUT1,
GLUT4, GAPDH, PGK1, trasferrin, etc.), angiogenesis
and cell proliferation (e.g., VEGF, TGFα, TGFβ3, IGF2,
OCT3/4), the length of the telomere (hTERT), etc. At
the same time HIF-1α has been identified as an important
modifier of longevity in animal models (11). In addition
other potential BMs have also raised as it is the case of
a common signature of miRNA expression in 7 different
human aging model systems (12) or the telomere length.
Within this complex framework, the “omic sciences” represent a significant aid to the study of potential BMs by

Figure 1
The “omic” sciences

In summary, early detection of subclinical changes or deficits at the molecular, cellular, and or physiologic level is key
to preventing or delaying the development of frailty, andits consequences too. However, data evaluating the role ofthese substances in providing significant support to theclinical diagnosis of frailty or any of its associated risks are
scarce.
THE FRAILOMIC INITIATIVE

It is noteworthy that one of the main characteristics offrailty is that its pathophysiological routes embrace several physiological systems (13). However, until now the approach to the study of the relationships between BMs andfrailty has been done one by one, ignoring the multiplicity of relationships that probably account for the role ofBMs in determining frailty. In addition, the usual tools todiagnose frailty used in the epidemiological studies show
some characteristics (including a low sensitivity and a low
positive predictive value) (14) that do not allow to use themfor clinical purposes. These are some of the gaps that the
recently launched Frailomic Initiative will try to fill (15).
The principal aim of the Frailomic Initiative is to develop
validated sets of measures comprising both classical andomics-based laboratory biomarkers (Table 1) to predict therisk of frailty, improve the diagnostic accuracy of frailty
in day-to-day clinical practice, and assess the benefits of aprognostic forecast of frailty on the onset of disability andother adverse outcomes. In order to identify predictive biomarkers, the European Union-funded Frailomic Initiative
follows an “omics” approach (genomics, transcriptomics,
proteomics and metabolomics), using existing large datasets from previous “omics” initiatives. These studies have77

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created a wealth of data that, so far, have not been usedin the field of frailty research until now. In addition, theparticipation of well-established cohorts aimed to the studyof the processes of aging, frailty and disability will allow atight assessment, due to the excellent phenotyping of thefunctional characteristics of those populations.
The approach taken by the Frailomic Initiative will allow
clinicians to go beyond the traditional disease-based approach to healthcare strategy and toward a strategy basedon comprehensive quality-of-life, since the impact will beon reducing disability. Secondary objectives of the Frailomic Initiative include assessing interactions among putative
biomarkers, nutrition, exercise and their effects on the natural history of frailty. In addition, the potential therapeutic
usefulness of identifying frailty status in special older populations such as those with metabolic syndrome, diabetes

and cardiovascular disease will be examined. The Frailomic
Initiative aims to provide useful tool kits for care providers
that will allow them to assess the risk of an older individual for developing frailty (i.e., “risk biomarkers”) as well its
identification (i.e., “diagnostic biomarkers”), clinical course(i.e., “prognostic biomarkers”), and likely response to treatment (i.e., “predictive biomarkers”) thus bridging the gaps
between epidemiology and clinical practice.
Conflict of interest: None
Acknowledgements: Supported by the Grant Nº 305483-2 ofthe 7th EU Health ProgramThis article was published in the Journal of Frailty and Aging
Volume 4, Number 3, 2015
http://www.jfrailtyaging.com/

Table 1
Non-classical Biomarkers of frailty assessed in the Frailomic Initiative
Biological process

Biomarker

Rationale for selection

Method of analysis

ACE

Association of genotype with muscle mass, response to muscle
power training and longevity

Openarray (SNP)ACTN3

Association of genotype with response to muscle power
training, muscle mass and risk of falling in older females

Openarray (SNP)

CNTF

Association of genotype and grip strength in older Caucasian
women
Association of genotype with muscle mass in elerly women

Openarray (SNP)

IL6

Implicated in muscle repair after exercise. Association between
genotype and human longevity

Openarray (SNP and mRNA)

mtDNA

Association between genotype and longevity in different
populations

Openarray (SNP)

VDR

Association of genotype with muscle strength and rate of falling Openarray (SNP)in the elderly

Metabolism / Muscle function

GDF8

Openarray (SNP)

AKT1

Reducing the activity of this pathway protects from ageingassociated pathologies and extends life-span in animal model
systems
Association of genotype with human longevity

Openarray (SNP and mRNA)

FOXOs

Association of genotype with human longevity

Openarray (SNP and mRNA)

Metabolism/ Insulin/IGF1
signaling pathway

mTOR

Openarray (SNP and mRNA)

Metabolism /Stress response
HIF1

Modulation of life-span in C. elegans

Openarray (mRNA); ELISA

PGC1αAssociation of genotype with diabetes, with age of onset ofneurodegenerative diseases and with longevity

Openarray (SNPs)

SIRT1

Over-expression delays ageing phenotypes and extends
life-span in model organisms; genotype associated with lipid
profiles in humans

Openarray (SNP and mRNA)

SOD2

Reduced expression associated with ageing phenotypes;
genotype associated with survival in very old women

Openarray (SNP and mRNA)

TP53

Increased expression is associated with ageing phenotypes inmice
Inactivation in Drosophila results in an ageing phenotype

Openarray (mRNA)

Response to stress

SESN2

78

Openarray (mRNA)USE OF BIOMARKERS

Biological process

Biomarker

Rationale for selection

Method of analysis

AGT

Association of genotype with hypertension

Openarray (SNP)NOS3

Association of genotype with disability in the elderly

Openarray (SNP)

AGEs

Increased in ageing, diabetes and cardiovascular diseases;
increased levels associated with reduced grip strength

ELISA

sRAGE

Decreased in diabetes; inverse association with atherosclerosis

ELISA

CCL11

Increased with ageing; elevated levels associated with decreased ELISA
cognitive function and lower grip strength

LGALS3

Association of genotype with cognitive function at old age

Openarray (SNP)

JAG1

Secreted by senescent endothelial cells

ELISA

VCAN

Secreted by senescent endothelial cells

ELISA

IGFBP6

Secreted by senescent endothelial cells

ELISA

Telomere

Association of telomere length with age-associated diseases
and life-span

HT-QFISH

miR-24,miR- 130,
miR-94miR-17,miR- 19b,
miR-20a,miR-106a
mir-31miR10a-5p,
miR-10b-5p,
miR-22-3p,
miR-133b,
miR-328-3p,
let-7g-5p

Longevity-associated miRNAs

miRNome profiling

Ageing and senescence associated miRNAs

miRNome profiling

Osteoporosis related circulating miRNAs

miRNome profiling

Cardiovascular homeostasis

Inflammation

Regulation of cell proliferation

Regulation of gene expression

REFERENCES
1. Rodriguez-Mañas L, Fried LP. Frailty in the clinical scenario. Lancet. 2014 Nov 6. pii: S0140-6736(14)61595-6. doi: 10.1016/S01406736(14)61595-6.
2. Ferrucci L1, Cavazzini C, Corsi A, et al. Biomarkers of frailty in older persons. J Endocrinol Invest. 2002;25(10 Suppl):10-5.
3. Fried LP, Guralnik JM. Disability in older adults: evidence regarding significance, etiology, and risk. J Am Geriatr Soc 1997; 45: 92100.
4. Xue QL, Walston JD, Fried LP, Beamer BA. Prediction of risk offalling, physical disability, and frailty by rate of decline in grip
strength: the women’s health and aging study. Arch Intern Med.
2011; 171: 1119-21.
5. Xue QL, Bandeen-Roche K, Varadhan R, Zhou J, Fried LP. Initial
manifestations of frailty criteria and the development of frailty
phenotype in the Women’s Health and Aging Study II. J Gerontol
A Biol Sci Med Sci. 2008; 63: 984-90.

6. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of structured
physical activity on prevention of major mobility disability in older
adults: the LIFE study randomized clinical trial. JAMA. 2014; 311:
2387-96.
7. Cesari M, Vellas B, Hsu FC, et al. A physical activity intervention totreat the frailty syndrome in older persons-results from the LIFE-P
study. J Gerontol A Biol Sci Med Sci. 2015 Feb;70(2):216-22.
8. Kelaiditi E1, van Kan GA, Cesari M. Frailty: role of nutrition andexercise. Curr Opin Clin Nutr Metab Care. 2014; 17: 32-9.
9. Rodríguez-Mañas L, Bayer AJ, Kelly M, et al. An evaluation of theeffectiveness of a multi-modal intervention in frail and pre-frail
older people with type 2 diabetes--the MID-Frail study: study protocol for a randomised controlled trial. Trials. 2014; 15: 34.
10. Vellas B, Pahor M, Manini T, et al. Designing pharmaceutical trials
for sarcopenia in frail older adults: EU/US Task Force recommendations. J Nutr Health Aging. 2013; 17: 612-8.

79

WHITE BOOK

11. Leiser SF, Begun A, Kaeberlein M. HIF-1 modulates longevity andhealthspan in a temperature-dependent manner. Aging Cell. 2011;
10: 318- 26
12. Hackl M, Brunner S, Fortschegger K, et al. miR-17, miR-19b, miR20a, and miR-106a are down-regulated in human aging. Aging
Cell. 2010; 9: 291-6
13. Fried LP, Xue QL, Cappola AR, et al. Nonlinear multisystem physiological dysregulation associated with frailty in older women: im-plications for etiology and treatment. J Gerontol A Biol Sci Med
Sci. 2009 Oct;64(10):1049-57.
14. Garcia-Garcia FJ, Carcaillon L, Fernandez-Tresguerres J, Alfaro A,
et al. A new operational definition of frailty: the Frailty Trait Scale. J
Am Med Dir Assoc 2014; 15: 371.e7-371.e13.
15. Lippi G, Jansen-Duerr P, Viña J, et al. Laboratory biomarkers andfrailty: presentation of the FRAILOMIC initiative. Clin Chem Lab
Med 2015 DOI 10.1515/cclm-2015-0147

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INTERVENTIONSAGAINST FRAILTY

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WHITE BOOKRAISING AWARENESS ON THE URGENT NEEDTO IMPLEMENT FRAILTY INTO
CLINICAL PRACTICE
THE ORLANDO FRAILTY CONFERENCE GROUP (see Appendix)

Correspondence: Bruno Vellas, MD, PhD, Service de Médecine Interne et Gérontologie Clinique, Gérontopôle,Centre Hospitalier Universitaire de Toulouse, 170 Avenue de Casselardit, 31059 Toulouse France, Phone: +33 (0)5 61776425,
Fax: +33 (0)5 61497109, email: vellas.b@chu-toulouse.fr

Abstract: Frailty has been linked to longer hospital stays
and increased mortality in hospitalized patients. Frailty was
found at the most common condition leading to death,followed by organ failure, cancer, other causes, advanced
dementia, and sudden death. Yet despite evidence linking
frailty to poor outcomes, frailty is not implemented clinically in most countries. Since many people are not identified
as frail, they frequently are treated inappropriately in healthcare settings. Participants in the international conferenceon frailty emphasized the importance of raising awarenessabout frailty among geriatricians, general practitioners, andother primary care providers in order to implement frailty
in clinical practice. The following recommendations wereagreed upon: 1. Prioritize the identification of frail older

persons in community settings, hospitals, and specialty clinics in order to ensure that people with frailty are treatedappropriately and have access to interventional studies;2. Build frailty clinics as a means of providing optimal management of frail elders; 3. Develop intervention programs
incorporating physical and cognitive exercise, social support, and nutrition for people in the earliest stages of frailty
in order to slow or reverse frailty; 4. Build stronger basic
and clinical research programs in order to better understand the underlying causes of frailty, identify therapeutictargets, and develop new treatment strategies.

INTRODUCTION

it may be possible to prevent disability and dependency bytargeting frail and pre-frail older adults with simple screening tools and effective and sustained interventions (3).

Key words: Frailty, prevention, primary care, public health,disability.

According to the United Nations, by 2050 there will be 2
billion people worldwide over the age of 60, more than
three times as many as in 2000 (1). While this reflects
improvements in the health of people worldwide and increased longevity, it also presents challenges for individuals,
families, and societies as the numbers of people with frailty,
chronic diseases and disabilities also increases (2).

Frailty has been recognized as an important condition by theInstitute of Medicine (IOM) (4) and the European Union(EU), although a consensus conference held in 2011 concluded that while frailty has a clear conceptual frameworkand is useful in clinical settings, there is no single operational definition of frailty that can satisfy all experts and more
research is needed (5). Thus, another consensus conference
was convened in October, 2012, in Orlando Florida. At thisconference, frailty experts met to develop a consensus statement along with delegates from the International Association of Geriatrics and Gerontology (IAGG), the Ameri-

Frailty has been conceptualized as a physiological syndromereflecting decreased reserve and resilience, which may leadto progressive functional decline, vulnerability to stressors,
and an elevated risk of adverse outcomes, including death.
It is a major cause of dependency, yet research suggests that82

RAISING AWARENESS ON THE URGENT NEED TO IMPLEMENT FRAILTY INTO CLINICAL PRACTICE

can Medical Directors Association (AMDA), the American
Federation of Aging Research (AFAR), European Union
Geriatric Medicine Society (EUGMS), International Academy of Nutrition and Aging (IANA), Society on Sarcopenia,
Cachexia, and Wasting Disorders (SSCWD), the EU, and the
Gateway Geriatric Education Center (GEC) (6).

status, and the likelihood of transitioning from being frail
to non-frail was very low, about 10% of prefrail subjects
transitioned to non-frail during each 18 month follow-up
period (13). Frailty is not synonymous with disability, although frailty is a strong predictor of disability. Both conditions are characterized by functional impairment, however,many disabled people are not frail and the underlying biology of frailty distinguishes it from disability (14). Nor isfrailty synonymous with sarcopenia, although sarcopenia isclearly a major contributing factor to frailty (15).

Strong evidence supports the definition of frailty as a syndrome with a distinct etiology and consisting of a constellation of signs and symptoms that increase vulnerability tostressors and that, taken together, are better at predicting
an adverse outcome than any individual characteristic. Friedand colleagues have proposed that the signs and symptoms
of frailty result from dysregulated energetics involving multiple molecular and physiological pathways, which lead tosarcopenia, inflammation, decreased heart rate variability,
altered clotting processes, altered insulin resistance, anemia,
altered hormone levels, and micronutrient deficiencies (7).
These physiological impairments result in the five clinicalcharacteristics of frailty: weakness, low energy, slow walking speed, low physical activity, and weight loss (8). The
presence of any three of these phenotypes indicates thata person is “frail”; one or two phenotypes indicates “prefrail”; and none of these characteristics indicates the person is “robust”. Fried and colleagues went on to validate
this concept in two large datasets from the Cardiovascular
Health Study (CHS) (8) and the Women’s Health and Aging Studies (WHAS) (9). In both data sets, among women
between the ages of 70 and 79, the prevalence of frailty
was approximately 11% and the presence of frailty was associated with an increased risk of mortality as well as witha dose-dependent (based on the number of frailty criteria)
increased risk of developing dependence in activities ofdaily living (10).
While the Fried and colleagues’ quantifies frailty using fivemeasures, Rockwood and colleagues have developed a frailty index (FI) based on the Comprehensive Geriatric Assessment (CGA), which counts up to 70 items. The FI-CGA
thus characterizes frailty across multiple dimensions by including measures of mood, cognition, and social vulnerability (11). In a study of community-dwelling older adults
in Canada, the FI- CGA estimated a frailty prevalence of
22.7%, with higher scores predicting an increased risk ofdeath (12).

Frailty has been linked to longer hospital stays and increased mortality in hospitalized patients (16). Moreover, in
their study of disability trajectories of community-dwellingolder persons during the last year of life, Gill and colleagues
found that frailty was the most common condition leading
to death, followed by organ failure, cancer, other causes,
advanced dementia, and sudden death (17). Yet despite evidence linking frailty to poor outcomes, frailty is not implemented clinically in most countries. Since many people are
not identified as frail, they frequently are treated inappropriately in health care settings. For example, regardless ofage, a frail person may be unable to withstand aggressive
medical treatment that could benefit a non-frail person.
IMPLEMENTING FRAILTY INTO CLINICAL PRACTICE

The identification of frailty in its early stages, i.e., the “prefrail” stage, is important because of the potential to address
treatable conditions such as fatigue and weakness, and slow
or reverse functional decline. Intervention studies have also
demonstrated the potential for improving frailty status,
particularly with exercise-based interventions (18). Nutritional supplementation to address weight loss and muscle
dysfunction (19-21), and drugs for conditions such as sarcopenia (22, 23), may also represent feasible approaches totreating the underlying conditions of frailty. Multidomaininterventions are also under investigation (24).
Polypharmacy is also thought to be a major risk factor for
frailty (25). Thus, identifying frailty in an older person may
motivate physicians to reevaluate the drugs they are prescribing. Another possible risk factor is vitamin D deficiency (26), although the evidence is contradictory.
In order for frailty to be incorporated into the routine practice of primary care physicians, a simple screening test isneeded. Several different methods of screening for frailty
have been developed and validated. The Fried criteria wereoperationalized into a screening algorithm for use in the
Cardiovascular Healthy Study (CHS). The FI-CGA wasvalidated in the Canadian Study of Health and Aging (27).
Other frailty measures have also been proposed, including

FROM FRAILTY TO DISABILITY

Frailty develops progressively, with the early phase likely
most responsive to intervention and the later, non-reversible stages most costly. In a study of 754 community-dwelling, non- disabled older adults, Gill and colleagues showedthat frailty is a dynamic process with frequent transitions.
While the overall trend was towards worsening of frailty
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the Study of Osteoporotic Fractures (SOF) Index (28). Allof these measures count deficits, and all of them quantify
the degree of frailty and thus, the degree of vulnerability
to adverse outcomes. Moreover, all of them reflect an aging-associated failure of physiological systems.

PSYCHOSOCIAL AND COGNITIVECONTRIBUTIONS TO FRAILTY

Research from the CSHA has also shown that social vulnerability, distinct but related to frailty, is also associated withhigher mortality in the elderly, and that social factors suchsocio-economic status, social support, and social engagement can be quantified using a social vulnerability index (11).
Using this tool, they found that even among healthy andfit elders, social vulnerability was associated with a 22% increased risk of mortality (33). Other frailty models incorporate psychosocial and cognitive components to varying degrees (34), acknowledging that these factors play importantroles in the development of frailty.

The IANA FRAIL scale, based on both the Fried (CHS)
and Rockwood (FI-CGA) scales, is a six-question self-report measure that takes less than 30 seconds to administerand has been shown to predict mortality and disability inolder Australians (29) and correlates IADLs and strengthand mobility outcomes in middle-aged African-Americans(29, 30).
Informant interviews, for example, the Canadian Study ofHealth and Aging (CSHA) Clinical Frailty Scale, can also be
used as a rapid and reliable screen for frailty. This scale asks
the physician to assign a score ranging from 1 (very fit) to 7
(severely frail) based on clinical impression of co-morbidity, cognitive impairment, and disability. It has been shownto correlate with the CGA-FI (31).

RECOMMENDATIONSParticipants in the Consensus Conference used a modified
Delphi process to reach consensus on major points related
to frailty (6). In addition, through their discussions, participants emphasized the importance of raising awarenessabout frailty among geriatricians, general practitioners, andother primary care providers in order to implement frailty
in clinical practice. The following recommendations wereagreed upon:• Prioritize the identification of frail older persons incommunity settings, hospitals, and specialty clinics inorder to ensure that people with frailty are treated appropriately and have access to interventional studies.
• Build frailty clinics such as the one built at the Gérontopôle of Toulouse as a means of providing optimal
management of frail elders.
• Develop intervention programs incorporating physicaland cognitive exercise, social support, and nutrition forpeople in the earliest stages of frailty in order to slow
or reverse frailty.
• Build stronger basic and clinical research programs inorder to better understand the underlying causes offrailty, identify therapeutic targets, and develop newtreatment strategies.

Another frailty screening tool that relies on the clinicalopinion of the general practitioner has been developed in
France. In response to the French government’s policy forpreventing disability in older persons, a day hospital was established in 2011 at the Gérontopôle of Toulouse (i.e., thegeriatric center of Toulouse) for the evaluation of frailty andprevention of disability (32). Geriatric patients are referredto the center by general practitioners who detect signs ofsymptoms of frailty and are screened using a simple, quick
frailty questionnaire as well as an assessment of gait speed.
The Gérontopôle Frailty Screening Tool asks six questions
regarding living alone, weight loss, fatigue, mobility, memory, and slow gait speed. If the physician identifies one ofthese areas as an area of concern, he/she is asked, “In yourown clinical opinion, do you feel that your patient is frail
and at an increased risk for further disabilities?” It is this last
question that is used to identify patients who are frail.
The goal of the Gérontopôle Center is to identify frailty inthe early stages through a multidisciplinary evaluation, attempt to identify the cause or causes (i.e., underlying diseases or risk factors), and implement multidisciplinary interventions adapted to each patient’s individual needs. These
interventions may include nutrition, physical exercise and/or physical therapy, social support, and education. Patientsare followed up principally by their general practitioner aswell as through phone contact and a structured interview
with a nurse from the center to assess the efficacy of theinterventional plan.

APPENDIXThe Orlando frailty conference group include six major
International (International Association of Gerontology
and Geriatrics, Society of Sarcopenia, Cachexia and Wasting Diseases, and the International Association of Nutrition and Aging), European (European Union GeriatricMedical Society) and United States of America societies(American Medical Directors Association and American
Federation of Aging Research) were asked to provide delegates to attend the consensus meeting.

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Members of the group and their affiliations: John E. Morley (Saint Louis University School of Medicine; St. Louis, MissouriUSA), Bruno Vellas (INSERM UMR 1027, Université de Toulouse III Paul Sabatier, CHU-Toulouse; Toulouse, France),
Gabor Abellan van Kan (INSERM UMR 1027, CHU-Toulouse; Toulouse, France), Stefan Anker (Applied Cachexia
Research, Department of Cardiology, Charité Medical School; Berlin, Germany), Jürgen Bauer (Department of Internal Medicine, Friedrich-Alexander University; Erlangen-Nuremberg, Germany), Roberto Bernabei (Centro Medicina
dell’Invecchiamento, Università Cattolica del Sacro Cuore; Roma, Italy), Matteo Cesari (INSERM UMR 1027, Universitéde Toulouse III Paul Sabatier, CHU-Toulouse; Toulouse, France), W. Cameron Chumlea (Department of Community
Health, Lifespan Health Research Center, Wright State University Boonshoft School of Medicine; Dayton, OH, USA),
Wolfram Doehner (Applied Cachexia Research, Department of Cardiology, Charité Medical School; Berlin, Germany),
Jonathan Evans (Charlottesville, VI, USA), Linda P. Fried (Joseph L. Mailman School of Public Health, Columbia
University; New York, NY and Johns Hopkins University; Baltimore, MD and NIA/NIH, USA), Jack Guralnik (Epidemiology and Public Health, University of Maryland; Baltimore, MD, USA), Paul R. Katz (Baycrest, Ontario, Canada),
Theodore K. Malmstrom (Division of Geriatric Medicine, and Department of Neurology and Psychiatry, Saint Louis
University School of Medicine; St. Louis, Missouri USA), Roger J. McCarter (Biobehavioral Health, The Pennsylvania
State University; University Park, PA, USA), Luis M. Gutierrez Robledo (Instituto de Geriatría; México DF, Mexico),
Ken Rockwood (Geriatric Medicine, Dalhousie University; Halifax, Nova Scotia, Canada), Stephan von Haehling (Applied Cachexia Research, Department of Cardiology, Charité Medical School; Berlin, Germany), Maurits F. Vandewoude(Department of Geriatrics, ZNA St. Elizabeth Hospital, University of Antwerp; Antwerp, Belgium), Jeremy Walston(Division of Geriatric Medicine and School of Public Health, Johns Hopkins University; Baltimore, MD, USA).
This article was published in the Journal of Frailty and Aging
Volume 2, Number 3, 2013
http://www.jfrailtyaging.com/

REFERENCES
1. UNDESA: World Population Aging 2011. 2011.
2. Seeman TE, Merkin SS, Crimmins EM, Karlamangla AS. Disability
trends among older Americans: National Health And Nutrition Examination Surveys, 1988-1994 and 1999-2004. Am J Public Health2010;100:100- 107.
3. Vellas B, Cestac P, Moley JE. Implementing frailty into clinicalpractice: we cannot wait. J Nutr Health Aging 2012;16:599-600.
4. Adams K, Corrigan JM (Eds.). Priority Areas for National Action:
Transforming Health Care Quality. Washington, D.C.: National
Academies Press 2003.
5. Rodriguez-Manas L, Feart C, Mann G, et al. Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus
Statement. The Frailty Operative Definition-Consensus Conference Project. J Gerontol A Biol Sci Med Sci 2013;68:62-67.
6. Morley JE, Vellas B, Abellan van Kan G, et al. Frailty Consensus: A
Call to Action. J Am Med Dir Assoc 2013;14(6):392-7.
7. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for frailty
in older adults: toward a better understanding of physiology andetiology: summary from the American Geriatrics Society/National
Institute on Aging Research Conference on Frailty in Older Adults.
J Am Geriatr Soc 2006;54:991-1001.
8. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J
Gerontol A Biol Sci Med Sci 2001;56:M146-156.
9. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of frailty:
characterization in the women's health and aging studies. J Gerontol A Biol Sci Med Sci 2006;61:262-266.
10. Boyd CM, Xue QL, Simpson CF, Guralnik JM, Fried LP. Frailty, hospitalization, and progression of disability in a cohort of disabledolder women. Am J Med 2005;118:1225-1231.
11. Andrew MK, Mitnitski AB, Rockwood K. Social vulnerability, frailty
and mortality in elderly people. PLoS One 2008;3:e2232.

12. Rockwood K, Rockwood MR, Mitnitski A. Physiological redundancy in older adults in relation to the change with age in the slope ofa frailty index. J Am Geriatr Soc 2010;58:318-323.
13. Gill TM, Gahbauer EA, Allore HG, Han L. Transitions between
frailty states among community-living older persons. Arch Intern
Med 2006;166:418-423.
14. Theou O, Rockwood MR, Mitnitski A, Rockwood K. Disability andco- morbidity in relation to frailty: how much do they overlap? Arch
Gerontol Geriatr 2012;55:e1-8.
15. Cooper C, Dere W, Evans W et al. Frailty and sarcopenia: definitions and outcome parameters. Osteoporos Int 2012;23:18391848.
16. Khandelwal D, Goel A, Kumar U, Gulati V, Narang R, Dey AB. Frailty
is associated with longer hospital stay and increased mortality in
hospitalized older patients. J Nutr Health Aging 2012;16:732-735.
17. Gill TM, Gahbauer EA, Han L, Allore HG. Trajectories of disability
in the last year of life. N Engl J Med 2010;362:1173-1180.
18. Lee P-H, Lee Y-S, Chan D-C. Interventions targeting geriatric frailty: A systemic review. J Clin Geront Geriat 2012;3:47-52.
19. Ferrando AA, Paddon-Jones D, Hays NP, et al. EAA supplementation to increase nitrogen intake improves muscle function during
bed rest in the elderly. Clin Nutr 2010;29:18-23.
20. Fitschen PJ, Wilson GJ, Wilson JM, Wilund KR. Efficacy of beta- hydroxy-beta-methylbutyrate supplementation in elderly and clinicalpopulations. Nutrition 2013;29:29-36.
21. Chale A, Cloutier GJ, Hau C, Phillips EM, Dallal GE, Fielding RA.
Efficacy of Whey Protein Supplementation on Resistance ExerciseInduced Changes in Lean Mass, Muscle Strength, and Physical
Function in Mobility-Limited Older Adults. J Gerontol A Biol Sci
Med Sci 2013;68(6):682-90

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22. Cadilla R, Turnbull P. Selective androgen receptor modulators in
drug discovery: medicinal chemistry and therapeutic potential.
Curr Top Med Chem 2006;6:245-270.
23. Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I. Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt
signaling pathways. Endocrinology 2010;151:628-638.
24. Singh NA, Quine S, Clemson LM, et al. Effects of high-intensity progressive resistance training and targeted multidisciplinary
treatment of frailty on mortality and nursing home admissions after hip fracture: a randomized controlled trial. J Am Med Dir Assoc
2012;13:24-30.
25. Hubbard RE, O'Mahony MS, Woodhouse KW. Medication prescribing in frail older people. Eur J Clin Pharmacol 2013;69(3):319-26.
26. Shardell M, D'Adamo C, Alley DE, et al. Serum 25-hydroxyvitaminD, transitions between frailty states, and mortality in older adults:
the Invecchiare in Chianti Study. J Am Geriatr Soc 2012;60:256-264.
27. Jones D, Song X, Mitnitski A, Rockwood K. Evaluation of a frailty index based on a comprehensive geriatric assessment in a
population based study of elderly Canadians. Aging Clin Exp Res
2005;17:465-471.

28. Ensrud KE, Ewing SK, Taylor BC, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older
women. Arch Intern Med 2008;168:382-389.
29. Lopez D, Flicker L, Dobson A. Validation of the frail scale in a cohort of older Australian women. J Am Geriatr Soc 2012;60:171-173.
30. Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging 2012;16:601-608.
31. Rockwood K, Song X, MacKnight C, et al. A global clinical measureof fitness and frailty in elderly people. CMAJ 2005;173:489-495.
32. Subra J, Gillette-Guyonnet S, Cesari M, Oustric S, Vellas B. The
integration of frailty into clinical practice: preliminary results fromthe Gerontopole. J Nutr Health Aging 2012;16:714-720.
33. Andrew MK, Mitnitski A, Kirkland SA, Rockwood K. The impact ofsocial vulnerability on the survival of the fittest older adults. Age
Ageing 2012;41:161-165.
34. Cigolle CT, Ofstedal MB, Tian Z, Blaum CS. Comparing models of frailty: the Health and Retirement Study. J Am Geriatr Soc
2009;57:830- 839.

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INCORPORATING FRAILTY INTO CLINICAL PRACTICE AND CLINICAL RESEARCH

INCORPORATING FRAILTY INTO CLINICALPRACTICE AND CLINICAL RESEARCH
J.W. ROWE, L.P. FRIED

Mailman School of Public Health, Columbia University, New York City, New York, USA.
Correspondence: John Rowe. Mailman School of Public Health, Columbia University; 600 West 168th Street, 6th Floor, Room
614, New York, NY 10032, USA. Phone: +1 (212) 305-3505; Fax: +1 (212) 305-3405; email: jwr2108@columbia.edu

While frailty is a common syndrome in older
persons that is associated with very significant
morbidity and mortality, the often subtle andvaried clinical manifestations have fostered disagreement
regarding its definition, causes, and natural history. Recently consensus has begun to emerge on the acceptance of thefollowing definition for physical frailty “a medical syndrome
with multiple causes and contributors that is characterized
by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability fordeveloping increased dependency and/or death” (1). Basedon this emerging consensus and the development of several
rapid, validated screening tests, our understanding of theepidemiology of this syndrome is rapidly advancing.

clinical relevance as a risk factor for the development or
aggravation of disability and dependence and risk for mortality and vulnerability to stressors (2). Frailty has several
distinct stages in its clinical evolution (Figure 1) with different potential for prevention on and treatment at different
stages (3). Substantial progress is being made in describing
the epidemiology and etiology, and at least four treatment
approaches have been identified as very promising, including exercise, protein-calorie supplementation, vitamin D
administration and reduction of polypharmacy.
In the context of this rapidly growing interest in frailty, we
identify several valuable strategies for inclusion of special
attention to the syndrome in the clinical care of older persons as well as a number of specific clinical research opportunities (Table 1).

There is now widespread recognition that frailty should be
distinguished from disability, and that it exerts its major
Figure 1
Continuum of resilience/frailty in older adults

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– recognition of the late stage of frailty which is not responsive to treatment, and is a pre-death phase during
which the patients should be eligible for hospice.
– the impact of frailty on the metabolism, distribution, effectiveness and toxicity of medications.
– the impact of frailty on recovery from stress, such as hip
fracture, major surgery and the like. Such research will
inform many guidelines as to how soon and how intense
rehabilitation efforts should be, and timing and duration,
as it may take frail individuals much longer to recoverfrom the acute effects of the stress and be prepared tobenefit from the rehabilitation therapy.
– design of hospital and other treatment settings to optimize recovery from illness for those who are frail.

Table 1
Clinical research opportunities in frailty

Record frailty status of all clinical research subjects
Identify patient selection criteria for treatments
Determine dose-response for effective treatments
Elucidate natural history of frailty
Evaluate impact of frailty on drug effects
Determine recovery time after stress in frail patients
Study value of volunteering in frail elders

CLINICAL PRACTICE

Recognition of the importance and prevalence of frailty,
and its various stages, is crucial to the effective managementof geriatric patients. Just as geriatric care routinely includes
screening for cognitive impairment, screening for frailty
should be incorporated into patients’ regular evaluations.
This screening, using standardized measures, can be accomplished quickly and a low cost by nurses or other healthcare providers and need not be conducted by physicians.
It’s is Important to identify and target both pre-frail andto identify the frail, especially those who do not yet show
disability/dependence, since frailty can be often be seen asa milestone on the pathway to disability.

Regarding the identification of new effective treatments,
we believe a strong case can be made for the potential value of social engagement, such as through volunteering,in preventing or mitigating frailty (4, 5). Volunteering has
clear beneficial health effects, including delaying the onset of some physical impairments, and seems to especiallybe effective in enhancing health status in individuals withlow socio-economic status or fair health status, who are atenhanced risk of frailty. Given its prevalence and clinicalimportance, frailty is a public health issue; broad-based volunteer programs can be seen as a public health intervention. Such studies, in addition to a focus on physical frailty,
should also include so called “psychological frailty” which
often includes isolation and an enhanced realistic, possible
sense of vulnerability. We hypothesize that dimension of
the volunteer experience, may be if well organized to enhance social connectedness, particularly effective in mitigating these symptoms. Advancement of research into therole of volunteering will be greatly facilitated by inclusionof formal screening for frailty in all ongoing private andgovernment-sponsored volunteer programs.

In addition to screening, the presence or absence of frailty, and its severity should be noted as a major diagnosis
as a routine component of the patient’s medical record,with specific indication of the treatment that has been
employed. This ‘red flag’ can be especially helpful in prospectively identifying patients who may be at special risk ofcomplication or prolongation of hospital stay after surgery
or acute illness.
CLINICAL RESEARCH

We are entering an era of great promise in our understanding of frailty. Scrupulous attention to the special needs andrisks patients will improve the quality and cost-effectivenessof care. And there is a growing sense that as research in thearea accelerates, interventions that prevent the initiation or
progression of the frailty pathway may soon be within our
grasp.

In clinical studies involving elderly, including interventionsof specific treatments or new models of care or observational studies that follow patients over time, individuals
should be routinely characterized as to their frailty status,
again using a validated scale, as this may be an important
determinant of their response to the various interventions.
Regarding research that specifically targets frailty, we needstudies of:– the best patient selection and ‘dose’ of currently recommended treatments (exercise, nutritional supplementation, Vitamin D) and optimal treatment combinationsand how to titrate to clinical status and stage of frailty.
– the natural history, with a focus on identification of factors that may initiate the pathway to frailty.

This article was published in the Journal of Frailty and Aging
Volume 2, Number 3, 2013
http://www.jfrailtyaging.com/

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INCORPORATING FRAILTY INTO CLINICAL PRACTICE AND CLINICAL RESEARCHREFERENCES
1. Morley J E et al, Frailty Consensus: A Call to Action. JAMDA 2013;392- 397
2. Fried LP, Walston JD, Ferrucci L. Frailty (Chapter 52). In: Halter JB,
Ouslander JG, Tinetti ME, Studenski S, High KP Asthana S and
Hazzard WR, (editors) Hazzard’s Geriatric Medicine and Gerontology. 6th edn. 2009. McGraw Hill, New York, pp 631-645
3. Yang Y and Lee, LC. Dynamics and heterogeneity in the process ofhuman frailty and aging: evidence from the U.S. older adult population. J Gerontol B Psychol Sci Soc Sci. 2010; 65B (2) : 246-255

4. Cutler SJ, Hendricks J, O’Neill G. Civic Engagement and Aging. In:
Binstock RH and George LK, (eds) Handbook of Aging and the Social Sciences. 7th edn. 2011. Academic Press, London, pp 221-233
5. Lum TY and Lightfoot E. The effects of volunteering on the physical and mental health of older people. Research on Aging 2005;
27(1): 31-55

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WHITE BOOKFRAILTY IS A COMPLEX GERIATRIC SYNDROME
WITH MULTIPLE FUNCTIONAL NEEDS:A COMPREHENSIVE APPROACH IS NEEDED
Liang-Kung CHEN1,2,3,*, An-Chun HWANG1,2,3, Li-Kuo LIU1,2,
Wei-Ju LEE1,2,4, Li-Ning PENG1,2,3

1 Aging and Health Research Center, National Yang Ming University, Taipei, Taiwan
2 Institute of Public Health, National Yang Ming University, Taipei, Taiwan
3 Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan
4 Department of Family Medicine, Taipei Veterans General Hospital Yuanshan Branch, Yi-Lan, Taiwan
Correspondence: Prof. Liang-Kung Chen, Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, No 201,
Sec 2, Shih-Pai Road, Taipei, Taiwan, Tel: +886-2-28757830, e-mail: lkchen2@vghtpe.gov.tw

ABSTRACT
Objective: To evaluate the prevalence and associated functional needs for frailty among otherwise healthy community-dwelling middle-aged and elderly people in Taiwan. Design: a cross-sectional study. Setting: communities in I-Lan
County of Taiwan. Participants: 1839 otherwise healthy
community-dwelling people aged 50 years and older. Intervention: None Measurements: Frailty defined by Fried’s
criteria, Charlson’s comorbidity index (CCI), Functional
Autonomy Measurement System (SMAF), Center for Epidemiologic Studies Depression Scale (CES-D), Mini-Nutrition Assessment (MNA), Mini–Mental State Examination(MMSE), and Short Form-12 quality of life questionnaire.
Results: Overall, 1839 subjects (mean age: 63.9±9.3 years,
47.5% males) participated in this study and men weremore likely to have more education year, smoking and alcohol drinking habit. The prevalence of frailty was 6.8%,
pre-frailty was 40.5% and 53.7% of all subjects were ro-bust. Compared to subjects with different frailty status, age,education year, alcohol drinking habit, hypertension, diabetes mellitus, hyperlipidemia, CCI, walking speed, handgrip
strength, score of SMAF, CES-D, MNA, MMSE, qualityof life were significantly different between groups (P all< 0.05). Older age, poorer physical function, poorer cognitive function, poorer nutritional status, more depressive
symptoms, higher CCI and poorer quality of life were all
independent associative factors for frailty. Conclusions:Frailty was not merely a geriatric syndrome, but the combination of multiple geriatric syndromes. Further study isneeded to evaluate the clinical benefits of integrated healthpromotion activities in the communities to reverse frailty
and associated functional care needs.

INTRODUCTION

comes1. Various adverse health outcomes have been reported to be associated with frailty, such as falls, disability, hospitalizations, reduced health-related quality of life, nursing
home admissions and mortality (1,2). In Taiwan, the prevalence of frailty differed from study to study according to

Key words: Frailty, Geriatric Syndrome, Comprehensive
Geriatric Assessment.

Frailty, a well-known geriatric syndrome, is featured by thevulnerable state of older people with reduced physiologicalreserve and increased susceptibility to adverse health out-90

Frailty is a complex geriatric syndrome with multiple functional needs: a comprehensive approach is needed

Demography and functional assessments
A questionnaire consisting of demographic information,socioeconomic condition, medical history and qualityof life was performed for the subjects by research nurses. The burden of multimorbidity was evaluated by using
Charlson’s Comorbidity Index (13). Tobacco use was categorized as follows: non-smoker, ex-smoker (quit in past 6months) and current smoker. Alcohol drinking status was
categorized as drinkers and non-drinkers. A comprehensivefunctional assessment was performed for all participants,
including the Functional Autonomy Measurement Systemfor physical function test (14), the Center for Epidemiologic Studies Depression Scale (CES-D) for measuring themood status (15), the Mini-Nutrition Assessment (MNA)
for nutritional status measurement (16), and the Mini-Mental State Examination (MMSE) for cognitive function measurement (17).

the different healthcare settings (3,4), but it was not greatly
different from the literature. More importantly, frailty usually was not present as an independent condition, and it frequently interacted with multimorbidity and disabilities (4).
A great body of evidences disclosed that the presence offrailty may complicate the management for individual clinical conditions (5-8). Therefore, managing elderly patientswith frailty usually needed a comprehensive approach inclinical practice. Nevertheless, frailty-related functional impairments of otherwise healthy people with frailty were lesscommonly reported.
I-Lan Longitudinal Aging Study (ILAS) recruited otherwise
healthy community-dwelling middle-aged and elderly population for study. ILAS excluded subjects with communication difficulty, dementia, nursing home residents, subjects
with limited life expectancy, as well as physical disability (9).
Despite the relatively better health conditions of ILAS
participants, results of ILAS have shown associations offrailty with cardiometabolic risk (10), cognitive decline (11),falls, fractures, low bone mineral density and sarcopenia, as
well as hospitalizations (12). These associations were notdifferent from that of the literature, which confirmed thesimilar health characteristics of frailty defined in ILAS toother studies. The main aim of this study was to explore theassociated functional care needs for frailty among otherwise
healthy community-dwelling middle-aged and elderly people to for the further comprehensive intervention programs
to promote overall health in the communities.

Quality of life measurement
In this study, quality of life was measured by the Short
Form-12 (SF-12) for quality of life, which consisted ofphysical component summary (PCS) and mental component summary (MCS) (18). Higher score in PCS and MCS
was considered having higher quality of life. In this study,
subjects with the higher than the mean of total score of
PCS and MCS were categorized as having good quality oflife.
Muscle strength and physical performance
For all participants, handgrip strength was measured using
digital dynamometers (Smedlay’s Dynamo Meter; TTM,
Tokyo, Japan), with participants standing in an upright position with both arms down on their sides. The best result
for three tests of the dominant hand was used for further
analysis (19). Moreover, participants performed a timed
6-meter walk with static start without deceleration for eachparticipant to evaluate their physical performance (20).

MATERIALS AND METHODS

Study subjects
The I-Lan Longitudinal Aging Study (ILAS) is a community-based aging cohort study in I-Lan County of Taiwan,
which randomly selected community-dwelling people aged
50 years and older to evaluate the complex interrelationshipbetween aging, frailty, sarcopenia and cognitive decline (9).
All participants were invited via mail or telephone to participate by the research team, and were enrolled when they
signed the consent forms. The inclusion criteria for ILAS
were: (1) residents aged 50 years and older, and (2) inhabitants who presently live in Yushan Township without a plan tomove to other places. Subjects with the following conditions
were excluded for study: (1) unable to communicate with theresearch nurses, (2) unable to complete all evaluation tests,(3) with a limited life expectancy due to major illnesses, (4)unable to complete functional assessments within a reasonable time, and (5) current residents in long-term care facilities.
Overall, 1,839 subjects participated in the study. The wholestudy and the consent procedure had been approved by theInstitutional Review Board of Taipei Veterans General Hospital and National Yang Ming University.

Definition of frailty
In this study, frailty was defined by using Fried’s criteria,
including exhaustion, weakness, slowness, physical inactivity and weight loss (1). Exhaustion was defined using the
2 statements by the CES-D. Weakness was defined by low
handgrip strength, and slowness was defined by slow gait
speed. Physical inactivity was evaluated by using Taiwaneseversion of International Physical Activity Questionnaire(IPAQ) (21). The cutoff for weakness, slowness and physical inactivity was determined by the gender-specific lowest
quintile of the study subjects of the corresponding tests.
Weight loss was defined as having involuntary weight lossof >5% in the past year or 3kgs within past 3 months. Frailty status (robust, pre-frail and frail) was determined basedon the Fried’s criteria.
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Statistical analysis
In this study, continuous variables were expressed as themean ± standard deviation, and the categorical data wasexpressed by percentages. Comparisons of continuous data
were done by Student’s t test and comparisons of categorical data were done by Chi square test when appropriate.
Comparisons between groups of different frailty statuses
were performed by using one-way ANOVA. To determine
the independent associative factors for frailty, logistic regression model was used by inputting variables with P<0.10
in the univariate analysis. Five items of frailty definition
were not entered for regression model to avoid over-adjustment. All statistical analysis was performed by the commercial software (SPSS 18.0, SPSS Inc, Chicago, IL, USA).
For all tests, the two-tailed P value<0.05 was considered
statistical significant.

Associative factors for frailty
Table 3 summarized independent associated factors forfrailty in this study. Older age, poorer physical function,
poorer cognitive function, poorer nutritional status, moredepressive symptoms, higher CCI and poorer quality of life
were all independent associative factors for frailty. Education year, alcohol drinking habit and multimorbidity were
not statistically significantly associated with frailty in the
regression model.
DISCUSSION

In this study, the prevalence of frailty was somewhat lower
than that in the Cardiovascular Health Study, which may berelated to the inclusion and exclusion criteria. Independentassociative factors for frailty in this study included older
age, poorer physical function, poorer cognitive function,
poorer nutritional status, more depressive symptoms, more
complex multimorbidity, and poorer quality of life. From
results of this study, frailty was not merely a geriatric syndrome, but frailty per se was the combination of multiple
geriatric syndromes. Therefore, frailty may pose a very
high risk of health for older people, even among otherwise
healthy community-dwelling middle-aged and older people.

RESULTS

Demography
Overall, 1839 subjects (mean age: 63.9±9.3 years, 47.5%
males) participated in this study. Table 1 summarized thedemographic characteristics of all study subjects and thecomparisons between men and women in this study. In thisstudy, men were older than women (65.1±9.7 vs 62.9±8.7
years, P<0.001) and having more education years (7.1±5.0
vs 5.4±4.8 years, P<0.001). Besides, men were more likely
to smoke and to carry current habit of alcohol consumption than women. In the comparisons of multimorbidity,
men were similar to women except that women had a higher percentage of hyperlipidemia. Despite men were having
faster gait speed (1.6±0.5 vs 1.4±0.4 m/s, P<0.001) andhandgrip strength (35.1±8.3 vs 21.8±5.4 kg, P<0.001) than
women, the frailty status of men were similar to women.
In functional assessment, women were poorer in nutritional
status (26.9±1.9 vs 27.4±1.7 in MNA, P<0.001), depressive
symptoms (2.8±5.2 vs 2.0±3.7 in CES-D, P<0.001) andcognitive status (25.1±4.4 vs 26.2±3.5, P<0.001) than men.
In the comparisons of quality of life, women were poorer
in both PCS (49.5±5.7 vs 50.8±5.6, P<0.001) and in MCS(53.6±5.5 vs 54.2±4.4, P<0.001) than men.

A number of frailty intervention programs have been developed with inconsistent results. The mainstream of frailty
intervention programs was exercises and nutrition, either
alone or in combinations (22). Different combinations of
exercise programs have been reported and the combined
aerobic and resistance exercise was considered the most effective approach (23). However, not every intervention program was effective and the newly developed programs were
through multifactorial intervention, which was compatible
to our study results. Associations between frailty, depression and cognitive decline have been reported as before, butrarely did the frailty intervention programs include thesecomponents. Our previous study in the post-acute settings
showed that improvement of physical functional could also
improve the depressive symptoms of older people without
use of antidepressants (24).

Epidemiology of frailty
In this study, the prevalence of frailty was 6.8%, pre-frailty
was 40.5% and 53.7% of all subjects were robust. The prevalence of frailty status between men and women was similar. Table 2 summarized the comparisons between subjects
with different frailty status, which showed that age significantly increased when the subjects became frailer. Similar
trends were identified in education year, alcohol drinking
habit, hypertension, diabetes mellitus, hyperlipidemia, CCI,
walking speed, handgrip strength, score of SMAF, CES-D,
MNA, MMSE, PCS and MCS (P all< 0.05).

From this study, we may consider frailty was not just a geriatric syndrome like others but a complex geriatric syndromethat was of much greater health risk for older people. The
associated conditions of frailty may lessen the benefits offrailty intervention programs if these conditions were nottaken as a whole. To apply the concepts of comprehensive
geriatric assessment (CGA) may play an active role in frailty
intervention programs (25). Patients in the post-acute caresettings may be the best scenario to demonstrate the potential benefits because these patients were frail and free fromacute illnesses. It has been shown that CGA-based inter92

Frailty is a complex geriatric syndrome with multiple functional needs: a comprehensive approach is needed

vention successfully promoted physical functional recovery
for post-acute care patients and the improvements wereshown in depressive moods, cognitive function, as well as
nutritional status (26). Moreover, these improvements significantly reduced 1-year mortality following post-acutecare services (27). Although the subjects in the communities were not as frail as patients in the post-acute care settings, they eventually shared similar challenges and deservea comprehensive approach. A recent study demonstrated
the success of an integrated intervention in the reversal offrailty (28).

per se was a longitudinal study design, we would be able toevaluate the interaction between frailty and other functional
deficits in the future. Second, this is an observational study
that limited the possibilities to know how other functional
deficits improved when frailty was improved. Third, resultsof this study may underestimate the complex care needs
for frailty since the study subjects were considered healthier than the general population. In conclusion, frailty was
not merely a geriatric syndrome, but the combination ofmultiple geriatric syndromes. Early identification of otheraccompanying functional care needs of frailty was of great
importance to design a comprehensive intervention program. Further study is needed to evaluate the clinical benefits of integrated health promotion activities in the communities to reverse frailty and associated functional care needs.

Despite all the efforts went into this study, there were stillsome limitations. First, the cross-sectional study design limited the possibilities to explore how frailty interacts withother functional deficits in the long term. However, ILAS
REFERENCES
1. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci
Med Sci 2001;56:M146-156
2. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381:752-62.
3. Lin CC, Li CI, Meng NH, Lin WY, Liu CS, Lin CH, et al. Frailty andits associated factors in an elderly Taiwanese metropolitan population. J Am Geriatr Soc 2013;61:292-4.
4. Chen CY, Wu SC, Chen LJ, Lue BH. The prevalence of subjective
frailty and factors associated with frailty in Taiwan. Arch Gerontol
Geriatr 2010;50 Suppl 1:S43-7.
5. Wilhelm-Leen ER, Hall YN, K Tamura M, Chertow GM. Frailty andchronic kidney disease: the Third National Health and Nutrition
Evaluation Survey. Am J Med 2009;122:664-71
6. Krumholz HM, Chen J, Chen YT, Wang Y, Radford MJ. Predicting
one-year mortality among elderly survivors of hospitalization for
an acute myocardial infarction: results from the Cooperative Cardiovascular Project. J Am Coll Cardiol 2001;38:453-9
7. Lichtman JH, Krumholz HM, Wang Y, Radford MJ, Brass LM. Risk
and predictors of stroke after myocardial infarction among the elderly: results from the Cooperative Cardiovascular Project. Circulation 2002;105:1082-7
8. Singh M, Rihal CS, Lenno RJ, Spertus J, Rumsfeld JS, Holmes DR.
Bedside estimation of risk from percutaneous coronary intervention: the new mayo clinic risk scores. Mayo Clin Proc 2007;82:701-8
9. Lee WJ, Liu LK, Peng LN, Lin MH, Chen LK; ILAS Research Group.
Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: Results from the I-Lan Longitudinal Aging
Study. J Am Med Dir Assoc 2013;14:528.e1-7
10. Hwang AC, Liu LK, Lee WJ, Chen LY, Peng LN, Lin MH, Chen LK.
Association of frailty and cardiometabolic risk among community-dwelling middle-aged and elderly people: Results from I-Lan
Longitudinal Aging Study. Rejuvenation Res 2015 (in press)
11. Wu YH, Liu LK, Chen WT, Lee WJ, Peng LN, Wang PN, Chen LK.
Cognitive function in individuals with physical frailty but without
dementia or cognitive complaints: Results from I-Lan Longitudinal Aging Study. J Am Med Dir Assoc 2015 Aug 25. Pii: S15258610(15)0049292. Doi: 10.1016/j.jamda.2015.07.013 Epub aheadof print

12. Liu LK, Lee WJ, Chen LY, Hwang AC, Lin MH, Peng LN, Chen LK
Association between frailty, osteoporosis, falls and hip fractures
among community-dwelling people aged 50 years and older in
Taiwan: Results from I-Lan Longitudinal Aging Study. Plos One
2015;10:e0136968
13. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method ofclassifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40:373-83.
14. Hebert R, Carrier R, Bilodeau A. The Functional Autonomy Measurement System (SMAF): description and validation of an instrument
for the measurement of handicaps. Age Ageing 1988;17: 293-302.
15. Radloff LS. The CES-D Scale: a self-report depression scale forresearch in the general population. Appl Psychol Meas 1977;1:
385–401
16. Guigoz Y. The Mini Nutritional Assessment (MNA) review of the literature--What does it tell us? J Nutr Health Aging 2006;10: 466-485
17. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A
practical method for grading the cognitive state of patients for theclinician. J Psychiatr Res 1975;12: 189-198.
18. Ware JE, Kosinski M, Turner-Bowker DM, Gandek B: How to Score
Version 2 of the SF-12 Health Survey (With a Supplement Documenting Version 1) Lincoln, RI: QualityMetric Incorporated; 2002.
19. Xue QL, Bandeen-Roche K, Varadhan R, Zhou J, Fried LP. Initial
manifestations of frailty criteria and the development of frailty
phenotype in the Women's Health and Aging Study II. J Gerontol
A Biol Sci Med Sci 2008;63:984-90.
20. Rolfson DB, Majumdar SR, Tsuyuki RT, Tahir A, Rockwood K.
Validity and reliability of the Edmonton Frail Scale. Age Ageing
2006;35:526-9.
21. Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth
BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exer 2003;35:1381-95.
22. Lee PH, Lee YS, Chan DC. Interventions targeting geriatric frailty:
a systemic review. J Clin Gerontol Geriatr 2012;3:47-52
23. Yamada M, Arai H, Sonoda T, Aoyama T. Community-based exercise program is cost-effective by preventing care and disability inJapanese frail older adults. J Am Med Dir Assoc 2012;13:507-11

93

WHITE BOOK

24. Liu ME, Chou MY, Liang CK, Ho CA, Lin YT, Lo YK, Peng LN, Chen
LK. No adverse impact of depressive symptoms on the effectiveness of postacute are service: a multicenter male-predominant
prospective cohort study. J Chin Med Assoc 2014;77:38-43
25. Nykanen I, Rissanen TH, Sulkava R, Hartikainen S. Effects of individual dietary counseling as part of a comprehensive geriatric assessment (CGA) on frailty status: a population-based intervention
study. J Clin Gerontol Geriatr 2012;3:89-93.
26. Lee WJ, Peng LN, Cheng YY, Liu CY, Chen LK, Yu HC. Effectivenessof short-term interdisciplinary intervention on postacute patientsin Taiwan. J Am Med Dir Assoc 2011;12:29-32

27. Chen LK, Chen YM, Hwang SJ, Peng LN, Lin MH, Lee WJ, Lee CH;
Longitudinal Older Veterans Study Group. Effectiveness of community hospital-based post-acute care on functional recovery and12-month mortality in older patients: a prospective cohort study.
Ann Med 2010;42:630-6.
28. Ng TP, Feng L, Nyunt MS, Niti M, Tan BY, Chan G, Khoo SA, ChanSM, Yap P, Yap KB. Nutritional, physical, cognitive, and combination interventions and frailty reversal among older adults: arandomized controlled trial. Am J Med 2015 Jul 6. pii: S00029343(15)00567-7. Doi: 10.1016/j.amjmed. 2015.06.017 [Epubahead of print]

Table 1.
Baseline demographic characteristics and comparisons between men and women of I-Lan Longitudinal Aging Study
Total(N=1839)

Men(N=873)

Women(N=966)

P valueAge (years)

63.9±9.3

65.1±9.7

62.9±8.7<0.001

Body mass index (Kg/m2)

24.9±3.624.9±3.3

24.8±3.8

0.433

Education year

6.2±5.0

7.1±5.0

5.4±4.8<0.001

Cigarette Smoking (%)
Never smoker
Ex-smoker
Current smoker

69.5
12.2
18.3

40.2
24.7
35.1

96.0
0.9
3.1

Current alcohol drinking (%)

33.0

49.8

17.8

<0.001

Multimorbidity
Hypertension (%)
Diabetes mellitus (%)
Coronary heart disease (%)
Hyperlipidemia (%)
CCI

41.4
16.8
5.2
7.8
1.0±1.3

42.2
16.4
4.4
6.1
1.0±1.2

40.8
17.2
5.9
9.3
1.0±1.3

0.570
0.662
0.141
0.011
0.959

Physical performance
Walking speed (m/s)
Handgrip strength (Kg)

1.5±0.528.1±9.6

1.6±0.535.1±8.3

1.4±0.4
21.8±5.4<0.001<0.001

52.7
40.5
6.8

50.9
42.3
6.9

54.5
38.8
6.7

Functional assessment
SMAF
CES-D
Mini-Nutritional Assessment
MMSE-0.18±1.63
2.4±4.627.2±1.825.6±4.0-0.20±1.79
2.0±3.727.4±1.726.2±3.5-0.16±1.47
2.8±5.2
26.9±1.925.1±4.4

0.575<0.001<0.001<0.001

Quality of life
PCS
MCS

50.1±5.753.9±5.0

50.8±5.654.2±4.449.5±5.7
53.6±5.5<0.001
0.007

Frailty status (%)
RobustPre-frail
Frail<0.001

0.289

CCI = Charlson’s Comorbidity Index; SMAF = the Functional Autonomy Measurement System; CES-D = the Center for Epidemiologic Studies Depression Scale; MMSE = Mini-Mental State Examination; PCS = Physical Component Summary; MCS = Mental Component Summary

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Frailty is a complex geriatric syndrome with multiple functional needs: a comprehensive approach is needed

Table 2.
Comparisons of clinical characteristics among subjects with different frailty status
Total(N=1839)

Robust(N=970, 52.7%)

Pre-frail(N=744, 40.5%)

Frail(N=125, 6.8%)

P valueAge (year)

63.9±9.3

60.7±7.566.3±9.3

74.6±9.2<0.001Sex (M%)

47.5

45.8

49.6

48.0

0.289

BMI (Kg/m2)

24.9±3.624.8±3.524.9±3.624.7±4.0

0.655

Education year

6.2±5.0

7.5±4.8

5.2±4.8

2.6±3.5<0.001

Cigarette smoking (%)
Never smoker
Ex-smoker
Current smoker

67.4
19.7
12.9

69.3
18.5
12.2

65.4
21.4
13.2

60.9
20.3
18.8

Current alcohol drinking (%)

35.0

38.7

32.1

15.4

Multimorbidity
Hypertension (%)
Diabetes mellitus (%)
Coronary heart disease (%)
Hyperlipidemia (%)
CCI

41.4
16.8
5.2
7.8
1.0±1.3

34.6
13.4
4.4
6.2
0.7±1.1

47.6
18.7
5.8
9.4
1.2±1.3

57.6
32.0
7.2
10.4
2.1±1.4

Physical performance
Walking speed (m/s)
Handgrip strength (Kg)

1.5±0.528.1±9.6

1.7±0.430.9±9.0

1.4±0.426.0±9.2

0.9±0.3
18.8±7.1<0.001<0.001

Functional assessment
SMAF
CES-D
Mini-Nutritional Assessment
MMSE-0.2±1.6
2.4±4.627.2±1.825.6±4.0-0.0±0.2
1.5±2.627.5±1.626.8±3.0-0.1±0.5
2.7±4.427.1±1.825.0±4.0-2.0±5.88.2±10.0
25.3±2.6
20.8±5.8<0.001<0.001<0.001<0.001

Quality of life
PCS
MCS

50.1±5.753.9±5.0

50.9±4.5
54.6±3.6

50.0±5.853.7±5.0

44.1±9.1
49.1±9.9<0.001<0.0010.359<0.001<0.001<0.0010.260
0.025<0.001

CCI = Charlson’s Comorbidity Index; SMAF = the Functional Autonomy Measurement System; CES-D = the Center for Epidemiologic Studies Depression Scale; MMSE = Mini-Mental State Examination; PCS = Physical Component Summary; MCS = Mental Component Summary

Table 3. Independent associative factors for frailty
Odds ratio

95% Confidence Interval

P valueAge (years)

1.105

1.069-1.143<0.001

Education year

1.026

0.958-1.100

0.460

Current alcohol drinking (%)

0.934

0.733-1.189

0.578

Multimorbidity
Hypertension (%)
Diabetes mellitus (%)
Hyperlipidemia
CCI

0.905
1.703
0.877
0.978

0.552-1.484
0.952-3.046
0.413-1.861
0.802-1.193

0.693
0.073
0.877
0.825

Functional assessment
SMAF
CES-D
Mini-Nutritional Assessment
MMSE

0.761
1.096
0.799
0.883

0.635-0.913
1.059-1.135
0.713-0.895
0.832-0.937

0.003<0.001<0.001<0.001

Poor quality of life

2.328

1.408-3.939

0.001

CCI = Charlson’s Comorbidity Index; SMAF = the Functional Autonomy Measurement System; CES-D = the Center for Epidemiologic Studies Depression Scale; MMSE = Mini-Mental State Examination; PCS = Physical Component Summary; MCS = Mental Component Summary

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HOW STUDIES SHOW THE BENEFITS
OF A MULTIDISCIPLINARY APPROACH
OF CARE APPLIED TO FRAIL OLD ADULTS
Matteo CESARI, MD, PhD1,2, Laurent DEMOUGEOT, PhD1,2

1 Centre Hospitalier Universitaire de Toulouse, Toulouse, France
2 INSERM UMR 1027, Université de Toulouse III Paul Sabatier, Toulouse, France
Correspondence: Prof. Matteo Cesari, Institut du Vieillissement, c/o Faculté de Médecine, 37 Allées Jules Guesde,
31000 Toulouse, France, e-mail: macesari@gmail.com

Demographic trends show absolute and relative
increases of older persons in our societies. Such
scenario endangers the sustainability of ourhealthcare systems. In fact, it is well established that age-related conditions and, in particular, disabilities are particularly burdening for the person but also for the public healthsystem. For this reason, in this last decade, a relevant bodyof scientific literature has focused the need of implementing preventive actions against disability in the elders.

ability conditions. It is likely that such heterogeneous translation of frailty is due to the need of measuring the “biological age” of the elder in the presence of different clinicalsubstrata and/or settings. In other words, a gradient of risk
for negative events can always be generated by assessment
instruments. Moreover, it should also be acknowledged thatfrailty is not (yet) a specific disease, but a syndrome requiring a multidomain and multidisciplinary approach. That is,after frailty is detected (whatever is the adopted instrument
to measure it), a comprehensive geriatric assessment should
follow.

The concept of “frailty syndrome” has been defined andincreasingly studied. Frailty is defined as the extreme vulnerability of the organism to endogenous and exogenous
stressors, exposing the individual at higher risk of negative
health-related outcomes (1). Too many and too heterogeneous are today the older persons in our societies for describing them only according to a pure chronological criterion(i.e., number of years lived). Frailty may indeed represent
a way for replacing the obsolete concept of “chronologicalage” with a more accurate and person-tailored parameter of“biological age” (2).

Scientific literature about the importance of conducting acomprehensive geriatric assessment in vulnerable elders isvast. The multidimensional and multidisciplinary approachto geriatric syndrome has documented beneficial effects
when applied in multiple clinical settings and conditions.
Several trials have demonstrated that person-tailored interventions based on results of a comprehensive geriatric assessment are able to prevent major negative health-related
outcomes in the older persons living in the community (3),home care (4), and hospital (5). It could be too long and
not within the scopes of the present summary to go in thedetails of the available evidence. Nevertheless, it might besufficient to simply cite the most relevant meta-analysis
conducted (already) in 1993 by Stuck and colleagues (6).
In this study, Authors examined results of 28 randomized
controlled trials (more than 9,000 participants) testing theeffects of comprehensive geriatric assessment-based in-

Although the theoretical concept of frailty is agreed, its
practical translation still presents some limitations due tothe existence of multiple (and largely non-overlapping)
operational definitions. It is noteworthy, for example, howsome authors have tended to consider frailty as a pre-disability phenomenon, whereas others have promoted thedetection of the syndrome even in patients with severe dis96

How studies show the benefits of a multidisciplinary approach of care applied to frail old adults

terventions versus controls. Findings clearly demonstrated
that comprehensive geriatric assessment programs linking
geriatric evaluation with strong long-term management are
effective for improving survival and function in older persons.

the Gérontopôle has been receiving non-disabled frail elders for assessing their overall health status through a comprehensive geriatric assessment, identifying the causes of
their frailty condition using a multidisciplinary approach,and then proposing a person-tailored plan of preventive
intervention. It is noteworthy that almost half of the frail
older persons assessed at our Frailty Clinic were found tohave at least one undiagnosed condition. This means thatthe presence of the general practitioner (who refers the individual to our service) may not be sufficient to comprehensively assess the older person's clinical complexity. A coordinated and multidisciplinary evaluation is indeed required
to identify the inner causes of the frailty condition. The
detection of a previously unknown clinical condition will
surely conduct to the need of a specific treatment. On theother hand, the early intervention may signify 1) preventing
more serious consequences in the future, and 2) potentiallysolve (part of) the individual's complaints. This infrastructure does not only play a major role at detecting early signsof diseases (thus anticipating the treatment/intervention to
the preliminary phases of the pathological process), but it
is also important to diffuse knowledge and awareness about
the importance of preventing disability at older age.

Probably, orthopaedic surgery represents the first discipline
which has successfully implemented a close collaboration
with geriatricians for the assessment and management ofolder persons (i.e., hip fracture patients). For example,
Antonelli Incalzi and colleagues (7) demonstrated that assigning a geriatrician to assist with the medical care of (hipfracture) older patients in orthopaedic wards was associated with increased operation rate, decreased mortality, andshortened length of stay. More recently, oncologists (8) andcardio-surgeons (9) have started more frequently looking
for the comprehensive geriatric assessment as the mean for
conducting a higher number of their old patients to their
specific interventions. The search of such collaborations iseasily explained by the common presence of “geriatric” patients (with all their complexities and peculiarities) in almost
every hospital ward and service. In fact, several medical
specialities are today facing the effects of the global aging
on their patients’ characteristics. Geriatric patients require
adaptations of care, personalization of interventions, andmodifications of standard protocols that can be reachedonly through the implementation of the comprehensive
geriatric assessment.

In conclusion, the frailty condition (and related literature)should always be considered together with the large amountof evidence supporting the adoption of the comprehensive geriatric assessment in older persons. More studies are
required to demonstrate that such multidimensional andmultidisciplinary approach is beneficial also when appliedamong community-dwelling older persons in the prevention of disability. Such evaluation should be particularly
focused at limiting the risk of “overdiagnosis” in order toassure an ethical and cost-effective conduction of the intervention.

The positive results obtained in specific clinical settings
have recently fostered geriatric research at trying to extend
the use of the multidimensional and multidisciplinary approach in primary care and as part of preventive strategies
dedicated to community-dwelling older persons. For example, since October 2011, the Gérontopôle of the Centre
Hospitalier Universitaire de Toulouse has been conducting
an innovative day hospital unit exclusively devoted to frailty in the community (the so-called Frailty Clinic) (10, 11).
In collaboration with the general practitioners of the area,
REFERENCES
1. Morley JE, Vellas B, Abellan van Kan G et al. Frailty consensus: acall to action. J Am Med Dir Assoc 2013;14:392-397.
2. Cesari M, Gambassi G, Abellan van Kan G, Vellas B. The frailty
phenotype and the frailty index: different instruments for different
purposes. Age Ageing 2014;43:10-12.
3. Stuck AE, Minder CE, Peter-Wüest I et al. A randomized trial of inhome visits for disability prevention in community-dwelling older
people at low and high risk for nursing home admission. Arch
Intern Med 2000;160:977-986.
4. Landi F, Onder G, Tua E et al. Impact of a new assessment system,
the MDS-HC, on function and hospitalization of homebound older
people: a controlled clinical trial. J Am Geriatr Soc 2001;49:1288-1293.

5. Baztán JJ, Suárez-García FM, López-Arrieta J, Rodríguez-Mañas
L, Rodríguez-Artalejo F. Effectiveness of acute geriatric units on
functional decline, living at home, and case fatality among older
patients admitted to hospital for acute medical disorders: meta-analysis. BMJ 2009;338:b50.
6. Stuck AE, Siu AL, Wieland GD, Adams J, Rubenstein LZ. Comprehensive geriatric assessment: a meta-analysis of controlled trials.
Lancet 1993;342:1032-1036.
7. Antonelli Incalzi R, Gemma A, Capparella O, Bernabei R, Sanguinetti C, Carbonin PU. Continuous geriatric care in orthopedic
wards: a valuable alternative to orthogeriatric units. Aging (Milano) 1993;5:207-216.

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8. Balducci L, Colloca G, Cesari M, Gambassi G. Assessment andtreatment of elderly patients with cancer. Surgical Oncology
2010;19:117-123.
9. Lilamand M, Dumonteil N, Nourhashemi F et al. Gait speed andcomprehensive geriatric assessment: Two keys to improve the management of older persons with aortic stenosis. Int J Cardiol 2014

10. Subra J, Gillette-Guyonnet S, Cesari M, Oustric S, Vellas B. The
integration of frailty into clinical practice: preliminary results fromthe gérontopôle. J Nutr Health Aging 2012;16:714-720.
11. Tavassoli N, Guyonnet S, Abellan Van Kan G et al. Description of
1,108 older patients referred by their physician to the “Geriatric Frailty Clinic (G.F.C) for assessment of frailty and prevention of disability” at the Gérontopôle. J Nutr Health Aging 2014;18:457-464.

98

FRAILTY IN GENERAL PRACTICEFRAILTY IN GENERAL PRACTICE
L. LETRILLIART1, S. OUSTRIC2

1 Collège Universitaire de Médecine Générale & EA 4129 “Santé Individu Société”, Université de Lyon, France;
2 Département Universitaire de Médecine Générale, UMR UPS Toulouse 3 Inserm 1027, Université de Toulouse, France
Correspondence: Laurent Letrilliart, Université Claude-Bernard Lyon 1, Faculté de médecine Lyon-Est, Département de médecine générale; 8 avenue Rockefeller, 69373 Lyon cedex 08, France. E-mail: laurent.letrilliart@univ-lyon1.fr

Key words: Prevention, aging, elderly, assessment, intervention.

CONTEXTCONCEPT

Western countries are currently undergoing a period of
demographic and epidemiologic transition. The prevalenceof chronic comorbidities and dependency rises with life expectancy (1). It is possible to identify persons at increased
risk of fall, hospitalization, dependency, or death (2). The“frailty” of these persons reflects their physiological age.
Frailty prevention concerns all adults and mainly relies onnutritional education, including physical activity and diet (3).

In clinical practice, frailty can be considered a risk factor
for health status deterioration, beyond the effect of chronological age. It is actually more a risk marker than a causal
factor for health status deterioration, as can be a disease (6).
Like metabolic syndrome, the frailty syndrome is not recognized in the International Classification of Primary Care(ICPC-2, WONCA) or in the International Classificationof Diseases (ICD-10, WHO).

DEFINITIONS

Frailty better predicts mortality risk than chronological age.
It also predicts the risk of complications arising from diseasea little better than the diseases themselves. A patient’s polypathological state incompletely covers the frailty status (7).
The ability to recognize the syndrome and to intervene appropriately represents an issue for general practitioners/
family physicians (8), as frailty situations are at the heart ofgeneral practice (9).

The Société Française de Gériatrie et Gérontologie defines
the frailty of the elderly as a clinical syndrome corresponding to a reduction of a person’s stress adaptation capacities,
modulated by physical, psychological and social factors. Its
evaluation must involve clinical criteria predictive of therisk of functional decline and adverse outcomes (2).
The Fried model, developed in the USA in the early 2000s,
is considered to be a reference model for frailty (4). It isbased on the assessment of five physiological criteria: unintentional weight loss, slow walking speed, feelings of exhaustion, low physical activity and self-perceived muscle
weakness. The presence of three criteria is enough to define
the frailty status, with the presence of one or two defining pre-frailty. The frailty clinical criteria are dynamic andpotentially reversible, particularly through pluriprofessional
intervention. While the Fried model is simple and robust,
it does not include any cognitive, psychological or social
criteria (5), dimensions which may alter the expression of
the somatic factors.

FREQUENCY

Frailty prevalence, measured according to the Fried model,
has been estimated at 15% of the French population over 65
years of age, and the prevalence of pre-frailty at 44% (10).
Frailty prevalence increases with age, is higher in womenthan in men, and decreases with education level. Since consultations of patients over 65 years of age account for 28%
of consultations, frail patients may represent around 4% of
those attending general practice (11).

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The aims of frailty evaluation are to improve the quality oflife and limit the management costs (12). It can also aid toorientate the management of elderly patients, in particularwhen facing high risk interventions (cancer treatment, surgery, etc.) or when the ranking of priorities is required (e.g.
in case of multiple chronic conditions).
Initial and follow-up frailty evaluation can benefit patientsliving at home or retirement home. It can be integrated
within the framework of mass screening or of an early diagnosis. The latter can be initiated based on warning signs,
such as non-specific signs (fatigue, unexplained weight loss,
repeated infections), falls, acute delirium or fluctuating
functional disabilities. Frailty evaluation can be complemented by a simplified comprehensive geriatric assessment.
Screening for frailty raises ethical issues, because it is applied to asymptomatic patients and could generate constraints and hazards (6). Pre-frailty detection looks uselessin clinical practice, owing to its very high frequency in the
population and the lack of specific intervention.
TOOLS

Various frailty indexes have been developed, which include
up to 70 variables. Several have a good statistical validity, inparticular an instrument derived from the Fried criteria to
distinguish between frail, pre-frail and non-frail patients (13),and the “frailty index” to measure the frailty level (14).
These available tools show acceptable negative predictive
values but low positive predictive values. The “frailty index” can eventually be used within a two-step strategy. In
general practice, any test may be administered across several
consultations.
Frailty evaluation by general practitioners implies the availability of a tool adapted to their practice, which is easy andquick to use. The clinical utility and user-friendliness of theavailable tools in primary care remain to be demonstrated. To comply with the biopsychosocial approach, which
is characteristic of general practice (15), the criteria should
encompass the psychological and social dimensions, beyond the mere biological dimension highlighted in theFried’s model. They should identify elements on which thegeneral practitioner can design a dashboard and a care plan.
INTERVENTIONS

A program of home visits to elderly persons, including
clinical examination, may reduce functional disabilities inmoderately aged individuals. The global evaluation of elderly patients in the ambulatory setting improves the qualityof care and, likely, patients’ quality of life and autonomy.
Some multidimentional interventions can decrease the riskof referring elderly patients to retirement homes or hospitals, especially for those under 65 years of age.
The management of frail elderly patients consists of initially treating the problems that may favor their frailty, goingon to correct reversible frailty elements (16). In moderately
frail patients, prolonged and intensive programs of physicalre-education can prevent dependency. On the other hand,
evidence is still lacking regarding the effectiveness of interventions targeting diet (17).
Practically, the management of frail elderly patients usually includes care and support, within an approach that canbe coordinated by the general practitioner, in collaboration
with other primary care professionals. Effective management, particularly for patients living at home, implies theavailability of the different professionals involved (physiotherapist, occupational therapist, ophthalmologist, dietician, etc.), which may vary with the patient’s location.
ON-GOING INVESTIGATIONS

An interesting investigation involving French general practitioners is currently being conducted by the Gérontopolein Toulouse (18). It is based on patients’ screening using asimple tool based on the Fried criteria and including thenotion of patient isolation, a cognitive dimension, and thephysician’s clinical sense. Patients identified as frail are thenreferred to a hospital platform for multidisciplinary evaluation.
At a national level, a project concerning the managementof elderly persons at risk of losing their autonomy (PAERPA) is being conducted in eight French regions, with theaim of optimizing elderly care pathways involving professionals from the health and social care fields. This project
consists of “opportunistically” detecting elderly persons at
risk of dependency (frail or having a chronic disease), performing a standardized geriatric assessment and then providing a personalized care plan.
PENDING ISSUES

Before any generalization, it is advisable to assess the reversibility of the different frailty elements and the risk- benefit and cost-benefit ratios of various evaluation and intervention strategies. The main points to compare are targets(mass screening vs. early diagnosis), evaluation features(tools, sequences), evaluation operator (general practitioners, other primary care professionals, geriatricians), intervention features (physical, psychological, social, etc.). These
strategies also need to be compared to traditional diagnostic and therapeutic management approaches, which target
symptoms and diseases. Ideally, current and future researchshould enable the development of a decision algorithm thatwill support pluriprofessional primary care. It is essential

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that the models investigated take into account patients’ adherence and preferences, because their priorities can differ
from those of the health professionals (19).
Acknowledgements: We are grateful to the College of teaching
general practitioners of Lyon (CLGE) to have funded theEnglish editing of the manuscript.

Conflict of Interest: None
This article is currently in press. Published online in the Journal of Frailty
and Aging 2016
http://www.jfrailtyaging.com/

REFERENCES
1. Meslé F. Progrès récents de l’espérance de vie en France:
Les hommes comblent une partie de leur retard. Population
2006;61:437–62.
2. Rolland Y, Benetos A, Gentric A, et al. La fragilité de la personneâgée : un consensus bref de la Société française de gériatrie etgérontologie. Geriatr Psychol Neuropsychiatr Vieil 2011;9:387–90.
3. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people Lancet 2013;381:752–62.
4. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence
for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56:146–56.
5. Fortun MP, Krolak-Salmon P, Bonnefoy M. Analyse descriptive
et comparative des différents modèles de fragilité. Cah Année
Gérontol 2008;22:12–27.
6. Bergman H, Ferrucci L, Guralnik J, et al. Frailty: an emerging research and clinical paradigm--issues and controversies. J Gerontol A Biol Sci Med Sci 2007;62:731–7.
7. Boeckxstaens P, Vaes B, Legrand D, Dalleur O, De Sutter A, Degryse J-M. The relationship of multimorbidity with disability andfrailty in the oldest patients: A cross-sectional analysis of threemeasures of multimorbidity in the BELFRAIL cohort. Eur J Gen
Pract 2015;21:39-44.
8. Rougé Bugat M-E, Cestac P, Oustric S, Vellas B, Nourhashemi F.
Detecting frailty in primary care: a major challenge for primarycare physicians. J Am Med Dir Assoc 2012;13:669–72.
9. Mission Evaluation des compétences professionnelles des métiers de la santé du Ministère de la santé et des sports, Collège
national des généralistes enseignants. Référentiel métier etcompétences des médecins généralistes, 2009.

10. Santos-Eggimann B, Cuénoud P, Spagnoli J, Junod J. Prevalence offrailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci 2009;64:675–81.
11. Letrilliart L, Supper I, Schuers M, et al. ECOGEN: étude desEléments de la COnsultation en médecine GENérale. exercer
2014;114:148–57.
12. Lacas A, Rockwood K. Frailty in primary care: a review of its conceptualization and implications for practice. BMC Med 2012;10:4.
13. Romero-Ortuno R, Walsh CD, Lawlor BA, Kenny RA. A frailty instrument for primary care: findings from the Survey of Health, Ageing
and Retirement in Europe (SHARE). BMC Geriatr 2010;10:57.
14. Drubbel I, Numans ME, Kranenburg G, Bleijenberg N, de Wit NJ,
Schuurmans MJ. Screening for frailty in primary care: a systematic
review of the psychometric properties of the frailty index in community-dwelling older people. BMC Geriatr 2014;14:27.
15. Wonca Europe. The European definition of general practice/family medicine. 2011 edition. http://www.woncaeurope.org/sites/
default/files/documents/Definition%203rd%20ed%202011%20
with%20revised%20 wonca%20tree.pdf.
16. De Lepeleire J, Iliffe S, Mann E, Degryse JM. Frailty: an emerging
concept for general practice. Br J Gen Pract 2009;59:e177–82.
17. Daniels R, van Rossum E, de Witte L, Kempen GIJM, van den Heuvel W. Interventions to prevent disability in frail community-dwelling elderly: a systematic review. BMC Health Serv Res 2008;8:278.
18. Oustric S, Renard V. Cibler et dépister la fragilité en médecine
générale : c’est maintenant... (Edit.). Cah Année Gérontol 2012;1–2.
19. Junius-Walker U, Wrede J, Schleef T, et al. What is important,what needs treating? How GPs perceive older patients’ multiple
health problems: a mixed method research study. BMC Res Notes
2012;5:443.

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WHITE BOOKFRAILTY AND DRUG USE
K. PALMER1, A. MARENGONI1,2, P. RUSSO1, F. MAMMARELLA1,3, G. ONDER1,3

1 Agenzia Italiana del Farmaco (Italian Medicines Agency), Rome, Italy;
2 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy;
3 Department of Geriatrics, Centro Medicina dell’Invecchiamento, Università Cattolica del Sacro Cuore, Rome, Italy

Correspondence: Graziano Onder, MD, PhD. Centro Medicina dell’Invecchiamento, Università Cattolica del Sacro Cuore; Largo
Agostino Gemelli 1, 00168 Roma, Italy. Phone: +39 06 30154341; e-mail: graziano.onder@rm.unicatt.it

Key words: Prevention, multimorbidity, polypharmacy, elderly.

Older adults often have co-occurring multiple
chronic and acute diseases, which progressively
and steadily increase in prevalence with age (1, 2).
The treatment of these diseases usually requires multiple
drugs (polypharmacy); it has been estimated that more than
50% of persons aged 65 years or older receive five or moredrugs concomitantly (3, 4). Drug use in the older population might raise several concerns related to an increased riskof drug-drug and drug-disease interactions, poor adherence
to treatment, and increased risk of adverse drug reactions(5-7). In this chapter we will discuss what role drugs andpolypharmacy play in the development, management andtreatment of frailty.

Frailty is a complex condition and there may be multiple
factors associated with its onset and development. The Figure illustrates potential targets for drug treatment of frailty: chronic somatic conditions, sarcopenia, and hormonal
deficits. Hormonal deficits in testosterone, Vitamin D, or
growth hormone may lead to neuroendocrine dysregulation, contributing to decreased muscle mass and ‘anorexia of aging’ (8). Chronic conditions can lead to frailty via
numerous pathways, including the onset of sarcopenia, orby causing disability or reduced physical functioning. Sarcopenia itself is associated with reduced physical functioning
and the onset of disability (9-12). All three pathways, contribute both separately and together to an overall syndromeof frailty in the elderly. Therefore, the role of drugs on thedevelopment, management and treatment of frailty shouldtake all three factors into account.
DRUGS TO TREAT CHRONIC CONDITIONS

Frailty is associated with numerous chronic somatic conditions, including cerebrovascular disease, diabetes, coronary
disease, and hypertension, among others. Given the association between chronic conditions and frailty, one angle totake when considering the treatment of frailty is whether
drugs used to treat the chronic conditions associated withfrailty may in turn lead to improvements in frailty and related functional outcomes. Currently, data concerning thisissue are poor. One reason for this is that large drug trials
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are often not designed to assess the impact of the respective treatment on outcomes other than the primary disease.
Thus, they may not adequately assess outcomes such as
frailty or improvements in functional outcomes. For example, Di Bari et al (13) looked at data from a randomized
control trial of antihypertensive medication in older adults,
where the primary and secondary endpoints were clinicaloutcomes such as stroke, myocardial infarction, coronary
disease, cardiovascular morbidity, and mortality. Using thisdata they subsequently examined whether the treatment
also had an effect on frailty-related outcomes such as functional factors. Their study identified a number of limitations
in examining these endpoints in such as study. In particular, there was a differential loss of data for participants inthe treatment and placebo group, which led to a bias in the
results concerning the functional and cognitive outcomes.
Older and more impaired elderly were more likely to be lost
to follow-up, and this selective drop out made it difficult todraw any firm conclusions about the effect of the treatment
on these frailty-related outcomes. This raises the issue that
there is a great need for well-conducted randomized control trials that examine ‘real world’ outcomes of drug treatments for chronic diseases, including frailty-related factors
such as improvements in physical functioning, hospitalization, dependency in activities of daily living, among others.
DRUGS TO TREAT SARCOPENIA

Sarcopenia, a clinical syndrome characterized by loss ofmuscle mass accompanied by functional deterioration suchas walking speed, walking distance, or grip strength (14),has been proposed as a biological substrate of physicalfrailty (9). Sarcopenia predicts frailty, as well as other pooroutcomes including hip fracture, disability, and mortality(10-12). Evidence suggests that treating sarcopenia maylead to clinically beneficial outcomes in older person withfrailty (15, 16).
There are numerous potential causes and associated factors
related to the development of sarcopenia, including genetic factors, vascular factors, mitochondrial defects, insulin
resistance, poor blood flow, and decreasing levels of testosterone, vitamin D, and growth hormone among others(for a recent review see (17)). Consequently, given the range
of factors involved in the pathophysiology of sarcopenia,
there might be numerous approaches for treating the disorder, including non-pharmacological interventions such as
resistance exercise (18), and pharmacological approaches
such as Creatine Selective Androgen Receptor Modulators(SARMS) to increase muscle mass and physical functioning(19), myostatin antibodies to increase muscle volume, andangiotensin converting enzyme inhibitors to improve physical functioning (20, 21), among others. In addition to thecurrent drug treatments, there is a wide range of pharma-cological options that can potentially be considered for developing future treatments for sarcopenia, such as growthdifferentiation factor, myokines activators and inhibitors,
nitric oxide, and biguanides, among others (17). Results oftrials focused on the use of these drugs to specifically treat
sarcopenia and prevent frailty have, so far, not providing
any convincing evidence.
HORMONAL TREATMENTS

Testosterone has been shown to increase muscle strengthand mass in older persons (22-24), as well as improving
functional outcomes such as strength and walking distancein patients with frailty (25, 26), and decreasing hospitalization in frail older persons (27). Testosterone is currently
considered to be the most effective and safest treatment forsarcopenia (17), although there are numerous potential side
effects. Current trials are ongoing, with particular emphasison comparing testosterone treatment with SARMs, which
may potentially be safer. There is currently little evidence
concerning the effect of SARMS on sarcopenia, as the only
clinical trial on the subject was halted, but initial evidence
from this study showed an improvement in functional
abilities such as stair climbing and gait speed (19). Other
SARMs trials on patients with other chronic diseases suchas COPD, osteoporosis, chronic kidney disease, and cancer
reported improvements in functional abilities such as stair
climbing (28), and increased muscle mass (29-31). Morestudies on the effect of SARMs on clinical and functional
outcomes in patients with sarcopenia are needed, as well as
studies directly comparing the treatment effect of SARMs
versus testosterone in patients with sarcopenia and frailty.
Vitamin D is an established treatment for sarcaponia (32);
it increases muscle strength (33, 34) and has positive effects on frailty-related outcomes in older persons such as
decreasing the incidence of falls (33), hip fractures (35),and mortality (36). Other hormonal treatments such as
growth hormone are currently not considered as effective
treatments for sarcopenia. Although growth hormone has
been shown to increase muscle mass and mean body massin older persons (37, 38) it does not appear to improve muscle strength, and is associated with numerous side effects(38-40).
DRUGS AS A CAUSE OF FRAILTY

In addition to the discussion of how to treat frailty, consideration also needs to be taken into the role that drugs
may have on the development of frailty. Numerous specific medications have been shown to be associated withfrailty and frailty-related factors. In particular, the use of
anticholinergic drugs is associated with frailty and related
factors such as falls, hip fractures, and reduced activities of103

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daily living functions (41-44). Inappropriate drug prescribing is also another pathway through which drugs mightcause frailty. For example, improper use of diuretics incertain patients could inadvertently lead to increased frailty
and frailty-related factors by causing dehydration (45-47).
Another such example is the overuse and inappropriate useof proton pump inhibitors in the elderly, which can cause
vitamin B12 deficiency, reduce calcium absorption, increase
fracture risk, and are associated with increased mortality(48-50). Further, poor management of drug regimes canlead to frailty. For example, the overtreatment of diabetes
in older persons is associated with frailty (51, 52), and diabetes treatment in frail older individuals needs to be carefully managed, especially in nursing home patients (52). Finally, polypharmacy is related to an increase in frailty in older
adults (53-55). This relationship may be bidirectional. On
one hand, an increase in the number of chronic conditions
that are associated with frailty can increase polypharmacy.
For example, diabetes is associated with frailty, as well as
comorbidity and polypharmacy in geriatric patients (2, 51,
56, 57). On the other hand, there is also evidence to suggest that polypharmacy itself may be involved in the development of frailty (58-60). Polypharmacy was shown to be
associated with more than a twofold increased incidence ofdeveloping frailty over two years in men (58). The authors
suggested that the high-risk prescribing may have directly
aggravated the clinical features of frailty. Thus, a reductionof polypharmacy is advised for both the prevention andmanagement of frailty (61).

ed in conditions such as chronic heart failure and chronic
kidney failure (62, 63), where certain risk factors, such as
hypertension, lose their importance and may actually become protective factors. This theory could apply similarly
to frailty. The pharmacological treatment of older adults
might differ based on their frailty status and, in particular,
the benefits of a given pharmacological treatment might be
reduced in the presence of frailty. For example, althoughantihypertensive treatment in robust older persons withhypertension is beneficial, the association between hypertension and mortality in older persons is mediated byfrailty factors such as slower walking speed (64). Treating
hypertension in frail older persons might have no benefits
and could lead to negative outcomes (65, 66). Similarly,
the treatment of diabetes to achieve tight glycemic control
might be unrewarding in frail people and the overtreatment
of diabetes is associated with frailty (51, 52, 67). If futurestudies can further support the theory of reverse epidemiology in frailty, it might be questionable whether pharmacological treatment in frailty is appropriate, given that the useof many medications leads to negative side effects.
In conclusion, the role of drugs on the onset, development and management of frailty is complex, and current
evidence is sparse. Specifically, more data are needed fromrandomized control trials examining ‘real world’ outcomesof drug treatments for chronic diseases, as well as evidence
concerning the treatment of sarcopenia and effects on frailty and frailty- related outcomes. Current research supports
the need for good drug management and reduction ofpolypharmacy to reduce frailty.

FRAILTY AS AN EFFECT MODIFIER

Conflict of Interest: None
Finally, it is necessary to discuss how frailty could act as aneffect modifier in the treatment of chronic diseases. The
concept of “reverse epidemiology” has been demonstrat-

This article is currently in press. Published in the Journal of Frailty andAging 2016
http://www.jfrailtyaging.com/

REFERENCES
1. Marengoni A, Angleman S, Melis R, et al. Aging with multimorbidity: a systematic review of the literature. Ageing Res Rev.
2011;10:430-9.
2. Onder G, Palmer K, Navickas R, et al. Time to face the challengeof multimorbidity. A European perspective from the joint action
on chronic diseases and promoting healthy ageing across the life
cycle (JA-CHRODIS). Eur J Intern Med. 2015;26:157-9.
3. Onder G, Bonassi S, Abbatecola AM, et al. High prevalence ofpoor quality drug prescribing in older individuals: a nationwide
report from the Italian Medicines Agency (AIFA). J Gerontol A Biol
Sci Med Sci. 2014;69:430-7.
4. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA.
Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA. 2002;287:337-44.

5. Marengoni A, Pasina L, Concoreggi C, et al. Understanding adverse drug reactions in older adults through drug-drug interactions. Eur J Intern Med. 2014;25:843-6.
6. Dumbreck S, Flynn A, Nairn M, et al. Drug-disease and drug-druginteractions: systematic examination of recommendations in 12
UK national clinical guidelines. BMJ. 2015:350;h949.
7. Nobili A, Pasina L, Tettamanti M, et al. Potentially severe drug interactions in elderly outpatients: results of an observational studyof an administrative prescription database. J Clin Pharm Ther.
2009;34:377-86.
8. Visvanathan R. Anorexia of Aging. Clin Geriatr Med. 2015;31:417-27.
9. Landi F, Calvani R, Cesari M, et al. Sarcopenia as the Biological
Substrate of Physical Frailty. Clin Geriatr Med. 2015;31:367-74.

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10. Landi F, Cruz-Jentoft AJ, Liperoti R, et al. Sarcopenia and mortality
risk in frail older persons aged 80 years and older: results from
ilSIRENTE study. Age Ageing. 2013;42:203-9.
11. Oliveira A, Vaz C. The role of sarcopenia in the risk of osteoporotic
hip fracture. Clin Rheumatol. 2015 Apr 26. [Epub ahead of print]
12. Hirani V, Blyth F, Naganathan V, et al. Sarcopenia Is AssociatedWith Incident Disability, Institutionalization, and Mortality in
Community- Dwelling Older Men: The Concord Health and Ageing in Men Project. J Am Med Dir Assoc. 2015;16:607-13.
13. Di Bari M, Pahor M, Franse LV, et al. Dementia and disability
outcomes in large hypertension trials: lessons learned from thesystolic hypertension in the elderly program (SHEP) trial. Am J
Epidemiol. 2001;153:72-8.
14. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing.
2010;39:412-23.
15. Rolland Y, Onder G, Morley JE, et al. Current and future pharmacologic treatment of sarcopenia. Clin Geriatr Med. 2011;27:423-47.
16. Sukuma K, Yamaguchi A. Molecular mechanisms in aging andcurrent strategies to counteract sarcopenia. Curr Aging Sci.
2010;3:90-101.
17. Morley JE. Pharmacologic Options for the Treatment of Sarcopenia. Calcif Tissue Int. 2015 Jun 23. [Epub ahead of print]
18. Michel JP, Cruz-Jentoft AJ, Cederholm T. Frailty, Exercise and Nutrition. Clin Geriatr Med. 2015;31:375-87.
19. Papanicolaou DA, Ather SN, Zhu H, et al. A phase IIA randomized, placebocontrolled clinical trial to study the efficacy andsafety of the selective androgen receptor modulator (SARM), MK0773 in female participants with sarcopenia. J Nutr Health Aging.
2013;17:533-43.
20. Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effectof perindopril on physical function in elderly people with functional
impairment: a randomized controlled trial. CMAJ. 2007;177:867-74.
21. Onder G, Penninx BW, Balkrishnan R, et al. Relation between useof angiotensin-converting enzyme inhibitors and muscle strengthand physical function in older women: an observational study.
Lancet. 2002;359(9310):926-30.
22. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone(T) alone or with finasteride increses physical performance, grip
strength, and lean body mass in older men with low serum T. J Clin
Endocrinol Metab. 2005;90:1502-10.
23. Sih R, Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Ross C. Testosterone replacement in older hypogonadal men: A 12-month randomized controlled trial. J Clin Endocrinol Metab. 1997;82:1661-7.
24. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P,
Morley JE. Oral testosterone supplementation increases muscle
and decreases fat mass in healthy elderly males with low-normal
gonadal status. J Gerontol A. 2003;58:618-25.
25. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: arandomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95:639-50.
26. Kenny AM, Kleppinger A, Annis K, et al. Effects of transdermal
testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J Am
Geriatr Soc. 2010;58:1134-43.
27. Chapman IM, Visvanathan R, Hammond AJ, et al. Effect of testosterone and a nutritional supplement, alone and in combination,
on hospital admissions in undernourished older men and women.
Am J Clin Nutr. 2009;89:880-9.

28. Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body massand physical function in healthy elderly men and postmenopausal
women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2:153-61.
29. Sharma S, Arneja A, McLean L, et al. Anabolic steroids in COPD:
a review and preliminary results of a randomized trial. Chron Respir Dis. 2008;5:169-76.
30. Macdonald JH, Marcora SM, Jibani MM, Kumwenda MJ, Ahmed
W, Lemmey AB. Nandrolone decanoate as anabolic therapy inchronic kidney disease: a randomized phase II dose-finding study.
Nephron Clin Pract. 2007;106:125–35.
31. Frisoli A Jr, Chaves PH, Pinheiro MM, Vl Szejnfeld. The effect ofnandrolone decanoate on bone mineral density, muscle mass,and hemoglobin levels in elderly women with osteoporosis: a double-blind, randomized, placebo-controlled clinical trial. J Gerontol
A. 2005;60:648– 53.
32. Rizzoli R. Nutrition and Sarcopenia. J Clin Densitom. 2015 Jun 6.
[Epub ahead of print]
33. Murad MH, Elamin KB, Abu Elnour NO, et al. Clinical review: The
effect of vitamin D on falls: a systematic review and meta-analysis.
J Clin Endocrinol Metab. 2011;96:2997-3006.
34. Beaudart C, Buckinx F, Rabenda V, et al. The effects of vitamin
D on skeletal muscle strength, muscle mass, and muscle power:a systematic review and meta-analysis of randomized controlled
trials. J Clin Endocrinol Metab. 2014;99:4336-45
35. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis
of vitamin D dose requirements for fracture prevention. N Engl J
Med. 2012;367:40-9.
36. Rejnmark L, Avenell A, Masud T, et al. Vitamin D with calcium
reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab.
2012;97:2670-81.
37. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth
hormone in men over 60 years old. N Engl J Med. 1990;323:1-6.
38. Kim MJ, Morley JE. The hormonal fountains of youth: myth or reality? J Endocrinol Invest. 2005;28:5-14.
39. Cohn L, Feller AG, Draper MW, Rudman IW, Rudman D. Carpal
tunnel syndrome and gynaecomastia during growth hormone
treatment of elderly men with low circulating IGF-1 concentrations. Clin Endocrniol (Oxf). 1993;39:417-25.
40. Liu H, Bravata DM, Olkin I, et al. Systematic review: the safety andefficacy of growth hormone in the healthy elderly. Ann Intern Med.
2007;146:104-15
41. Moulis F, Moulis G, Balardy L, et al. Exposure to atropinic drugs
and frailty status. J Am Med Dir Assoc. 2015:16:253-7.
42. Landi F, Dell’Aquila G, Collamati A, et al. Anticholinergic drug use
and negative outcomes among the frail elderly population living ina nursing home. J Am Med Dir Assoc. 2014;15:825-9.
43. Lowry E, Woodman RJ, Soiza RL, Mangoni AA. Associations between the anticholinergic risk scale score and physical function:
Potential implications for adverse outcomes in older hospitalized
patients. J Am Med Dir Assoc. 2011;12:565-72.
44. Moga DC, Carnahan RM, Lund BC, et al. Risks and benefits of bladder antimuscarinics among elderly residents of Veterans Affairs
Community Living Centers. J Am Med Dir Assoc. 2013;14:749-60.
45. Thomas DR, Cote TR, Lawhorne L, et al. Understanding clinical dehydration and its treatment. J Am Med Dir Assoc. 2008;9:292-301.
46. Wilson MM. The management of dehydration in the nursing
home. J Nutr Health Aging 1999;3:53-61.

105

WHITE BOOK

47. Schols JM, De Groot CP, van der Cammen Tj, Olde Rikkert MG.
Preventing and treating dehydration in the elderly during periodsof illness and warm weather. J Nutr Health Aging. 2009;13:150-7.
48. de Souto Barreto P, Lapeyre-Mestre M, Mathieu C, et al. Prevalence and associations of the use of proton-pump inhibitors innursing homes: a cross-sectional study. J Am Med Dir Assoc.
2013;14:265-9.
49. Maggio M, Corsonello A, Ceda GP, et al. Proton pump inhibitors
and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med.
2013;173:518-23.
50. Ngamruengphong S, G.I. Leontiadis, S. Radhi, et al. Proton pumpinhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol. 2011;106:1209-18.
51. Sinclair A, Morley JE, Rodriguez-Mañas L, et al. Diabetes mellitus
in older people: position statement on behalf of the International
Association of Gerontology and Geriatrics (IAGG), the European
Diabetes Working Party for Older People (EDWPOP), and the International Task Force of Experts in Diabetes. J Am Med Dir Assoc.
2012;13:497-502.
52. Sinclair A, Morley JE. How to manage diabetes mellitus in older
persons in the 21st century: applying these principles to long term
diabetes care. J Am Med Dir Assoc. 2013;14:777-80.
53. Gnjidic D, Hilmer SN, Blyth FM, et al. Polypharmacy cutoff andoutcomes: Five or more medicines were used to identify community- dwelling older men at risk of different adverse outcomes. J
Clin Epidemiol. 2012;65:989-95.
54. Bennett A, Gnjidic D, Gillett M, et al. Prevalence and impact of fallrisk- increasing drugs, polypharmacy, and drug-drug interactions
in robust versus frail hospitalised falls patients: a prospective cohort study. Drugs Aging. 2014;31:225-32.
55. Moulis F, Moulis G, Balardy L, et al. Searching for a polypharmacy
threshold associated with frailty. J Am Med Dir Assoc. 2015;16:259-61.

56. Chen LK, Chen YM, Lin MH, Peng LN, Hwang SJ. Care of elderly
patients with diabetes mellitus: a focus on frailty. Ageing Res Rev.
2010;9 Suppl 1:S18-22.
57. Araki A, Ito H. Diabetes mellitus and geriatric syndromes. Geriatr
Gerontol Int. 2009;9:105-14.
58. Gnjidic D1, Hilmer SN, Blyth FM, et al. High-risk prescribing andincidence of frailty among older community-dwelling men. Clin
Pharmacol Ther. 2012;91:521-8.
59. Bronskill SE, Gill SS, Paterson JM, et al. Exploring variation inrates of polypharmacy across long term care homes. J Am Med
Dir Assoc. 2012;13:309e15-21.
60. Gokce Kutsal Y, Barak A, Atalay A, et al. Polypharmacy in the elderly: A multicenter study. J Am Med Dir Assoc. 2009;10:486-90.
61. Morley JE, Vellas B, van Kan GA, et al. Frailty consensus: a call toaction. J Am Med Dir Assoc. 2013;14:392-7.
62. Kalantar-Zadeh K, Block G, Horwich T, Fonarow GC. Reverse epidemiology of conventional cardiovascular risk factors in patientswith chronic heart failure. J Am Coll Cardiol. 2004;43:1439-44.
63. Kopple JD. The phenomenon of altered risk factor patterns or reverse epidemiology in persons with advanced chronic kidney failure. Am J Clin Nutr. 2005;81:1257-66.
64. Odden MC, Peralta CA, Haan MN, Covinsky KE. Rethinking theassociation of high blood pressure with mortality in elderly adults:
the impact of frailty. Arch Intern Med. 2012;172:1162-8.
65. Goodwin JS. Embracing complexity: A consideration of hypertension in the very old. J Gerontol A Biol Sci Med Sci. 2003;58:653-8.
66. Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs invery old people: a subgroup meta-analysis of randomised controlled trials. INDANA Group. Lancet. 1999;353:793-6.
67. Benetos A, Novella JL, Guerci B, et al. Pragmatic diabetes management in nursing homes: individual care plan. J Am Med Dir Assoc.
2013;14:791- 800.

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EXERCISE: AN IMPORTANT KEY TO PREVENT PHYSICAL AND COGNITIVE FRAILTY

EXERCISE: AN IMPORTANT KEY TO PREVENTPHYSICAL AND COGNITIVE FRAILTY
M.C. DULAC1, M. AUBERTIN-LEHEUDRE1,2

1 Faculty of Science, Department of Exercise Science, Université du Québec à Montréal, Montréal, Canada;
2 Centre de recherche de l’Institut universitaire de gériatrie de Montréal, Montréal, Canada
Correspondence: Mylene Aubertin-Leheudre, Faculty of Science, Department of Exercise Science, Sciences Biologiques Building,SB-4615, 141 av president Kennedy, Montréal, Quebec, Canada, H3C 3P8, Phone: 514-987-3000 #5018, Fax: 514-987-6166,
Email: aubertin-leheudre.mylene@uqam.ca

Key words: Frailty, physical function, cognition, exercise, guidelines.

INTRODUCTION

The life expectancy of older individuals continues to increase with persons aged 70 years and more representing thefastest growing proportion of the western population (1).
At the same time, this extended life should involve the preservation of autonomy through the maintenance of physical and cognitive function. However, with normal aging,people will develop frailty. Thus, identifying cost-effective
interventions, which prevent frailty, is one of the mostimportant challenges of health care systems. The difficulty in developing specific interventions to prevent or delay
frailty is due to the complexity of the phenomenon, which
involves many different physiological, cognitive, and psychological systems. Because no single manifestation offrailty can encompass the whole of the symptoms or signs
present, consensual exercise training guidelines remain paradoxically difficult. Therefore, the aim of this review is toaddress an overview of the literature regarding the effect of
exercise/physical activity in the prevention of physical andcognitive frailty.
EXERCISE AND PHYSICAL FRAILTY

Although there is not a universally accepted operational
definition of frailty, the most commonly used definition ofa physical phenotype of frailty comes from the Fried Frailty
Index (FFI). Fried proposed identifying frailty in the indi-vidual by observing the presence of at least three of thefive following symptoms: shrinking (nutritional/metabolic
component assessed by unintentional weight loss), weakness (indicated by muscle strength), poor endurance andenergy (per self-reported exhaustion), slowness (demonstrated by slow walking speed) and low amounts of physicalactivity (2).
There is evidence to suggest that history of leisure timephysical activity (LTPA) is related to frailty. In fact; Savela etal. showed that people with high LTPA had up to 80% lower risk of frailty compared to sedentary subjects (3). Thisconclusion has been confirmed by others who observedthat regularly engaged exercise activities in elderly individuals were less likely to develop frailty through a 5 year period
than those who were sedentary (4, 5).
The benefits of exercise in improving functional capacities
which include daily living activities, falls and quality of lifeof frail older adults has been considerably reported throughreviews or meta-analyses (6-9). Regarding the literature, lowintensity resistance training (10, 11), power resistance training (12), multimodal (13, 14); could be recommended toolder frail individuals but not flexibility home programs orchair based exercises alone (10, 15, 16). In addition, aerobic
exercise could also counteract physical frailty through the
improvement of the maximal oxygen uptake (Vo2max) (17)and increased muscle mass (18, 19).

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EXERCISE AND COGNITIVE FRAILTY

PRACTICAL GUIDELINES

It is not satisfactory to define frailty in the physical domainalone since there are other factors that have not yet been
examined, but are recognized as part of the frailty syndrome such as cognition. While physical frailty is a widely
recognized problem in the elderly, cognitive frailty has only
recently become the focus of inquiry. Recently, the International Academy of Nutrition and Aging (IANA) and theInternational Association of Gerontology and Geriatrics(IAGG) summarized cognitive frailty as a heterogeneous
clinical manifestation characterized by the simultaneouspresence of physical frailty and cognitive impairment, inthe absence of dementia (20).
It is well establish that aerobic exercises such as walking
may prevent the decline in cognitive function in non-frail
older adults (21-23). However, few studies have examined the effect of other types of exercises (tai-chi, bodyand mind, resistance training) on cognitive function. For
example, it has been observed that resistance training contributes positively and significantly in the improvement ofbrain functional plasticity, executive function and response
inhibition (24, 25). There is also evidence to suggest thathome based exercises may improve executive function, specifically response inhibition, after 6 months (26). Moreover,studies have shown that Tai Chi could positively affect cognitive performance in older adults (27). It should also be
noted that combining aerobic training to resistance training
is more efficient in improving cognitive function in older
adults than aerobic or resistance training alone (28, 29).
However, current evidence is limited, and research is needed on the role of exercise parameters (e.g. volume, types,
and intensity) on specific cognitive functions. Indeed, it has
been reported that the volume, intensity and variation ofphysical activities as well as the history of practice was positively associated with processing speed, memory, mental
flexibility, executive function and overall cognitive function(30, 31). Finally it has been proposed that exercise could
prevent cognitive frailty through an improvement on brain
plasticity, structural brain reserves and cerebral blood flow
(32-34).
Thus, even if exercise is promising to improve cognitive
decline with age in non-frail individuals, to our knowledge
only one study has been conducted to improve cognitive
function using exercise alone in frail older adults (35). This
study concluded that aerobic training combined to resistance training is efficient to improve executive functions,processing speed and working memory. Thus, RCT using
exercise training to counteract cognitive frailty are neededin frail elderly because this population is poorly studied.

Overall, it is important to propose an exercise program reproducible at home including gradual increases in the volume, intensity, complexity and type of all of the exercises
through resistance, aerobic, as well as body and mind training. Since 64 % of older people are considered as sedentary,
increasing the long-term adherence is important in orderto create a specific training program that includes regularchanges in the intensity and type of exercises and is feasible
at home (counteract the transportation).
More specifically, resistance-training programs should be
performed two to three times per week, with two sets of
8-12 repetitions at an intensity that starts at 20%-30% andprogresses to 80% of 1RM. In addition, progressively, we
could increase the tempo to turn on power training, which
is more efficient to improve or maintain muscle quality. All
these exercises should be realized in exercise rooms under
supervision or at home using for example Swissball; freeweight, elastic band, chair and others with occasional supervision. To optimize the functional capacity of individuals,
resistance/power training programs should be combinedwith exercises in which daily activities are simulated, such as
the sit- to- stand, tandem foot standing, heel–toe walking,line walking, stepping practice, standing on one leg, weighttransfers (from one leg to the other). These exercises areoften offered through body and mind activities such as tai
chi and pilates. Aerobic training should include walking
with changes in pace and direction, treadmill walking, stepups, stair climbing, and stationary cycling. Aerobic exercise
may start at 5-10 min during the first weeks of training andprogress to 15-30 min for the remainder of the program.
The Rate of Perceived Exertion scale should be used forprescribing the exercise intensity, and an intensity of 12–14
on the Borg scale appears to be well tolerated.
CONCLUSIONIn General, to prevent physical and cognitive frailty adverse
effects, frail older adults could practice multimodal physicalactivity programs (resistance/power, aerobic and body andmind exercise) at least twice a week during 30-45 min persession at moderate to high intensity. In addition, to optimize the physical training prescription and meet these goals
in subjects with physical and/or cognitive frailty, the mosteffective type of exercise program should be identified byconsidering the optimal combination of intensity, volume,and frequency training that would promote neuromuscular,
muscular and cardiovascular adaptations and thus result in
improved functional and cognitive capacity in the frail elderly.
Conflict of Interest: None108

EXERCISE: AN IMPORTANT KEY TO PREVENT PHYSICAL AND COGNITIVE FRAILTYThis article was published in the Journal of Frailty & Aging
2016;5(1):3-5. doi: 10.14283/jfa.2015.72.
http://www.jfrailtyaging.com/

REFERENCES
1. Manton KG, Vaupel J. Survival after the Age of 80 in the United States, Sweden, France, England, and Japan. N Engl J Med
1995;333:1232-5.
2. Fried LP, Tangen CM, Walston J et al. Frailty in Older Adults: Evidence
for a Phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-56.
3. Savela SL, Koistinen P, Stenholm S, et al. Leisure-Time Physical
Activity in Midlife Is Related to Old Age Frailty. J Gerontol A Biol
Sci Med Sci 2013;68:1433-8.
4. Brach JS, Simonsick EM, Kritchevsky S, Yaffe K, Newman AB. The
Association between Physical Function and Lifestyle Activity andExercise in the Health, Aging and Body Composition Study. J Am
Geriatr Soc 2004;52:502-9.
5. Peterson MJ, Giuliani C, Morey MC, et al. Physical Activity as aPreventative Factor for Frailty: The Health, Aging, and Body Composition Study. J Gerontol A Biol Sci Med Sci 2009;64:61-68.
6. Cadore EL, Moneo AB, Mensat MM, et al. Positive Effects of Resistance Training in Frail Elderly Patients with Dementia after LongTerm Physical Restraint. Age (Dordr) 2014;36:801-11.
7. Chou CH, Hwang CL, Wu YT. Effect of Exercise on Physical Function, Daily Living Activities, and Quality of Life in the Frail Older
Adults: A Meta-Analysis. Arch Phys Med Rehab 2012;93: 237-44.
8. Gine-Garriga M, Roque-Figuls M, Coll-Planas L, Sitja-Rabert M,
Salva A. Physical Exercise Interventions for Improving Performance-Based Measures of Physical Function in Community-Dwelling, Frail Older Adults: A Systematic Review and Meta-Analysis.
Arch Phys Med Rehabil 2014;95:753-69 e3.
9. Weening-Dijksterhuis E, de Greef MHG, Scherder EJA, Slaets JPJ,
van der Schans CP. Frail Institutionalized Older Persons: A Comprehensive Review on Physical Exercise, Physical Fitness, Activities of Daily Living, and Quality-of-Life. Am J Phys Med Rehab
2011;90:156-68.
10. Brown M, Sinacore DR, Ehsani AA, Binder F, O Holloszy J, Kohrt
WM. Low-Intensity Exercise as a Modifier of Physical Frailty in Older Adults. Arch Phys Med Rehab 2000;81:960-65.
11. Chandler JM, Duncan PW, Kochersberger G, Studenski S. Is Lower
Extremity Strength Gain Associated with Improvement in Physical
Performance and Disability in Frail, Community-Dwelling Elders?
Arch Phys Med Rehab 1998;79:24-30.
12. Izquierdo M, Lusa Cadore E. Muscle Power Training in the Institutionalized Frail: A New Approach to Counteracting Functional Declines and Very Late-Life Disability. Curr Med Res Opin
2014;30:1385-90.
13. Gill TM, Baker DI, Gottschalk M, Peduzzi PN, Allore H, ByersA. A
Program to Prevent Functional Decline in Physically Frail, Elderly
Persons Who Live at Home. New Engl J Med 2002;347:1068-74.
14. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of Structured
Physical Activity on Prevention of Major Mobility Disability inOlder Adults: The Life Study Randomized Clinical Trial. JAMA
2014;311:2387-96.
15. Anthony K, Robinson K, Logan P, Gordon AL, Harwood RH, Masud T. Chair-Based Exercises for Frail Older People: A Systematic
Review. BioMed Res Int 2013 (2013).
16. Binder EF, Schechtman KB, Ehsani AA, et al. Effects of Exercise
Training on Frailty in Community-Dwelling Older Adults: Results ofa Randomized, Controlled Trial. J Am Geriatr Soc 2002;50:1921-28.
17. Ehsani AA, Spina RJ, Peterson LR et al. Attenuation of Cardiovascular Adaptations to Exercise in Frail Octogenarians. J Appl Phys
2003;95:1781-88.

18. Harber MP, Konopka AR, Douglass MD, et al. Aerobic Exercise
Training Improves Whole Muscle and Single Myofiber Size andFunction in Older Women. Am J Physiol Regul Integr Compar
Physiol 2009;297:R1452-R59.
19. Sugawara J, Miyachi M, Moreau KL, Dinenno FA, DeSouza CA,
Tanaka H. Age-Related Reductions in Appendicular Skeletal Muscle Mass: Association with Habitual Aerobic Exercise Status. Clin
Physiol Functional Imaging 2002;22:169-72.
20. Kelaiditi E, Cesari M, Canevelli M, et al. Cognitive Frailty: Rationaland Definition from an (I.A.N.A./I.A.G.G.) International Consensus Group. J Nutr Health Aging 2013;17:726-34.
21. Hindin SB, Zelinski EM. Extended Practice and Aerobic Exercise
Interventions Benefit Untrained Cognitive Outcomes in Older
Adults: A Meta-Analysis. J Am Geriatr Soc 2012;60: 136-41.
22. Landi F, Onder G, Carpenter I, Cesari M, Soldato M, Bernabei R.
Physical Activity Prevented Functional Decline among Frail Community-Living Elderly Subjects in an International Observational
Study. J Clin Epidemiol 2007;60:518-24.
23. Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic Exercise and
Neurocognitive Performance: A Meta-Analytic Review of Randomized Controlled Trials. Psychosomatic Med 2010;72:239.
24. Cassilhas RC, Viana VAR, Grassmann V, et al. The Impact of Resistance Exercise on the Cognitive Function of the Elderly. Med Sci
Sports Exer 2007;39:1401.
25. Liu-Ambrose T, Nagamatsu LS, Graf P, Beattie BL, Ashe MC, Handy
TC. Resistance Training and Executive Functions: A 12-Month Randomized Controlled Trial. Arch Intern Med 2010;170:170-78.
26. Liu-Ambrose T, Donaldson MG, Ahamed Y, et al. Otago HomeBased Strength and Balance Retraining Improves Executive Functioning in Older Fallers: A Randomized Controlled Trial. J Am Geriatr Soc 2008;56:1821- 30.
27. Chang YK, Nien YH, Tsai CL, Etnier JL. Physical Activity and Cognition in Older Adults: The Potential of Tai Chi Chuan. J Aging Phys
Act 2010;18:451-72.
28. Bherer L, Erickson KI, Liu-Ambrose T. A Review of the Effects ofPhysical Activity and Exercise on Cognitive and Brain Functions inOlder Adults. J Aging Res 2013;657508.
29. Rolland Y, Abellan van Kan G, Vellas B. Physical Activity and Alzheimer’s Disease: From Prevention to Therapeutic Perspectives. J
Am Med Dir Assoc 2008:9:390-405.
30. Arab L, Sabbagh MN. Are Certain Life Style Habits Associated withLower Alzheimer Disease Risk? J Alzheimer Dis 2010;20:785.
31. Voelcker-Rehage C, Niemann C. Structural and Functional Brain
Changes Related to Different Types of Physical Activity across theLife Span. Neurosci Biobehavioral Rev 2013;37:2268-95.
32. Angevaren M, Vanhees L, Wendel-Vos W et al. Intensity, but Not
Duration, of Physical Activities Is Related to Cognitive Function.
Eur J Cardiovasc Prev Rehab 2007;14:825-30.
33. Cotman CW, Berchtold NC. Exercise: A Behavioral Intervention to Enhance Brain Health and Plasticity. Trends Neurosci 2002;25:295-301.
34. Ide K, Secher NH. Cerebral Blood Flow and Metabolism During
Exercise. Progr Neurobiol 2000;61:397-414.
35. Langlois F, Minh Vu TT, Kergoat MJ, Chassé K, Dupuis G, Bherer
L. The Multiple Dimensions of Frailty: Physical Capacity, Cognition, and Quality of Life. Int Psychogeriatr 2012;24:1429-36.

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THE ROLE OF NUTRITION FOR THE PREVENTION
AND TREATMENT OF FRAILTY
Sabine GOISSER, PhD1,2, Sophie GUYONNET, PhD3, Dorothee VOLKERT, PhD1

1 Institute for Biomedicine of Aging (IBA), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Kobergerstr. 60, D-90408
Nuremberg, Germany.
2 Institut du Vieillissement, Gérontopôle, Centre Hospitalier Universitaire (CHU) de Toulouse, 37 allées Jules Guesde, 31000
Toulouse, France.
3 Gérontopôle, Centre Hospitalier Universitaire (CHU) de Toulouse, 170 avenue de Casselardit, 31059 Toulouse, France.
Correspondence: Dr. Sabine Goisser, Institut du Vieillissement, c/o Faculté de Médecine, 37 Allées Jules Guesde,
31000 Toulouse, France, e-mail: sabinegoisser@gmx.de

INTRODUCTION

While definitions of frailty still vary, it is generally agreed
upon that frailty is characterized by decreased reserve androbustness, causing extreme vulnerability to stressors (1)that is mainly observable as diminished physical strengthand endurance (2-4). Nutrition is a crucial contributing factor in the complex etiology of frailty and its key component
sarcopenia (5), as it provides the energy and essential nutrients needed for the maintenance and performance of all organs and bodily functions, including muscle. However, nutritional intake in general decreases with ageing (among thereasons is the so-called anorexia of ageing) (6-8), and moreover, older individuals with anorexia seem to exhibit alteredeating patterns characterized by lower consumption of nutrient-rich foods (9). This may be aggravated by functional
problems impairing food access (10) and/or by following
restrictive diets (i.e. low-cholesterol, low-salt, diabetes) (11).
Monotonous diets result, and it is often challenging for older adults to meet their needs for energy and protein (1215), but in particular for micronutrients (16-19). A chroniclack of energy, macro- and/or micronutrients, however,
not only limits bodily functions, but over time promotes
atrophy and subsequent loss of body tissues, including
muscle (20-22). Thereby, chronic malnutrition is disturbing metabolic balance, decreasing the reserves of the bodyand diminishing its abilities to cope with stressors (4,21),i.e. promoting frailty.

This article aims to give a short overview on current knowledge concerning the role of nutrition for the prevention
and treatment of frailty, while providing readers with references giving an overview for further reading.
OBSERVATIONAL DATA

Epidemiological studies examining the association between
dietary intake or nutritional status and frailty have indeed
supported a putative role for nutrition in the developmentof frailty (17,23) and its key components sarcopenia andfunctional decline (10,18,21,24-26). In these studies, malnutrition, the risk of malnutrition, the presence of weightloss and/or low body weight/BMI were shown to be closely associated with frailty (17,27,28). Older adults that were
frail (17,28,29) (or, in some studies, had less lean/muscle
mass and/or worse physical performance, which may be regarded as signs for sarcopenia and frailty) (18,24,26,30-32)
were found to have lower intakes of energy, protein and/orof several micronutrients, as well as lower plasma concentrations of various nutrients when compared with non-frail
older individuals (or better performing persons, respectively). Semba et al. (33) observed in their study that each additional nutrient deficiency raised the risk of frailty in older
women by almost 10%. This emphasises the importance ofensuring a high quality of older persons’ diets in addition to
sufficient quantity as an essential component in the prevention and treatment of frailty.

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Although weight loss often is the most visible sign of chronic malnutrition (and one of the defining characteristics ofphysical frailty according to Fried et al.) (34), the absence of
weight loss as well as a normal or even elevated body weight
does not necessarily signify an adequate nutritional intake,especially with regard to micronutrients (35). Moreover, astable or even increasing body weight may mask an “internal” gradual reduction in lean body mass (skeletal muscle
and bone mass) that is accompanied by gains in (visceral)
fat mass (20,36). In recent years, epidemiological research
has come to notice that also the presence of obesity (beginning from BMI>30 kg/m2, but certainly at BMI>35 kg/m2)
and/or of excessive (visceral) fat mass heavily aggravates
the risk of mobility limitations and frailty (27,28,36-39), especially when it occurs in combination with sarcopenia (sarcopenic obesity)(36). Putting the focus on weight loss orbody weight alone may thus inadvertently lead to overlook
frailty and/or nutritional deficits in overweight and obese
older adults or those with no obvious weight loss.
INTERVENTION STUDIESSupplementation with protein or specific amino acids
Given their important role in (muscle) metabolism, the nutrients most extensively studied for the treatment or prevention of frailty, and especially of sarcopenia, are proteinsand (essential) amino acids (AA). Current evidence indicatesthat older persons may have reduced ability to use ingested
protein for muscle protein synthesis, and it is suggested toincrease the recommendations for protein intake in this age
group to at least 1,0-1,2 g/kg body weight/day in order tomaintain, or help regain, muscle mass (for an extensive review of these topics see (10,12–15,17,20,21,24,25,30-32,4044). Under debate is also whether the source of ingested
protein, specific AA or the timing of protein ingestion are
relevant factors affecting the anabolic effect of protein intake in older adults.
To date, reliable evidence from RCTs including frail older
individuals is scarce (28,45), and most studies in this area
focus on sarcopenia and/or include healthy older persons.
Moreover, interventional studies using protein supplements(mainly whey/casein protein or mixed/individual AA), andin rare cases protein rich foods such as meat or dairy products (31,42,46), mostly focus on the gain of body weight
and/or lean/muscle mass or on metabolic outcomes. Studies reporting functional outcomes so far provide heterogeneous results: supplementation has been shown to increaselean mass and to improve (or at least to reduce the declinein) physical function in some studies (13,14,28,41-43,46-49)
and was able to attenuate frailty in one small RCT(50). In
other trials, however, such interventions failed to show
beneficial effects on strength and performance, althoughsometimes achieving an increase in body weight and/or
lean mass (15,31,32,51,52).

Supplementation with other substances
Other nutritional supplements that have been tested in older adults, although again mostly in healthy and not frail persons, and mainly in relation to sarcopenia, are vitamin D,
creatine, beta-hydroxy-beta-methylbutyrate (ß-HMB), arginine, beta-alanine and citrulline, omega 3 fatty acids andantioxidants including carotenoids, selenium, vitamin E and
C and isoflavones (reviewed in (10,13,15,17,24,25,28,32,4043,47,53).). However, to date the number of studies is too
small and their designs and results are too heterogeneousto draw reliable conclusions regarding relevant effects ofsupplementation of these substances to help maintain or
restore robustness in the older population.
Combination of nutrition and exercise interventions
As described before, based on the currently available evidence it remains unclear if nutritional supplementationof protein and/or any other substance in itself may havesufficient effects to attenuate frailty (28). As in some studies the combination with exercise and/or physical activity was most effective to reinforce lean/muscle mass andphysical performance (28,31,45-47,54,55) and to decreasefrailty (50), it is currently recommended to combine both
approaches (21,44).
This is especially important in the case of frail but excessively obese older persons: future treatment strategies forthese individuals might need to include the considerationof potential functional benefits of weight loss (39), however, any weight loss (whether intentional or not) in older
persons may have potentially harmful effects by promoting
sarcopenia, bone loss, nutritional deficiencies, disability andeven excess mortality (36,37,56,57). It is therefore of utmost importance for these individuals to achieve a gain (oras a minimal requirement, avoiding a loss) of muscle mass
while losing excess fat mass. This implies that it is advisable to judge the benefits of any intervention in such obese(but also in in non-obese) frail participants not according to(change of) body weight, but instead to focus on changes
in body composition and, most importantly, on functional
outcome parameters.
The goal of maintaining muscle is most effectively achievedby adding physical activity and/or exercise components (58).
Indeed, in the few studies with older adults conducted inthis field, any intervention including nutritional changes
with the goal of losing weight provided the best functional
results when combined with exercise as a supporting factor (36,39,59-61). However, taking into consideration the111

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“obesity paradox” (57) (several meta-analyses indicate thatbeing overweight up to a BMI of 30 kg/m² or even more
may protect older persons against mortality and morbidity),
and that the harmful effects of obesity only increase at a
BMI >30 kg/m² or more, for every frail obese individual
the necessity of weight loss has to be really thoroughly reflected (57).
WHOLE DIET APPROACH

A major problem regarding the use of single nutrients infrailty prevention and therapy is that people do not eat single
nutrients, but foods and meals containing a whole range ofinteracting constituents. Therefore it may be more appropriate to consider the influence of the whole diet on frailty,
and also on its key components sarcopenia and functional
decline (10,18,62). Indeed, some epidemiological studies
have indicated that high adherence to “healthy” dietary patterns such as the currently best-investigated Mediterranean
diet (characterised by high consumption of nutrient-dense
foods such as fruits and vegetables, wholemeal cereals andoily fish, but low intake of saturated fats (18,62,63) in older
adults is associated with a lower risk of frailty (17,28,64),
or with greater muscle strength and/or better functional
performance (10,64,65). However, research in this field has
only started recently (63), and there is still a paucity of data
regarding the effects of certain food groups and/or dietaryintake patterns on the risk of frailty in older age.

CONCLUSIONSInadequate nutritional intake is an important modifiablerisk factor for frailty. Existing evidence supports the importance of adequate dietary quantity and especially quality toensure sufficient intakes of energy, protein and micronutrients (21). However, to date no nutritional intervention
or supplementation concept has emerged as being effective
for the prevention or treatment of frailty (17). Further research, including specifically the group of frail older persons and those at risk of frailty, and focussing on functional
benefits as an outcome, is needed to allow definite recommendations for optimal diet, i.e. food and nutrient intakes,
for this population.
Consequently, current best practice for frail older persons
remains to recommend the intake of high-quality, nutrient-dense foods in order to achieve adequate provision ofenergy, protein and micronutrients, and to avoid weight loss,
together with the promotion of physical activity (21). For
severely obese frail older adults, if the benefits of weightloss are clearly established, the most appropriate therapeutic approach might consist of a very moderate energy restriction of 200-500 kcal/day, targeted at a moderate weightloss of 0,5-1 kg/week (or 8-10% of initial body weight after
6 months), while assuring a protein intake of at least 1 g/kg
body weight/day and appropriate intake of micronutrients,
and always combined with physical activity and/or exercise(36,57,59).

REFERENCES
1. Rodríguez-Mañas, L., Féart, C., Mann, G. et al. (2013) Searchingfor an operational definition of frailty: a Delphi method based consensus statement: the frailty operative definition-consensus conference project. The Journals of Gerontology Series A: Biological
Sciences and Medical Sciences 68, 1, 62-67.
2. Clegg, A., Young, J., Iliffe, S. et al. (2013) Frailty in elderly people.
The Lancet 381, 9868, 752-762.
3. Morley, J. E., Vellas, B., Abellan van Kan, G. et al. (2013) Frailty consensus: a call to action. Journal of the American Medical Directors
Association 14, 6, 392-397.
4. Cooper, C., Dere, W., Evans, W. et al. (2012) Frailty and sarcopenia:
definitions and outcome parameters. Osteoporosis International23, 7, 1839-1848.
5. Landi, F., Calvani, R., Cesari, M. et al. (2015) Sarcopenia as the
biological substrate of physical frailty. Clinics in Geriatric Medicine
31, 3, 367-374.
6. Morley, J.E. (2013) Pathophysiology of the anorexia of aging. Current Opinion in Clinical Nutrition and Metabolic Care 16, 1, 27-32.
7. Martone, A.M., Onder, G., Vetrano, D.L. et al. (2013) Anorexia of
aging: a modifiable risk factor for frailty. Nutrients 5, 10, 4126-4133.
8. Porter Starr, K.N., McDonald, S.R., Bales, C.W. (2015) Nutritional vulnerability in older adults: a continuum of concerns. Current
Nutrition Reports 4, 2, 176-184.
9. Donini, L.M., Poggiogalle, E., Piredda, M. et al. (2013) Anorexia
and eating patterns in the elderly. PloS one 8, 5, e63539.

10. Robinson, S., Cooper, C., Sayer, A.A. (2012) Nutrition and sarcopenia: a review of the evidence and implications for preventive
strategies. Journal of Aging Research 2012, 510801.
11. Zeanandin, G., Molato, O., Le Duff, F. et al. (2012) Impact of restrictive diets on the risk of undernutrition in a free-living elderly
population. Clinical Nutrition 31, 1, 69-73.
12. Paddon-Jones, D. & Leidy, H. (2014) Dietary protein and muscle
in older persons. Current Opinion in Clinical Nutrition and Metabolic Care 17, 1, 5-11.
13. Deutz, N.E.P., Bauer, J.M., Barazzoni, R. et al. (2014) Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN expert group. Clinical Nutrition 33, 6,
929–936.
14. Beasley, J.M., Shikany, J.M., Thomson, C.A. (2013) The role of dietary protein intake in the prevention of sarcopenia of aging. Nutrition in Clinical Practice 28, 6, 684-690.
15. Millward, D.J. (2012) Nutrition and sarcopenia: evidence for an interaction. The Proceedings of the Nutrition Society 71, 4, 566-575.
16. Ter Borg, S., Verlaan, S., Mijnarends, D.M. et al. (2015) Macronutrient Intake and Inadequacies of Community-Dwelling Older
Adults, a Systematic Review. Annals of Nutrition & Metabolism
66, 4, 242-255.
17. Bonnefoy, M., Berrut, G., Lesourd, B. et al. (2015) Frailty and nutrition: searching for evidence. The Journal of Nutrition, Health &Aging 19, 3, 250-257.

112

The role of nutrition for the prevention and treatment of frailty

18. Inzitari, M., Doets, E., Bartali, B. et al. (2011) Nutrition in the
age-related disablement process. The Journal of Nutrition, Health& Aging 15, 8, 599-604.
19. Zujko, M.E., Witkowska, A.M., Waskiewics, A. et al. (2015) Dietary
antioxidant and Flavonoid intakes are reduced in the elderly. Oxidative Medicine and Cellular Longevity, Article ID 843173, 1-8.
20. Boirie, Y., Morio, B., Caumon, E. et al. (2014) Nutrition and protein
energy homeostasis in elderly. Mechanisms of Ageing and Development 136-137, 76-84.
21. Volkert, D. (2011) The role of nutrition in the prevention of sarcopenia. Wiener Medizinische Wochenschrift 161, 17-18, 409-415.
22. Schneider, S.M., Al-Jaouni, R., Pivot, X. et al. (2002) Lack of adaptation to severe malnutrition in elderly patients. Clinical Nutrition
21, 6, 499-504.
23. Kaiser, M., Bandinelli, S., Lunenfeld, B. (2010) Frailty and the roleof nutrition in older people. A review of the current literature. Acta
Biomedica Atenei Parmensis 81 Suppl 1, 37-45.
24. Rondanelli, M., Faliva, M., Monteferrario, F. et al. (2015) Novelinsights on nutrient management of sarcopenia in elderly. BioMed
Research International 2015, 524948.
25. Calvani, R., Miccheli, A., Landi, F. et al. (2013) Current nutritional
recommendations and novel dietary strategies to manage sarcopenia. The Journal of Frailty & Aging 2, 1, 38-53.
26. Milaneschi, Y., Tanaka, T., Ferrucci, L. (2010) Nutritional determinants of mobility. Current Opinion in Clinical Nutrition and Metabolic Care 13, 6, 625-629.
27. Hubbard, R.E., Lang, I.A., Llewellyn, D.J. et al. (2010) Frailty, Body
Mass Index, and abdominal obesity in older people. The Journalsof Gerontology Series A: Biological Sciences and Medical Sciences
65A, 4, 377-381.
28. Secher, M., Guyonnet, S., Ghisolfi, A. et al. (2014) Nutrition, Frailty
and prevention of disabilities with ageing. Clinical Nutrition Highlights 9, 1, 1-26.
29. Kobayashi, S., Asakura, K., Suga, H. et al. (2014) Inverse association between dietary habits with high total antioxidant capacityand prevalence of frailty among elderly Japanese women: a multicenter cross-sectional study. The Journal of Nutrition, Health &Aging 18, 9, 827-839.
30. Deer, R.R. & Volpi, E. (2015) Protein intake and muscle function inolder adults. Current Opinion in Clinical Nutrition and Metabolic
Care 18, 3, 248-253.
31. Nowson, C. & O'Connell, S. (2015) Protein requirements andrecommendations for older people: a review. Nutrients, 7, 68746899.
32. Welch, A.A. (2014) Nutritional influences on age-related skeletal
muscle loss. The Proceedings of the Nutrition Society 73, 01, 16-33.
33. Semba, R.D., Bartali, B., Zhou, J. et al. (2006) Low serum micronutrient concentrations predict frailty among older women livingin the community. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61, 6, 594-599.
34. Fried, L.P., Tangen, C.M., Walston, J. et al. (2001) Frailty in older
adults: evidence for a phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56, 3, M146-56.
35. Agarwal, S., Reider, C., Brooks, J.R. et al. (2015) Comparison ofprevalence of inadequate nutrient intake based on body weightstatus of adults in the United States: an analysis of NHANES
2001-2008. Journal of the American College of Nutrition 34, 2,
126-134.
36. Normandin, E., Houston, D.K., Nicklas, B.J. (2015) Caloric restriction for treatment of geriatric obesity: Do the benefits outweigh
the risks? Current Nutrition Reports 4, 2, 143-155.

37. Porter Starr, K.N. & Bales, C.W. (2015) Excessive body weight inolder adults. Clinics in Geriatric Medicine 31, 3, 311-326.
38. García-Esquinas, E., José García-García, F., León-Muñoz, L.M. etal. (2015) Obesity, fat distribution, and risk of frailty in two population-based cohorts of older adults in Spain. Obesity 23, 4, 847-855.
39. Anton, S.D., Karabetian, C., Naugle, K. et al. (2013) Obesity anddiabetes as accelerators of functional decline: can lifestyle interventions maintain functional status in high risk older adults? Experimental Gerontology 48, 9, 888-897.
40. Bauer, J.M. & Diekmann, R. (2015) Protein supplementation withaging. Current Opinion in Clinical Nutrition and Metabolic Care18, 1, 24-31.
41. Cruz-Jentoft, A.J., Landi, F., Schneider, S.M. et al. (2014) Prevalence of and interventions for sarcopenia in ageing adults: a systematic review. Report of the International Sarcopenia Initiative(EWGSOP and IWGS). Age and Ageing 43, 6, 748-759.
42. Fukagawa, N.K. (2013) Protein and amino acid supplementationin older humans. Amino acids 44, 6, 1493-1509.
43. Bauer, J.M., Biolo, G., Cederholm, T. et al. (2013) Evidence-based
recommendations for optimal dietary protein intake in older people: a position paper from the PROT-AGE study group. Journal of
the American Medical Directors Association 14, 8, 542-559.
44. Morley, J.E., Argiles, J.M., Evans, W.J. et al. (2010) Nutritional recommendations for the management of sarcopenia. Journal of theAmerican Medical Directors Association 11, 6, 391-396.
45. Bendayan, M., Bibas, L., Levi, M. et al. (2014) Therapeutic interventions for frail elderly patients: part II. Ongoing and unpublished randomized trials. Progress in Cardiovascular Diseases 57,
2, 144-151.
46. Bibas, L., Levi, M., Bendayan, M. et al. (2014) Therapeutic interventions for frail elderly patients: part I. Published randomized
trials. Progress in Cardiovascular Diseases 57, 2, 134-143.
47. Malafarina, V., Uriz-Otano, F., Iniesta, R. et al. (2013) Effectivenessof nutritional supplementation on muscle mass in treatment ofsarcopenia in old age: a systematic review. Journal of the American Medical Directors Association 14, 1, 10-17.
48. Cawood, A.L., Elia, M., Stratton, R.J. (2012) Systematic review andmeta-analysis of the effects of high protein oral nutritional supplements. Ageing Research Reviews 11, 2, 278-296.
49. Bauer, J.M., Verlaan, S., Bautmans, I. et al. (2015) Effects of a vitamin D and leucine-enriched whey protein nutritional supplement
on measures of sarcopenia in older adults, the PROVIDE study: arandomized, double-blind, placebo-controlled trial. Journal of theAmerican Medical Directors Association.
50. Ng, T.P., Feng, L., Nyunt, M.S.Z. et al. (2015) Nutritional, physical, cognitive, and combination Interventions and frailty reversal
among older adults: a randomized controlled trial. The American
Journal of Medicine, 1-12.
51. Milne, A.C., Potter, J., Vivanti, A. et al. (2009) Protein and energy supplementation in elderly people at risk from malnutrition.
Cochrane Database Systematic Review, 2, Cd003288.
52. Komar, B., Schwingshackl, L., Hoffmann, G. (2015) Effects of leucine-rich protein supplements on anthropometric parameter andmuscle strength in the elderly: a systematic review and meta-analysis. The Journal of Nutrition, Health & Aging 19, 4, 437-446.
53. Halfon, M., Phan, O., Teta, D. (2015) Vitamin D: a review on its
effects on muscle strength, the risk of fall, and frailty. BioMed Research International 2015, 953241.
54. Denison, H.J., Cooper, C., Sayer, A.A. et al. (2015) Prevention andoptimal management of sarcopenia: a review of combined exercise and nutrition interventions to improve muscle outcomes inolder people. Clinical Interventions in Aging 10, 859-869.

113

WHITE BOOK

55. Cermak, N.M., Res, P.T., de Groot, L.C. et al. (2012) Protein supplementation augments the adaptive response of skeletal muscle
to resistance-type exercise training: a meta-analysis. The American Journal of Clinical Nutrition 96, 6, 1454-1464.
56. Murphy, R.A., Reinders, I., Register, T.C. et al. (2014) Associationsof BMI and adipose tissue area and density with incident mobility
limitation and poor performance in older adults. The American
Journal of Clinical Nutrition 99, 5, 1059-1065.
57. Mathus-Vliegen, E.M.H. (2012) Prevalence, pathophysiology,
health consequences and treatment options of obesity in the elderly: a guideline. Obesity facts 5, 3, 460-483.
58. Weinheimer, E.M., Sands, L.P., Campbell, W.W. (2010) A systematic review of the separate and combined effects of energy restriction and exercise on fat-free mass in middle-aged and older
adults: implications for sarcopenic obesity. Nutrition Reviews 68,
7, 375-388.
59. Freiberger, E., Goisser, S., Porzel, S. et al. (2015) Sarcopenic obesity and complex interventions with nutrition and exercise in community-dwelling older persons - a narrative review. Clinical Interventions in Aging, 1267.
60. Porter Starr, K.N., McDonald, S.R., Bales, C.W. (2014) Obesity andphysical frailty in older adults: a scoping review of lifestyle inter-

vention trials. Journal of the American Medical Directors Association 15, 4, 240-250.
61. Poggiogalle, E., Migliaccio, S., Lenzi, A. et al. (2014) Treatment ofbody composition changes in obese and overweight older adults:
insight into the phenotype of sarcopenic obesity. Endocrine 47, 3,
699-716.
62. Wirfält, E., Drake, I., Wallström, P. (2013) What do review papers
conclude about food and dietary patterns? Food & Nutrition Research 57.
63. Kiefte-de Jong, J.C., Mathers, J.C., Franco, O.H. (2014) Nutritionand healthy ageing: the key ingredients. The Proceedings of the
Nutrition Society 73, 249-259.
64. León-Muñoz, L.M., García-Esquinas, E., López-García, E. et al.
(2015) Major dietary patterns and risk of frailty in older adults: aprospective cohort study. BMC Medicine 13, 11.
65. Panza, F., Solfrizzi, V., Giannini, M. et al. (2014) Nutrition, frailty,
and Alzheimer's disease. Frontiers in Aging Neuroscience 6, 221.

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HOW TO INCLUDE THE SOCIAL FACTOR FOR DETERMINING FRAILTY?

HOW TO INCLUDE THE SOCIAL FACTORFOR DETERMINING FRAILTY?
L. MIGUEL GUTIERREZ-ROBLEDO1, J.A. AVILA-FUNES2,3

1 Instituto de Geriatría at the National Institutes of Health Mexico, Mexico City, Mexico;
2 Department of Geriatrics. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico;
3 Centre de recherche Inserm, U897, Bordeaux, F-33076 France; Univ Victor Segalen Bordeaux 2, Bordeaux, F-33076 France.
Correspondence: Luis Miguel Gutiérrez-Robledo. Director General. Instituto de Geriatría at the National Institutes of Health
Mexico. Periférico Sur 2767 Col. San Jerónimo Lídice. CP 10200; Magdalena Contreras, Distrito Federal, México. E-mail: luis.
gutierrez@salud.gob.mx.
Alternate Corresponding Author: José Alberto Ávila-Funes. E-mail: avilafunes@live.com.mx

Abstract: Traditionally, frailty has been understood as a
biological syndrome associated with bad health-related
outcomes. However, nowadays there are no universally
accepted diagnostic criteria for this syndrome, much lessstudies approaching it from a non-biological framework.
Some previous work has been able to highlight social factors as important features implicated in the developmentof this entity, and are now recognized as relevant to understand frailty. However, research in this field is still limited. It
seems clear that social factors, often ignored in the medical
context, might represent risk factors for the developmentof this geriatric syndrome. To identify these factors, as wellas their role in the physiopathology of frailty, could be ofgreat importance in order to establish potential multidimensional models to treat frailty. A life course approach todetermine the correlates and trajectories of frailty seems tobe necessary. The allostatic load through life and chronic
inflammation in the elderly are potential mediators of thisrelationship. Therefore, social profile should be systematically assessed and taken into account when evaluating anelderly person. So, the present review proposes how to include social factors as another determinant of frailty.

SOCIAL FACTORS AS DETERMINANTS
OF FRAILTY STATUS

nal and nationally representative studies with extensive information on socioeconomic status and health status gives
us an opportunity to understanding how early, middle, andlate life factors influence the life cycle trajectory of healthand thus of frailty (1).

Social determinants of health
Nowadays, it is clear that health inequities arising from thesocietal conditions in which people are born, grow, live,
work and age, are all social determinants of health. These
include early years’ experiences, education, economic status, employment and work conditions, housing and environment, and access to effective systems of preventing andtreating ill health. In addition, research on the determinantsof adult and old-adult health recognizes the need to incorporate earlier life circumstances. The scarcity of longitudi-

Key words: Frailty, social factors, allostatic load,immunosenescence, disability.

Life course perspective
Since the seminal paper by Ben Shlomo and Kuh (2), a
number of studies have reported associations between
socioeconomic status (SES) and health in adulthood withconsistent evidence that the socioeconomically disadvantaged have higher prevalence of chronic disease and rates
of mortality than the more advantaged. Evidence also in-

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dicates that socioeconomic disadvantage in childhood is
associated with a range of adverse health-related outcomesin adulthood often independent of adult SES. Childhood
SES, through its association with a range of factors, including growth and early life nutrition, may influence thepeak level of physical capability attained in early adulthood,thereby affecting levels later in life. Adverse effects of SES
may also accumulate across the life course. Poor adult SES
is associated with worse objectively measured physical performance levels, and it has been recently shown that this effect is also seen with childhood SES independently of adultSES (3). Such an association has important implications forthe development of interventions programs targeting frail
persons and the prevention and improving the physical capability levels of elderly.
The specific aging experience of some populations, characterized by poverty and poor social conditions alongwith high comorbidity, disability and a scarcity of healthand social services, has only recently been recognized. Research among Latin American older persons arising fromthe SABE (Salud Bienestar y Envejecimiento; Spanishfor Health, Well-being and Aging) survey, a multicentriccross-sectional study involving 10,661 men and women 60
years and older in seven large Latin American cities (4), indicates that a poor material environment during childhood
is associated with poor physical functioning and mental
health. In the same vein, they have shown that a differential
exposure and vulnerability to social and biological factors
among men and women are associated with gender differences in physical function and mental health. In addition,social and health conditions of the life course were associated with the phenotype of frailty, and that differential exposure and/or vulnerability to social and health conditionsof life course may account for gender differences in frail
persons. This association between life course factors andfrailty increases our understanding about the social origins
of frailty.
Disadvantages existing in early life and reproduced along
the life course may then account for the syndrome of physical frailty. New theoretical models aiming to explain genderand social differences in frailty status should emphasize theuse of a life course perspective.

Social and life-style correlates of frailty
Thus, social factors are now recognized as relevant to understand frailty. However, research into the prevalence offrailty and its correlates, particularly social influences, is still
limited. A group in Hertfordshire, at the United Kingdom,using data from the Hertfordshire Cohort Study, has shownthat frailty (defined by the Fried et al. criteria) is partly determined by social inequalities across levels of education,home ownership, and car availability. These results seem tobe mediated by co-morbidities that occur more frequently
among socially disadvantaged individuals (5). On the other
hand, previous research in Latin American elderly has also
found that social factors such as poorer socio-economic
conditions, little education, non-white-collar occupation, orinsufficient income are more frequently present in frail subjects. Recent findings in a Mexican cohort partially replicate
those previously reported. A cross-sectional analysis of the
Mexican Study of Nutritional and Psychological Markers
of Frailty (the Coyoacán cohort) (6), has shown that nothaving a partner, not participating in important decisions,and having a poor self-perceived economic situation were
all correlates of prevalent frailty. In addition, those receiving a pension were protected against frailty, which may be
a reflection of having better life conditions and access tohealth-care of these participants. The sum of these factors
might traduce a socially adverse environment increasing
the odds for elderly to be frail. However, a longitudinal approach is needed in order to better understand this association.
It seems clear that social factors, often ignored in the medical context, might represent risk factors for the development of frailty. Therefore, social profile should be systematically assessed and taken into account when evaluating anelderly person for the development and implementation ofmultidimensional prevention and treatment programs.

Trajectories of frailty as a function of social vulnerability
This longitudinal approach has been thoroughly exploredin the Health and Retirement Survey (7), where the frailty
index (FI) for cohorts born before 1942 exhibit quadraticincreases with age and accelerated increases in the accumulation of health deficits. At any age, females, non-white
individuals, and those with lower education and income exhibit greater degrees of deterioration than their male, white,and higher SES counterparts. Patterns of sex, race, and SES
differentials in rates of aging vary across cohorts. The authors report that adjusting for social behavioral factors, theanalysis provides evidence for physiological differences in
the aging process among older adults. Their results allow
concluding that the expression of biological aging and theaccumulation of general system damage do not follow thesame path, under different circumstances, within a humanpopulation. In fact, individuals’ slopes of change with age
are sensitive to the social conditions in which they are embedded.

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MECHANISMS AND MEDIATORS

Allostatic load
There is a growing interest in understanding how the experience of SES adversity across the life course may accumulate to negatively affect the functioning of biologicalregulatory systems, which are important to functioning andhealth in late adulthood. In this vein, allostatic load (AL)is conceptualized as a cumulative index of wear and tearacross multiple physiological systems involved in the body’s
effort to adapt to internal and external stressors over time.
AL has been examined as a preclinical physiological marker
of risk for adverse health-related outcomes. Recent analyses indicate higher AL as a function of greater SES adversity at each phase of, and cumulatively across, the life
course. This association is only modestly attenuated when
accounting for a wide array of health status, behavioral, andpsychosocial factors (8). So, SES adversity experience may
cumulate across the life course to have a negative impact on
multiple biological systems in adulthood. Then, AL could
be related to an indicator of decreased reserves such as
frailty. In fact, higher baseline value for the AL score has
been associated with greater likelihood of frailty in two recent surveys. In the MacArthur Successful Aging Study (9),higher levels of AL were associated with greater probability of development of frailty over a 3-year follow-up in asample of initially high-functioning older adults. This association remains even after adjustments by for co- occurring
physical disability and co-morbidity, which may be associated with alterations in biomarker levels. In the Women’s
Health and Aging studies, regression models showed thatby one unit of increase in the AL score was associated withincreasing strata of frailty (OR = 1.16; 95% CI = 1.04 to1.28) adjusting by race, age, education, smoking status, andco- morbidities (10).
Inflammation
Disturbances in many interacting physiological systems
may contribute to decrease resilience face to adverse stressors, and will need systems biological approaches to analysis.
Inflammation contributes to these alterations, which are
determined and feeding back by alterations in the immune
system with aging.
Being as the potential ill effect of a lower SES can be observed across such a wide range of such conditions, it suggests a common biological mechanism through which SES
adversity is related to health. The underlying hypothesis of
this general conceptual model is that those with a lower
SES are subject to environmental, psychological and behavioral characteristics, and experiences that more often put
demands on these biological systems, leading to greater system wear and tear over time, and subsequently enhancing
risk for poor health and functioning. Evidence for SES gra-dients in biomarkers of these potential physiological pathways to disease is increasing. Lower SES, assessed by several indicators (e.g.: education, income, occupational status,
financial strain, etc.), has been associated with more “risky”
patterns of biological functioning, including higher levelsof hormones, which have been hypothesized to be elevated under conditions of stress. Sympathetic nervous systemand hypothalamic-pituitary- adrenal hormones axis, poorer
metabolic profiles or higher circulating levels of C-reactive
protein, fibrinogen, and other indicators of inflammatoryburden have also been found to be increased among thosewith lower SES. This effect is further complicated by thehigher occurrence of chronic diseases associated with, or
driven by, chronic inflammation. There is likely a final common pathway for interactions of these many factors altering the immune response to infections and leading to theincreased prevalence and incidence of chronic inflammatory diseases. The clinical burden most likely resulting fromsuch immune dysregulation could be overwhelming. Thus,
understanding the pathophysiological basis of frailty would
be of great importance as a handle for manipulation and,eventually, prevention.
Although it is currently very difficult to assign a definitive and unique biological pathway to frailty, inflammation
could eventually take this role. This means that inflammation should already be considered an important target for
prevention and intervention to investigate whether thiswould decrease the incidence of frailty in the elderly population. Despite these reservations, it is still worthwhile to try
to intervene. In the meantime, our research efforts should
continue to elucidate the pathophysiological basis of frailty
in order to design better interventions to improve the quality of life of the elderly in the rapidly increasing aging populations of the developed, and even developing countries.
SOCIAL FACTORS AS MODULATORS OF FRAILTYOUTCOMES

Social vulnerability is related to the health of elderly people,
but its measurement and relationship with frailty is controversial. In order to compare social vulnerability and frailty,
and to study social vulnerability related to mortality, Andrew et al (11) have tried to operationalize social vulnerability according to a deficit accumulation approach. They haveshown how it increases with age, women having higher index values than men. It also tends to be higher amongst
people who are frail, and it is associated with higher mortality, independent of frailty. Nevertheless, social vulnerability
was shown to be only weakly to moderately associated withfrailty. The authors consider that both frailty and social vulnerability may be related, they seem to be distinct, particularly since each contributes independently to mortality.

117Figure 1
Levels of influence of socioeconomic status (SES) on
frailtyand its outcomes. Modified from: (18)
WHITE
BOOK

Figure 1
Levels of influence of socioeconomic status (SES) on frailty and its outcomes. Modified from: (18)

In the Dutch experience (12), social vulnerability has been
approached as “social frailty”, and it has been measured
through the Tilburg Frailty Indicator on the basis of threecriteria: living alone, lack of contacts, and lack of support. If someone meets at least two of these three criteria,
they are considered as socially frail. Those individuals inthis category will not necessarily become physically frail,or be admitted to a care or nursing home or will die. The
observed relationship between social and physical frailty
could strengthen if other indicators of social frailty wereused. Research has shown that health problems can lead toshrinkage of personal networks and withdrawal from social
contacts (13). In the English Longitudinal Aging Study (14),neighborhood deprivation and individual socioeconomic
status were independently associated with frailty in community-dwelling older people. FI scores were higher in thosewith low individual socioeconomic resources who also lived
in deprived neighborhoods. In a survey in several Hispanic
communities in the southern United States (15), respondents at risk of increasing frailty lived in a less ethnically dense
Mexican-American neighborhood, were older, do not haveprivate insurance or Medicare, had higher levels of medical
conditions, had lower levels of cognitive performances, andreported less positive affect. In this population, personalas well as neighborhood characteristics confer protective
effects on individuals’ health. Besides a protective environment, engagement in productive activities is also positively associated with physical and psychological health aswell as survival of older adults. It has also been shown thathigh-functioning older adults who participate in productive
activities are less likely to become frail, even after adjusting
for age, disability, and cognitive function. Activities such as

volunteering, but not childcare or paid works, have been
independently associated with a lower cumulative odd offrailty (16). Another seemingly useful dimension of social
functioning is “life space” defined upon the distance a person routinely travels to perform activities. Determining
how far and how often the person leaves his or her placeof residence and the degree of independence has beenshown useful to predict frailty (17). Multivariate survival
models showed that, in comparison to women who left theneighborhood four or more times per week, those who left
the neighborhood less frequently were 1.7 times (95% CI:
1.1 to 2.4; p<0.05) more likely to become frail, and those
who never left their homes experienced a threefold increasein frailty-free mortality (95% CI: 1.4 to 7.7; p<0.01), after adjustment for chronic disease, physical disability, andpsychosocial factors. Together, these results suggest that aslightly constricted life space may be a marker and/or risk
factor for the development of frailty that may prove usefulas a screening tool or a target of intervention. The LifeSpace Assessment scale measures mobility in terms of thespatial extent of a person’s life and has been shown to be
useful for this purpose.
Based on this evidence, the relationship between physicaland social frailty may thus be stronger; further research on
the different indicators of objective and subjective social
frailty could provide more clarity. The implication for measuring frailty is that social frailty items should be included in
the measure, but perhaps should not be given the greatest
weight in assessing frailty. Consideration could even be given to starting from a minimum criterion for physical frailty
when determining the frailty of an individual, supplement-

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HOW TO INCLUDE THE SOCIAL FACTOR FOR DETERMINING FRAILTY?

ed by social frailty. Although much work remains to bedone to characterize social vulnerability among the elderly,
we need to recognize that it plays a role in modulating theadverse health-related outcomes of frailty.
Acknowledgments: Dr L. M. Gutiérrez-Robledo presented
this paper in part as oral communication at the IAGG/
WHO/SFGG Workshop nº 3 “Promoting access to innovation and clinical research for frail old persons” in Athens, Greece (January 19 and 20, 2012). The Mexican Studyof Nutritional and Psychosocial Markers of Frailty among
Community-Dwelling Elderly (Estudio de marcadores nu-

tricios y psico-sociales del síndrome de fragilidad en adultos mayores Mexicanos) was funded by the National Council for Science and Technology of Mexico (CONACyT)
Clave del proyecto: SALUD- 2006-C01- 45075. Dr J. A.
Ávila-Funes is supported by a Bourse ECOS (2010-2012)
from the Ministère des Affaires Étrangères in France andthe Secretaría de Educación Pública (SEP), the Asociación
Nacional de Universidades e Instituciones de Educación
Superior (ANUIES), and CONACyT in Mexico.
This article was published in the Journal of Frailty and Aging
Volume1, Number1, 2012
http://www.jfrailtyaging.com/

REFERENCES
1. Johnson RC, Schoeni RF, Rogowski JA. Health disparities in
mid-to-late life: The role of earlier life family and neighborhoodsocioeconomic conditions. Soc Sci Med 2011;doi: 10.1016/j.
socscimed.2011.10.021.
2. Ben-Shlomo Y, Kuh D. A life course approach to chronic disease
epidemiology: conceptual models, empirical challenges and interdisciplinary perspectives. Int J Epidemiol 2002;31:285-293.
3. Birnie K, Cooper R, Martin RM, Kuh D, Sayer AA, Alvarado BE, et
al. Childhood socioeconomic position and objectively measured
physical capability levels in adulthood: A systematic review andmeta-analysis. PLoS One 2011;6:e15564.
4. Alvarado BE, Zunzunegui MV, Béland F, Bamvita JM. Life course
social and health conditions linked to frailty in Latin American older men and women. J Gerontol A Biol Sci Med Sci 2008;63:13991406.
5. Syddall H, Roberts HC, Evandrou M, Cooper C, Bergman, H, Aihie
Sayer
A. Prevalence and correlates of frailty among community-dwellingolder men and women: findings from the Hertfordshire Cohort
Study. Age ageing 2010;39:197-203.
6. Casale-Martínez RI, Navarrete-Reyes AP, Avila-Funes JA. Social determinants of frailty among Mexican community-dwelling elderly J
Am Geriatr Soc 2012;60:In press.
7. Yang Y, Lee LC. Dynamics and heterogeneity in the process of human frailty and aging: evidence from the US older adult population. J Gerontol B Psychol Sci Soc Sci 2010;65B:246-245.
8. Gruenewald TL, Karlamangla AS, Hu P, Stein-Merkin S, Crandall
C, Koretz B, et al. History of socioeconomic disadvantage and allostatic load in later life. Soc Sci Med 2012;74:75-83.
9. Gruenewald TL, Seeman TE, Karlamangla AS, Sarkisian CA.
Allostatic load and frailty in older adults. J Am Geriatr Soc
2009;57:1525-1531.

10. Szanton S, Allen J, Seplaki C, Bandeen-Roche K, Fried L. Allostaticload and frailty in the women’s health and aging studies. Biol Res
Nurs 2009;10:248–256.
11. Andrew MK, Mitnitski AB, Rockwood K Social vulnerability, frailty
and mortality in elderly people. PLoS One 2008;3: e2232.
12. van Campen C. Frail older persons in the Netherlands. The Netherlands Institute for Social Research The Hague. 2011. www.scp.
nl/english/ dsresource? objectid=29060&type=org. Accessed 31
January 2012.
13. Ertel KA, Glymour MM, Berkman LF. Social networks and health:A life course perspective integrating observational and experimental evidence. JSPR 2009;26:73-92.
14. Lang, IA, Hubbard RE, Andrew MK, Llewellyn DJ, Melzer D, Rockwood
K. Neighborhood deprivation, individual socioeconomic status, andfrailty in older adults. J Am Geriatr Soc 2009; 57:1776-1780.
15. Aranda MP, Ray LA, Snih SA, Ottenbacher KJ, Markides KS. The
protective effect of neighborhood composition on increasing frailty among older Mexican Americans: a barrio advantage? J Aging
Health 2011;23:1189-1217.
16. Jung Y, Gruenewald TL, Seeman TE, Sarkisian CA. Productive activities and development of frailty in older adults. J Gerontol B
Psychol Sci Soc Sci 2010;65:256-261.
17. Xue QL, Fried LP, Glass TA, Laffan A, Chaves PH. Life-space constriction, development of frailty, and the competing risk of mortality: the Women’s Health And Aging Study I. Am J Epidemiol
2008;167:240–248.
18. Rosero-Bixby L, Dow WH. Surprising SES gradients in mortality,
health, and biomarkers in a Latin American Population of adults. J
Gerontol B Psychol Sci Soc Sci 2009;64B:105-117.

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IMPLEMENTING FRAILTY SCREENING,
ASSESSMENT, AND SUSTAINED INTERVENTION:
THE EXPERIENCE OF THE GÉRONTOPÔLE
B. VELLAS1,2

1. Gérontopôle de Toulouse, Département de Médecine Interne et Gérontologie Clinique, Centre Hospitalier Universitaire deToulouse, 170 avenue de Casselardit, 31300 Toulouse, France;
2. INSERM U1027, 37 Allées Jules Guesde, F-31073 Toulouse, France.
Correspondence: B. Vellas, Gérontopôle de Toulouse, Département de Médecine Interne et Gérontologie Clinique, Centre Hospitalier Universitaire de Toulouse, 170 avenue de Casselardit, 31300 Toulouse, France. E-mail: vellas.b@chu-toulouse.fr

Abstract: Despite its interest, frailty is not yet adequately implemented in the everyday clinical practice. Frailty is
characterized by an initial functional loss which 1) still allows the individual to be independent in the daily life (although with some difficulties), and 2) may be reversed bytargeted interventions. In the present article, we discuss:
Why frailty is clinically relevant? Why frailty has not yet

been implemented in daily clinical practice? How to implement frailty into clinical practice following the Gérontopôle
experience? Intervention to be effective must be targeted,strong, and maintained.

INTRODUCTION

in charge of older persons at risk of negative outcomes.
For these reasons, more and more medical specialties (e.g.,
oncology, cardiology, neurology…) has started looking withgreater interest at the geriatric experience simply because
they have found themselves at treating geriatric conditions
and geriatric patients in their daily routine practice.
In order to objectively define the condition of risk preceding disability and representing the ideal target for ad hoc
preventive interventions, the scientific community has developed and described the so-call frailty syndrome. Suchearly stage of the disabling cascade is characterized by aninitial functional loss which 1) still allows the individual to
be independent in the daily life (although with some difficulties), and 2) may be reversed by targeted interventions(2-14). In theory, older persons might be classified in threegroups, each one with specific necessities and peculiarities
to consider in the clinical practice:a. Older adults in overall healthy conditions (i.e., robust).
These individuals may present diseases and clinical con-

One of the challenges for our society is the prevention ofage-related disabilities and dependency. The number of severely dependent older adults is projected to rise from 350
million in 2010, to 488 and 614 in 2030 and 2050, respectively (1). Geriatric medicine has consequently to modify itself and adapt its practice in order to adequately counteract
such dramatic scenario.
Geriatric medicine started to be systematically developed
approximately 40 years ago when the increasing number ofolder adults with disability and dementia admitted to hospital emergency units threatened the sustainability of thehealthcare organizations. Today, almost 95% of the geriatric medicine forces are devoted to the care of age-related disabilities. The epidemiological scenario and the highhealthcare costs required for the management of dependent
individuals require the adoption of strategies aimed at preventing the loss of physical function and anticipate the take

Key words: Frailty, intervention, clinical practice, sarcopenia.

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IMPLEMENTING FRAILTY SCREENING, ASSESSMENT, AND SUSTAINED INTERVENTION: THE EXPERIENCE OF THE GÉRONTOPÔLE

ditions (e.g., hypertension, diabetes, history of treatedmalignancies, vascular diseases…), but these are not affecting their physical function and quality of life. Roughly, older persons represent between 50 and 60% of older
adults (7).
b. On the other hand, we have older persons presenting
disabilities. These individuals (dependent for the performance of basic activities of daily living, such as eating,walking, dressing, bathing, toileting, personal hygiene)
are confined to their houses or reside in nursing homes.
At old age, the condition of disability is hard to be reversed, especially if it is due to chronic and degenerative
disorders. Disabled elders represent approximately 10%of the population aged 65 years and older, but are thevast majority of patients usually seen in geriatric departments. The maintenance of an efficient healthcare system
necessarily passes through the prevention of such catastrophic condition. After all, primary aim of geriatrics
is indeed the extension of disability-free life expectancy.
c. The third group is composed by frail older adults (approximately 30 to 40% of older persons aged 65 years andolder). The frailty condition has often been operationalized using the criteria proposed and validated by Friedand colleagues, the so-called « frailty phenotype » (4).
It is assessed by considering five signs/symptoms: unintentional weight loss, muscular weakness, exhaustion,
slow gait speed, and sedentary behavior. The individual is considered as « frail » if presenting three or moreof these criteria, and « pre-frail » in the presence of one
or two. Studies indicate that non-disabled pre-frail andfrail older persons represent about 30% and 10% of thecommunity- dwelling older population, respectively. It
is noteworthy that frail elders are a group of individuals
with major unmet medical needs, mainly because not frequently referring to clinical services. Nevertheless, this isindeed an optimal target population for developing effective programs aimed at preventing disability in the elderly.
In fact, these individuals are not disabled, but present an
extreme vulnerability to stressors and a high risk for major negative health-related outcomes (8, 15).
In the present article, we will discuss:- Why frailty is clinically relevant-W hy frailty has not yet been implemented in daily clinicalpractice-H ow to implement frailty into clinical practice following
the experience of the Gérontopôle?
WHY FRAILTY IS CLINICALLY RELEVANT

Using the previously mentioned frailty phenotype, a study
conducted in a large cohort study including a population
representative of several European countries found thatpre- frail and frail elders are highly prevalent in our societies (about 40% and 10%, respectively) (16). These findings
have been confirmed by a more recent systematic review
taking into account studies also from other continents (17).
The frailty syndrome is strongly related to an increase riskof major health- related outcomes, including severe disability, hospitalization, institutionalization, and mortality(4, 17-23). Frail older persons are not exposed to negative
outcomes, but (if left untreated) will generate a relevant
consumption of healthcare resources in the next future (3).
Moreover, evidence exists that effective and multidimensional interventions (largely based on the comprehensive
geriatric assessment) in frail individuals may prevent functional decline, institutionalization, and mortality (24-26).
The role of geriatric medicine is indeed to much more focus on the preservation of the older person’s physical function. It is not surprisingly, for example, that the concept of«dismobility» (parallel to that of frailty) was recently proposed by Cummings and colleagues (and operationalized
as a gait speed slower than 0.6 m/sec) (27). The loss of
capacity in mobility increases with age in both men (from1.2% between 50 to 54 years up to 31% after 85 years ofage) and women (from 0.4% between 50 to 54 years up
to 52% after 85 years of age). Such relevant burden (forthe person as well as for the society) implicitly indicate theneed of developing services and practices for «novel» clinical conditions, peculiar of the still not sufficiently studied
growing older population.
WHY FRAILTY HAS NOT YET BEEN IMPLEMENTED IN
DAILY CLINICAL PRACTICE

Despite its interest, frailty is not yet adequately implemented in the everyday clinical practice. We may identify threemain reasons:• Up to few years ago, geriatric medicine was not sufficiently strong from an academic viewpoint. This has beenchanging in these last years and geriatrics has assumed amore relevant position in many countries.
• Public policies have not adequately considered the costsof aging population. Today, a restructuring of healthcare
systems is becoming urgent in order to face the increasing(absolute and relative) number of elders seeking for care.
• In parallel, the interest of pharmaceutical industries has
started to become attracted by the geriatric syndromes.
Age-related conditions (e.g., frailty) may not be so clear
and straightforward as traditional diseases (e.g., diabetes,
hypertension…), but are largely prevalent suggesting interesting marketing perspectives.
It means that some barriers (or red lights) have being passed(and lights are becoming green)!
The number of publications indexed in PubMed about
frailty is exponentially increasing (Figure 1). International

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meetings such as the International Conference on Frailty
and Sarcopenia Research (ICFSR) attract a growing number of participants with a parallel improvement of quantityand quality of scientific data in the field (28). New drugs
are under development in the domain of sarcopenia (i.e.,
the age-related skeletal muscle decline, a cornerstone of
the frailty syndrome). Frailty is today becoming one of thepriorities for international institutions, including the European Commission and the World Health Organization.
Major scientific projects have been recently funded from
European Agencies such as the Innovative Medicines Initiative (IMI), for example the SPRINT-T study (29). The
Journal of Frailty & Aging is becoming widely diffused (30)and some web sites (e.g., “Implementing Frailty into Clinical Practice” (31) or the French site “Ensemble prévenonsla dépendance” (32) help the diffusion of knowledge andawareness on the theme.
Figure 1
The evolution of number of publications on Frailty from 1950 to 2014

HOW TO IMPLEMENT FRAILTY INTO CLINICAL PRACTICEFOLLOWING THE EXPERIENCE OF THE GÉRONTOPÔLE?

The Gérontopôle has been missioned twice by the French
Ministry of Health. The first mandate was received under
the Nicholas Sarkoz’s presidency, the second (few months
later) from François Hollande. In both documents, theGérontopôle is asked to:a. Implement screening procedures for identifying frail elders in order to target preventive strategies against disabilityb. Design and develop frailty clinics aimed at proposing
person-tailored and multidomain interventions against
disabilityc. Designing models of long-term preventive interventions
against disabilityd. Promote the prevention of iatrogenic disability in hospitalized frail elders.
Every intervention in medicine (and especially in geriatrics)
will be effective only if optimally targeted, powered, andmaintained.

THE SCREENING OF FRAILTY FOR IDENTIFYING THE
TARGET POPULATIONAs mentioned, frail elders represent an optimal target forinterventions against disability because 1) not yet experiencing the outcome of interest, and 2) expressing a potential
for risk reversibility. It is likely that the cost-effectiveness oftargeting this population may also be convenient (3, 8). To
facilitate the screening of frail elders in the clinical practice,multiple instruments have been developed. Of particular interest, the FRAIL instrument by Morley and colleagues (33)and the Gérontopôle Frailty Screening Tool (GFST) (34-36)(Figure 2). The GFST is specifically designed to be used bygeneral practitioners (GPs). It first supports the GP in theevaluation of the main frailty criteria (according to the frailty phenotype). In the case one or more frailty signs/symptoms are presents, the GP is then invited at expressing his/her clinical judgment about the vulnerability of the subject.
It is only then that the GP (according to his/her clinicaljudgment) is invited at referring the patient to a frailty clinic. Such design of the instrument prioritizes the subjective
impression of frailty provided by the clinician. Moreover,it will directly involve the GP in the future care of the frail
person after the frailty clinic will release the person-tailored
recommendations (thus guaranteeing adherence to them).
We found that almost 95% of the patients referred to ourfrailty clinic by the mean of the GFST were indeed frail andat risk for disability (37, 38), implying the efficacy of the instrument for its task. The GFST was also recently approvedby the French National Authority for Health [Haute Autorité de Santé (HAS)] as the national tool for the detectionof frailty in older persons aged 65 years and older (39). The
instrument has also been translated in several languages andvalidated (versus standard assessment tools of frailty anddisability) by a recent European initiative (31, 40) (Figure 2).
A self-reported screening tool for detecting communitydwelling older persons with frailty syndrome in the absenceof mobility disability (i.e., the FiND questionnaire) has
also been recently validated by our group (41). The questionnaire can be sent by mail or completed over a phoneinterview. This tool is specifically designed for large-scalecampaigns in the population. It enables the individual to auto-detect his/her health profile, raising awareness about thepossible need of medical attention. In other words, positive
results at the FiND questionnaire should encourage the individual at looking for a medical evaluation. The GP (possibly with the GFST) will then judge whether the conditionof risk for disability indeed exists or not, taking the propercountermeasures if necessary. The FiND questionnaire isvalidated and has also been translated in several languages(31) (Figure 3).

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IMPLEMENTING FRAILTY SCREENING, ASSESSMENT, AND SUSTAINED INTERVENTION: THE EXPERIENCE OF THE GÉRONTOPÔLE

Figure 2
The Gérontopôle Frailty Screening Tool (GFST) for the detection of frail older patients (Vellas et al. J Nutr Health Aging 2013;17:629-631)

Figure 3
The self-reported screening tool for detecting community-dwelling older persons with frailty syndrome in the absence of mobility disability(The FiND Questionnaire) - English version (Cesari et al. PLoS One 2014;9:e101745)

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Table 1
Settings, target population, persons involved, and possible tools for the evaluation of frailty
Setting

Population

Persons involved

Possible Tool

Community Health
Promotion Program

Older persons living in thecommunity

Responsible for the screening campaigns (e.g.,municipalities, health insurance, public healthauthorities…), researchers involved in large-scale studies

FiND Questionnaire

Outpatients’ Clinic
for Frailty

Pre-frail and frail older
persons

Responsible for the referral to the clinic: GP, healthcare
professional, Geriatrician, individual or his/her proxies
Responsible for the assessment at the clinic: GP(specifically trained), Geriatrician

GFST

Day Hospital for
Frailty

Pre-frail and frail older
persons (usually more
complex cases)

Responsible for the referral to the day hospital: GP,
Geriatrician Responsible for the assessment at the day
hospital: GP (specifically trained), Geriatrician

GFST (for referral only)
Frailty phenotype,comprehensive
geriatric assessment

DEVELOPMENT OF FRAILTY CLINICS FOR AN
ADEQUATELY POWERED INTERVENTION

In the presence of frailty, the first action to take is the identification of the underlying causes. This will allow the definition of the most effective and tailored intervention.

Outpatients’ clinics for frailty
A first access to the frailty evaluation is possible at the socalled « outpatients’ clinic for frailty ». In this setting, theolder person is referred by his/her proxies as well as healthcare professionals. The older person him/herself may independently look for an evaluation in this setting.
In this setting, the physician assesses physical and cognitive
domains, social status, and clinical conditions. He/she thenprovides his/her recommendations for preventing disability. A geriatrician or a specifically trained GP can conduct
such frailty outpatient’s clinics. However, other health professionals (e.g., nurses, dieticians, physical therapists, neuropsychologists) should be available in the case of a single
and specific recommendations might be needed.
If the older person is found to present a light-mild stageof frailty in the absence of complex comorbidities, thefrailty assessment and intervention will be conducted andconcluded during such ad hoc outpatient consultation.
If the problem appears to be more complicated (e.g., objective cognitive impairment, malnutrition, depression…) andrequiring a multidisciplinary intervention, the patient willthen be referred to the frailty day hospital (38).
Day hospital for frailty
Frail older persons admitted to the day hospital for frailty
undergo a comprehensive geriatric assessment. The activities of the Gérontopôle day hospital for frailty have been
described in previous papers (37, 38). The characteristics of
persons admitted to this service are summarized in tables
2 and 3. Our population was found to be old (mean age

82.9 years), and composed in majority by women (69%).
More than 40% of the evaluated persons lived alone; oursample presented mean number of comorbid conditionsof 4.8. According to the frailty phenotype, 423 patients(39.1%) were pre-frail, and 590 (54.5%) frail. The meanscore at the Activities of Daily Living (ADL) scale was
5.5/6. This shows that subjects were still autonomous forbasic activities of daily living, although an initial functional
decline was present (and highlighted by the reduced scoreat the Instrumental ADL, mean score 5.6/8). A relevant
part of the sample (37.9%) presented history of falls. The
mean usual gait speed was 0.78 m/sec, and 74.4% presented a score equal to or lower than 9 at the Short Physical
Performance Battery (SPPB), indicating a moderate to highrisk of disability. Early dementia was observed in 14.9%of the patients referred to our frailty day hospital, 51.5%
had a Clinical Dementia Rating score of 0.5 reflecting mild
cognitive impairment. Protein-energy malnutrition was reported in 8% of the evaluated subjects, and about 40% of
the sample presented risk of malnutrition.
For what concerns the proposed Personalized Prevention
Plan (PPP), it is noteworthy that in 54.6% of the subjects
we identified at least one medical condition requiring medical attention, and in 32.8% substantial therapeutic changes were required. A nutritional, physical activity, and social
interventions were proposed in 61.8%, 56.7%, and 25.7%of the cases.
It is thus evident that without our process of screening,assessment and intervention, this population would haveremained exposed to uncontrolled medical conditions and/or difficulties, that is feeding the vicious cycle ending in theonset of negative health outcome. Since October 2011 (andup to August 2014), 1,841 frail older persons have been
evaluated at the Gérontopôle Frailty day hospital.

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Community health promotion program
Community health promotion programs should be developed under the initiative of health authorities, municipalities, and health insurances. We have developed such program in a rural area in Midi-Pyrénées region (the MINDED
Program) with the support of the Agence Nationale de laRecherche (ANR) (40). The self-reported screening tool for
detecting community-dwelling older persons with frailty(the FiND questionnaire) was specifically developed within
the context of this study. We are now extending such programs in urban communities: in the suburbs of Toulouse(city of Cugnaux) as well as in some low-income districts
characterized by high prevalence of elders (e.g., Empalot
district). All these programs are done in collaboration with
the GPs, pharmacists, and health professionals.

Table 2
Baseline socio-demographic characteristics of the G.F.C population(n=1,108) (Tavassoli et al. J Nutr Health Aging 2014; J Nutr Health
Aging 2014;18:457-64)
G.F.C population(n=1,108) Mean ±SD or n (%)

Age (y), n=1,10882.9±6.1

Gender (female), n=1,108

20 (69.0)

BMI (kg/m ), n=698

25.9±5.1

Living home alone, n=1,083

460 (42.5)

Mean number of comorbidities/person

4.8±3.0

Comorbidities (all types), n=560

487 (87.0)

2

PROLONGED INTERVENTION

Frail subjects usually present comorbidities and require
powered and prolonged interventions in order to meet criteria of effectiveness. For this reason, the support of GPs
is particularly important. The intervention should be practical and feasible. At the end of frail person’s assessment
at the frailty day hospital, the proposed interventions are
discussed with the subject and members of his/her family (if possible). The referent GP is also contacted on thesame day. Two weeks after the assessment, a nurse calls thefrail person to verify that the proposed recommendations
have been put in place, and discuss about potential issues.
After one month from the initial evaluation, the nurse carries out a second phone contact. In this case, she fills out aquestionnaire assessing the impact of intervention on thesubject’s general health and function. An annual follow-up
visit at frailty day hospital is also proposed to most of thefrail persons. For those who present a particularly highrisk of disability, a shorter delay between follow-up visit isadopted. The intervention is usually multi-domain (simultaneously including physical and cognitive exercises, nutrition intervention, social intervention, and/or control ofcomorbidities and risk factors). However, stronger action isusually foreseen for one (pivotal) domain according to priorities generated by the comprehensive geriatric assessment
and the subject’s needs/resources. Overall, the physical andcognitive interventions are similar to those we previously
adopted in the MAPT study (42). The MAPT intervention
proposed two sessions per week (for the first month), one
session per week (for the second month), and then one session per month thereafter. We are planning to implementin the next future the use of novel technologies to support
the monitoring of the subjects’ physical and cognitive functions as well as their nutrition status and behaviors.

Characteristic

Heart diseases

149 (26.6)

Vascular diseases

345 (61.6)

Endocrine or metabolic disorders

145 (25.9)

Chronic pulmonary diseases

88 (15.7)

Neurological diseases

86 (15.4)

Psychiatric disorders

96 (17.1)

Renal, urological or genital disorders

142 (25.4)

Gastrointestinal or liver diseases

135 (24.1)

Osteo-articular diseases

227 (40.5)

ORL or ophthalmology disorders

130 (23.2)

Cancer or malignant blood diseases/AIDS

165 (29.5)

Fall history in last 3 months, n=285

108 (37.9)

Having any kind of human help, n=1,105

767 (69.4)

Home maid

575 (52.0)

Old age allowance

190 (17.2)

BMI, Body Mass Index; G.F.C, Geriatric Frailty Clinic; ORL, OtoRhino-Laryngologist

Implementation at the regional level(Midi-Pyrénées region)
The Gérontopôle in collaboration with the Midi-Pyrénées
Regional Health Authority [Agence Régionale de Santé(ARS)] has deployed the activity of frailty in all the eight
departments (healthcare areas) of the Midi-Pyrénées region(South-West of France).
To make this possible, we created the “Regional team foraging and prevention of disabilities” [Equipe Régionale
Viellissement et Prévention de la Dépendence (ERVPD)].
This team includes not only the chair and co-chair of thedepartments of geriatrics of the main hospitals of the region, but also more than 700 volunteers working in the fieldof geriatrics [i.e., 305 physicians, 110 directors of healthfacilities, 59 directors of social and medical facilities (nursing home, home care…), 57 nurses…]. We have conducted
multiple actions with this team on the topic of frailty and125

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prevention of disability. For example, we have distributed
more than 70,000 brochures throughout the Midi-Pyrénées
region [published by the French Mutuality (Mutualité
Française)] for raising awareness about frailty and possibility to intervene.

HHIE-S score (/40), n=1,055

Characteristic

423 (39.1)
590 (54.5)

Frailty criteria, n=1,082

2.6±1.4

Unintentional weight loss, n=1,098

358 (32.6)

Feeling of exhaustion, n=1,083

353 (32.6)

Slow gait speed, n=1,065

547 (51.4)

Decreased muscle strength, n=1,084

722 (66.6)

Sedentariness, n=1,096

665 (60.7)

MMSE score (/30), n=1,071

24.6±4.9353 (34.0)

CDR=0.5531 (51.1)

CDR=1111 (10.7)

CDR≥2

44 (4.2)

MIS score (/8), n=1,038

6.6±1.9

MIS-D score (/8), n=1,036

6.0±2.3

ADL score (/6), n=1,102

5.5±1.0

IADL score (/8), n=1,094

5.6±2.4

SPPB score (/12), n=1,063

7.3±2.9Good performance (SPPB=10-12),272 (25.6)

Medium performance (SPPB=7-9),

388 (36.5)

Poor performance (SPPB=0-6),

403 (37.9)

Gait speed (m/s), n=1,065

0.78±0.27

Wrist strength (kg), n=1,083

20.6±8.2

MNA score (/30), n=1,04823.2±4.1

Good nutritional status (MNA>23.5)

550 (52.5)

Risk of malnutrition (MNA=17-23.5)

414 (39.5)

Malnourished (MNA<17)84 (8.0)

Vitamin D concentration (ng/ml),
n=1,06518.1±11.3≤ 10 ng/ml

343 (32.2)

11-29 ng/ml

563 (52.9)≥ 30 ng/ml

159 (14.9)

GDS score (/15), n=424
Presence of depressive symptoms(GDS>5)4.8±3.1
155 (36.6)

Abnormal distance vision, n=1,019

840 (82.4)

Abnormal near vision, n=1,039

232 (22.3)

Abnormal Amsler grid, n=1,060

177 (16.7)

2.8±2.4
44 (16.2)

ACTIONS AGAINST IATROGENIC DISABILITY
OCCURRING DURING THE HOSPITALIZATION
OF THE FRAIL OLDER ADULTCDR score (/3), n=1,039
CDR=0215 (76.8)

ADL, Activities of Daily Living [0 = Low (patient very dependent),
6 = High (patient independent)]; CDR, Clinical Dementia Rating(0= no dementia, 0.5= very mild dementia, 1= mild dementia,
2= moderate dementia, 3= severe dementia); GDS, GeriatricDepression Scale; G.F.C, Geriatric Frailty Clinic; HHIE-S,
Hearing Handicap Inventory for the Elderly - Screening; IADL,
Instrumental Activities of Daily Living [0 = Low (patient very
dependent), 8 = High (patient independent)]; MIS, Memory
Impairment Screen free; MIS-D, Memory Impairment Screen
delayed recall; MNA, Mini Nutritional Assessment; MMSE, Mini
Mental State; OHAT, Oral Health Assessment Tool; SD, Standard
Deviation; SPPB, Short Physical Performance Battery.

69 (6.4)

Frail (≥3 criteria)

1.7±1.4

The mouth not considered healthy(OHAT>4)

G.F.C population (n=1,108)
Mean ± SD or n (%)

Pre-frail (1-2 criteria)

Urinary incontinence score (/6), n=280

OHAT score (/16), n=271

Frailty status, n=1,082
Not frail

330 (31.3)

Urinary disorders causing discomfort
for everyday life (score≥1)

Table 3Baseline characteristics of the G.F.C population (n=1,108) (Tavassoli
et al. J Nutr Health Aging 2014; J Nutr Health Aging 2014;18:457-64)

9.5±9.8

Significant hearing impairment(HHIE-S>21)

It is very well known to both health professionals and general public that hospitalizations often represent a cause forfurther dependency in frail older adults. However, such risk
is usually accepted as a fatality. The loss of autonomy occurring during the hospitalization to the frail elder is often
due to the non-adaptation of our healthcare services andinfrastructures to the needs of the aging population. It isindeed a matter of raising knowledge and improving thecultural background about aging and age-related conditions
among the healthcare personnel.
We have recently conducted a study at the Gérontopôlewith the objective to determine the frequency, causes, andthe potential for preventing iatrogenic disability (43). We
assessed 503 hospitalized older persons aged 75 years andmore from 105 medical and surgical units of Toulouse University Hospital (the 4th largest hospital in France). The
study was conducted between October 2011 and March
2012. All the participants with a hospital stay of two days or
longer were included. Iatrogenic disability (i.e., determinedby the hospitalization) was defined as the loss of 0.5 points
or more on the ADL scale occurring between the timefrom the hospital admission and the discharge. The prevalence of this condition was 11.9%. Among the 60 casesof iatrogenic disability we identified, it was judged that 49(81.7%) could have been potentially preventable. The main
factors associated with iatrogenic disability were the overuse of diapers (49.0%), the transurethral urinary catheterization (30.6%), the poor mobilization or excessive bed
rest (26.5%), and lack of encouragement in the mobility
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IMPLEMENTING FRAILTY SCREENING, ASSESSMENT, AND SUSTAINED INTERVENTION: THE EXPERIENCE OF THE GÉRONTOPÔLE

(55.1%). Due to the fact that around 30% of older adults
aged 75 years and older are hospitalized each year, actions
aimed at limiting iatrogenic disability may represent an important and cost-effective strategy to consider. It is urgent
to systematically act, as it has been doing for other conditions (e.g., nosocomial infections).
COMMENTS AND RESEARCH DIRECTIONS: TARGETINGFRAILTY TO DEVELOP INNOVATION, CLINICALRESEARCH AND THE « SILVER ECONOMY »Two domains appear to be of high priority to maintain autonomous living with advancing age: mobility and memory.
In the recent years (and likely more in the future), the agerelated mobility loss has been studied in the framework ofsarcopenia. It is noteworthy that the SPRINT-T programaims to operationalize a clinical condition simultaneously
combining frailty and sarcopenia. This may lead to the identification of an objective and clinical target for non-pharmacological and pharmacological interventions (e.g.,
myostatin inhibitors currently under development) (44).
On the other hand, if we want to fight dementia we mustagain work in the prevention and at its earliest stages. It isinteresting that more than 50% of the older adults seen at
our frailty day hospital have some objective cognitive impairment. Thus, it becomes important understanding therelationship between frailty and neurodegenerative disorders (e.g., Alzheimer’s disease). This may help us at bettertuning the diagnostic procedures and interventions against
disabling conditions. In fact, it is possible that not all of
the subjects with cognitive impairment have or will develop

a neurodegenerative disorder. It is likely that their cognitive loss might be explained by other causes (e.g., vasculardisease, depression, earing and visual impairment…), implicitly indicating the need of differentiating the subsequentinterventions. This might foster research in the amelioration of current biomarkers of risk (e.g., those capturing thepathological features of dementias). In the next years, it islikely that a primary role as matter of research will be playedby the so-called cognitive frailty (or cognitive impairment
due to frailty conditions) (45).
We need to move the geriatric practice from the standard
services to the field of prevention. Frail older adults indeed
represent an optimal target for implementing strategies
aimed are counteracting the detrimental manifestations of
the aging process.
Finally, it is important to mention how the accomplishmentof our ambitious objective (i.e., prevention of disability)
passes through a reformulation and creation of novel resources. In the war against age-related frailty, disability anddependency, we need ad hoc clinical and research infrastructures as well as promotion of international collaborations. We need to learn from our experiences with the aimof improving our messages and strategies in the view ofclinically relevant and innovative results.
Conflict of Interest: Research grants and consultancy from
Nestle, Nutritia, Pierre Fabre, Sanofi.
This article was published in the Journal of Nutrition, Health and Aging
Volume 19, Number 6, 2015
http://www.springer.com/medicine/internal/journal/12603

REFERENCES
1. Alzheimer Disease International: World Alzheimer Report
2013, Journey of Caring. http://www.alz.co.uk/research/WorldAlzheimerReport2013.pdf (accessed August 19, 2014).
2. Katz S, Branch LG, Branson MH, Papsidero JA, Beck JC, Greer DS.
Active life expectancy. N Engl J Med 1983; 309: 1218-1224.
3. Fried TR, Bradley EH, Williams CS, Tinetti ME. Functional disability and health care expenditures for older persons. Arch Intern Med
2001; 161: 2602-2607.
4. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA. Frailty
in older adults: evidence for a phenotype. J Gerontol A Biol Sci
Med Sci 2001; 56: M146-56.
5. Rodríguez-Mañas L, Féart C, Mann G et al. Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus
Statement. The Frailty Operative Definition-Consensus Conference Project. J Gerontol A Biol Sci Med Sci 2012; 68: 62-67.
6. Morley JE, Vellas B, Abellan van Kan G et al. Frailty consensus: acall to action. J Am Med Dir Assoc 2013; 14: 392-397.
7. Vellas B, Cestac P, Morley JE. Implementing frailty into clinicalpractice: we cannot wait. J Nutr Health Aging 2012; 16: 599-600.

8. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013; 381: 752-762.
9. Cesari M, Vellas B, Gambassi G. The stress of aging. Exp Gerontol
2013; 48: 451- 456.
10. Bernabei R, Landi F, Gambassi G et al. Randomised trial of impact
of model of integrated care and case management for older people living in the community. BMJ 1998; 316: 1348-1351.
11. Stuck AE, Minder CE, Peter-Wüest I et al. A randomized trial of inhome visits for disability prevention in community-dwelling older
people at low and high risk for nursing home admission. Arch
Intern Med 2000; 160: 977-986.
12. Glasziou P, Moynihan R, Richards T, Godlee F. Too much medicine; too little care. BMJ 2013; 347: f4247.
13. Moreno-Aguilar M, Garcia-Lara JMA, Aguilar-Navarro S, Navarrete-Reyes AP, Amieva H, Avila-Funes JA. The phenotype of frailty
and health-related quality of life. J Frailty Aging 2013; 2: 2-7.
14. O’Connell MDL, Tajar A, O’ Neill TW et al. Frailty is associatedwith impaired quality of life and falls in middle-aged and older
European men. J Frailty Aging 2013; 2: 77-83.

127

WHITE BOOK

15. Cesari M, Gambassi G, Abellan van Kan G, Vellas B. The frailty
phenotype and the frailty index: different instruments for different
purposes. Age Ageing 2014; 43: 10-12.
16. Santos-Eggimann B, Cuénoud P, Spagnoli J, Junod J. Prevalence offrailty in middle- aged and older community-dwelling Europeans
living in 10 countries. J Gerontol A Biol Sci Med Sci 2009; 64: 675681.
17. Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalenceof frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc 2012; 60: 1487–92.
18. Gutman GM, Stark A, Donald A, Beattie BL. Contribution ofself-reported health ratings to predicting frailty, institutionalization, and death over a 5-year period. Int Psychogeriatr 2001; 13Supp 1: 223-31.
19. Frisoli A Jr, Chaves PH, Ingham SJ, Fried LP. Severe osteopenia
and osteoporosis, sarcopenia, and frailty status in community-dwelling older women: results from the Women’s Health andAging Study (WHAS) II. Bone 2011; 48: 952-7.
20. Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM,
Chaves P, Zeger SL, Fried LP. Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci
Med Sci. 2006; 61: 262-6.
21. Rantanen T, Guralnik JM, Sakari-Rantala R, Leveille S, Simonsick EM, Ling S, Fried LP. Disability, physical activity, and muscle
strength in older women: the Women’s Health and Aging Study.
Arch Phys Med Rehabil 1999; 80: 130-5.
22. Ensrud KE, Ewing SK, Taylor BC, Fink HA, Cawthon PM, Stone KL,
Hillier TA, Cauley JA, Hochberg MC, Rodondi N, Tracy JK, Cummings SR. Comparison of 2 frailty indexes for prediction of falls,
disability, fractures, and death in older women. Arch Intern Med
2008; 168: 382-9.
23. Ensrud KE, Ewing SK, Cawthon PM, Fink HA, Taylor BC, Cauley JA,
Dam TT, Marshall LM, Orwoll ES, Cummings SR. A comparison offrailty indexes for the prediction of falls, disability, fractures, andmortality in older men. Osteoporotic Fractures in Men ResearchGroup. J Am Geriatr Soc 2009; 57: 492-8.
24. Ellis G, Whitehead MA, Robinson D, O’Neill D, Langhorne P.
Comprehensive geriatric assessment for older adults admitted tohospital: meta-analysis of randomised controlled trials. BMJ 2011;
343: d6553.
25. Beswick AD, Rees K, Dieppe P, Ayis S, Gooberman-Hill R, Horwood J, Ebrahim S. Complex interventions to improve physicalfunction and maintain independent living in elderly people: a systematic review and meta-analysis. Lancet 2008; 371: 725-735.
26. Stuck AE, Egger M, Hammer A, Minder CE, Beck JC. Home visits to prevent nursing home admission and functional decline inelderly people: systematic review and meta-regression analysis.
JAMA 2002; 287: 1022-1028.
27. Cummings SR1, Studenski S2, Ferrucci L. A diagnosis of dismobility-giving mobility clinical visibility: a Mobility Working Group
recommendation. JAMA 2014; 311: 2061-2062.
28. International Conference on Frailty and Sarcopenia Research.
http://www.frailty- sarcopenia.com/ (accessed August 19, 2014).
29. The Innovative Medicines Initiative. http://www.imi.europa.eu/(accessed August 19, 2014).
30. The Journal of Frailty and Aging. www.jfrailtyaging.com/ (accessed
August 19, 2014).
31. Implementing Frailty into Clinical Practice. http://www.frailty.net/(accessed August 19, 2014).
32. Ensemble prévenons la dépendence. http://www.ensembleprevenonsladependance.fr/ (accessed August 19, 2014).

33. Morley JE, Malmstrom TK, Miller DK. A simple frailty questionnaire (FRAIL) predicts outcomes in middle aged African Americans. J Nutr Health Aging 2012; 16: 601-608.
34. Vellas B, Balardy L, Gillette-Guyonnet S, Abellan Van Kan G,
Ghisolfi-Marque A, Subra J, Bismuth S, Oustric S, Cesari M. Looking for frailty in community-dwelling older persons: the Gérontopôle Frailty Screening Tool (GFST). J Nutr Health Aging 2013; 17:629-631.
35. Xue QL, Varadhan R. What is missing in the validation of frailty
instruments? J Am Med Dir Assoc 2014; 15(2): 141-142.
36. Cesari M, Vellas B. Response to the letter to the editor: “what is
missing in the validation of frailty instruments?”. J Am Med Dir
Assoc 2014; 15(2): 143-144.
37. Subra J, Gillette-Guyonnet S, Cesari M, Oustric S, Vellas B; Platform Team. The integration of frailty into clinical practice: preliminary results from the Gérontopôle. J Nutr Health Aging. 2012; 16:714-720.
38. Tavassoli N, Guyonnet S, Abellan Van Kan G, Sourdet S, Krams
T, Soto ME, Subra J, Chicoulaa B, Ghisolfi A, Balardy L, Cestac P,
Rolland Y, Andrieu S, Nourhashemi F, Oustric S, Cesari M, Vellas
B and the Geriatric Frailty Clinic (G.F.C) for Assessment of Frailty and Prevention of Disability Team. Description of 1,108 Older
Patients Referred by their Physician to the “Geriatric Frailty Clinic(G.F.C) for Assessment of Frailty and Prevention of Disability” at
the Gerontopole. J Nutr Health Aging 2014; 18: 457-464.
39. Fiche points clés et solutions, Haute Autorité de Santé (HAS).
http://www.has-sante.fr/portail/upload/docs/application/
pdf/2013-06/fiche_parcours_fragilite_vf.pdf (accessed August 19,2014).
40. Cesari M, Demougeot L, Boccalon H, Guyonnet S, Vellas B, Andrieu S. The Multidomain Intervention to preveNt disability in
ElDers (MINDED) project: rationale and study design of a pilot
study. Contemp Clin Trials 2014; 38: 145-154.
41. Cesari M, Demougeot L, Boccalon H, Guyonnet S, Abellan Van
Kan G, Vellas B, Andrieu S. A self-reported screening tool for detecting community-dwelling older persons with frailty syndromein the absence of mobility disability: the FiND questionnaire. PLoS
One 2014; 9: e101745.
42. Vellas B, Carrie I, Gillette-Guyonnet S, Touchon J, Dantoine T,
Dartigues JF, Cuffi MN, Bordes S, Gasnier Y, Robert P, Bories L,
Rouaud O, Desclaux F, Sudres K, Bonnefoy M, Pesce A, DufouilC, Lehericy S, Chupin M, Mangin JF, Payoux P, Adel D, LegrandP, Catheline D, Kanony C, Zaim M, Molinier L, Costa N, Delrieu J,
Voisin T, Faisant C, Lala F, Nourhashemi F, Rolland Y, Abellan Van
Kan G, Dupuy C, Cantet C, Cestac P, Belleville S, Willis S, Cesari
M, Weiner MW, Soto ME, Ousset PJ, Andrieu S. MAPT Study: A
Multidomain Approach for Preventing Alzheimer’s Disease: Design and Baseline Data. JPAD 2014; 1: 13-22.
43. Sourdet S, Lafont C, Rolland Y, Nourhashemi F, Andrieu S, Vellas
B. Preventable Iatrogenic Disability in Elderly Patients during hospitalization. PLoS One 2014; in press.
44. White TA, LeBrasseur NK. Myostatin and sarcopenia: opportunities and challenges - a mini-review. Gerontology 2014; 60: 289-93.
45. Kelaiditi E, Cesari M, Canevelli M, van Kan GA, Ousset PJ, Gillette-Guyonnet S, Ritz P, Duveau F, Soto ME, Provencher V, Nourhashemi F, Salvà A, Robert P, Andrieu S, Rolland Y, Touchon J,
Fitten JL, Vellas B; IANA/IAGG. Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group.
J Nutr Health Aging 2013; 17: 726-734.

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LOOKING FOR FRAILTY IN COMMUNITY-DWELLING OLDER PERSONS: THE GERONTOPOLE FRAILTY SCREENING TOOL (GFST)LOOKING FOR FRAILTY IN COMMUNITY-DWELLING
OLDER PERSONS: THE GERONTOPOLE FRAILTYSCREENING TOOL (GFST)
B. VELLAS1,2,3, L. BALARDY1,2, S. GILLETTE-GUYONNET1,2,3, G. ABELLAN VAN KAN1,3,
A.GHISOLFI-MARQUE1,3, J. SUBRA4, S. BISMUTH4,
S.OUSTRIC3,4, M. CESARI1,2,3

1 Gérontopôle, Centre Hspitalier Universitaire de Toulouse, Toulouse, France;
2 INSERM UMR1027, Toulouse, France;
3 Université de Toulouse III Paul Sabatier, Toulouse, France;
4 Département de médecine générale, Université de Toulouse III Paul Sabatier, Toulouse, France.
Correspondence: Matteo Cesari, MD, PhD, Institut du Vieillissement, Gérontopôle, Université Toulouse III –Paul Sabatier, 37 Allées Jules Guesde, 31000 Toulouse, France. Phone: +33 (0)5 61145628; Fax: +33 (0)5 61145640;
Email: macesari@gmail.com

Abstract: The frailty syndrome is a pre-disability condition
suitable to be targeted by preventive interventions against
disability. In order to identify frail older persons at risk ofnegative outcomes, general practitioners must be provided
with an easy and quick screening tool for detecting frailty
without special effort. In the present paper, we present thescreening tool for frailty that the Gérontopôle of Toulouse(France) has developed and implemented in primary carein the region with the collaboration of the Department
of Family Medicine of the University of Toulouse. The
Gérontopôle Frailty Screening Tool (GFST) is designed tobe administered to persons aged ≥65 years with no physicaldisability and acute clinical disease. It is composed by an initial questionnaire aimed at attracting the general practitioner’s attention to very general signs and/or symptoms suggesting the presence of an underlying frailty status. Then,in a second section, the general practitioner expresses his/her own view about the frailty status of the individual. The
clinical judgment of the general practitioner is finally retained for determining the eventual presence of frailty. Preliminary data document that almost everyone (95.2%) of
the 442 patients referred to the Gérontopôle frailty clinic
by general practitioners using the GFST indeed presents a
condition of (pre-)frailty according to the criteria proposedby Fried and colleagues in the Cardiovascular Health Study.
The use of the GFST may help at raising awareness about
the importance of identifying frailty, training healthcare
professionals at the detection of the syndrome, and developing preventive interventions against disabling conditions.

INTRODUCTION

practice is still lacking (1, 2). Geriatric medicine is very focused at taking care of older persons with disabilities, andthe attempts to anticipate the disabling cascade are still preliminary and/or not sufficiently convinced. Nevertheless,in order to reduce the burdens posed by disabilities (to the

Although a growing body of literature demonstrates thehigh prevalence and major clinical relevance of the frailty
syndrome in older adults, its implementation in the daily

Key words: Preventive medicine, primary care, elderly; risk
factors, frailty.

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older person as well to the public health systems), it important to preventively act, when clinical conditions of risk canstill be reversed or at least attenuated. The frailty syndrome
is today largely recognized as the pre-disability condition
more suitable to be targeted by preventive interventions
against disability (3, 4).
One of the major challenges in implementing preventive
interventions against disability resides in the need of redesigning part of the current clinical standards. In fact,
the detection of frailty can be adequately conducted only
by anticipating the “medicalization” of the older subject.
Leaving undetected and/or untreated the frailty syndrome
means delaying possible interventions, rendering potentiallyirreversible the process directed towards the spiral cascadeof disability. For this reason, it is necessary to take adequate countermeasures as soon as the first signs/symptoms
of frailty become manifest. In other words, it is needed to
identify subjects at risk before their vulnerability is madeevident by the onset of a major clinical event (e.g., falls,
emergency room admissions, hospitalizations). In this context, a key role is played by general practitioners, primaryreferents for the individual’s health as well as crucial for the
implementation of every preventive action. Regrettably, thegeneral practitioner’s activity is often too busy to foresee
the addition of new tasks or clinical duties to the daily routine. To efficiently and correctly identify frail older persons
among his/her patients, the general practitioner must be
supported, starting with the provision of an easy and quick
screening tool for detecting the frailty status without special
effort.
As previously described (5), since October 2011, we havedeveloped in Toulouse (France) an innovative clinical setting specifically focused at targeting frailty with the aimof preventing incident disability in community-dwellingolder persons. Such initiative, highly responsive to publichealth demands (6), has been designed and developed by
the Gérontopôle and the Department of Family Medicineof the University of Toulouse. General practitioners in the
Toulouse area have been first educated to the concept offrailty and the importance of detecting it in clinical practice.
Then, they have been trained at the use of a specificallydeveloped screening tool assisting their evaluation.
The Gérontopôle Frailty Screening Tool (GFST, Table 1)
is designed to be applied to older persons (aged 65 years
and older) with no physical disability (defined by complete
preservation of the Activities of Daily Living (7)) and acuteclinical disease. Two different parts compose the instrument. The first one appears as a questionnaire. Its main
objective is to attract the general practitioner’s attention tovery general signs and/or symptoms potentially indicating
the presence of an underlying frailty status. These questions
largely mirror the criteria that are commonly used to operationalize the frailty status (8, 9). For example, they remind

the general practitioner to pay attention to the gait speed
and mobility of the individual, his/her weight stability, or
the possible presence of exhaustion. This part also contains a specific question about eventual memory complaintsof the subject (in agreement with current evidence linking
the cognitive and physical domain in the determination andmanifestation of frailty (10-13)) and another one about thesocial status of the person (a major component to consider
in the design of preventive interventions against disability(14, 15)).
This preliminary, almost pedagogic, section is then followed by a second part in which the general practitioner
expresses his/her own view about the frailty status of theindividual. The clinical judgment of the general practitioner
is here used to determine whether, after the evaluation of
the previous criteria, he/she indeed believes the person isfrail or not. Only if he/she agrees with the results of thefirst section identifying the possible presence of frailty, theintervention is proposed.
It might be argued that the design of the GFST may leave
the detection of frailty to the subjective perception of thegeneral practitioner. Such choice is mainly motivated by two
reasons: 1) to avoid that a major clinical decision (i.e., referral of the individual to a clinical intervention) is solely leftto a screening tool, and 2) to directly involve the generalpractitioner in the diagnosis and subsequent follow-up of
the detected condition. Moreover, although the final decision is left to the clinical judgment of the general practitioner, it is still driven by the preliminary section listing themain defining criteria of the frailty syndrome.
In the context of Toulouse, taking action after the identification of frailty means explaining the subject the opportunity to undergo a multidisciplinary clinical assessment
at the dedicated platform of the Gérontopôle (5). Here,the individual is comprehensively evaluated by a team ofdifferent healthcare professionals (i.e., geriatrician, nurse,
neuropsychologist, physical therapist, dietician) with theobjective of designing a personalized plan of intervention
against disability.
The instrument provided by the Gérontopôle to the general practitioners of the Toulouse area is not yet validated. In particular, we do not know exactly how many false
negatives were excluded from the preventive intervention
at the platform. Current studies are ongoing to fill this gap.
Nevertheless, the GFST has shown to adequately support
the identification of frailty in community-dwelling older
persons. In fact, data from the first 442 participants evaluated at the platform show that almost everyone (95.2%)
resulted pre-frail (31.1%) or frail (64.1%) according to thecriteria proposed by Fried et al. (8). Less than 5% was incorrectly referred to the platform as being robust or alreadydisabled in the Activities of Daily Living. It is also noteworthy the high acceptance that the instrument had among

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LOOKING FOR FRAILTY IN COMMUNITY-DWELLING OLDER PERSONS: THE GERONTOPOLE FRAILTY SCREENING TOOL (GFST)

general practitioners, especially because not time- consuming or invasive of their clinical decisions and daily practice.
All this implies that, after training the general practitioners at the detection of frailty, their clinical judgment may
suffice at accurately estimating the risk profile of the older
individual and seek for support. The use of the instrument
we propose will likely become unnecessary once that theconcept of frailty will be better established, the healthcare

professionals will have familiarized with the detection of
the syndrome, and specifically devoted clinical settings for
its assessment/treatment will be available. At this time, we
believe the GFST might optimally serve to diffuse knowledge about the detrimental syndrome of frailty, and render
general practitioners more active in the promotion of preventive interventions against disability in older persons.

Table 1The Gérontopôle Frailty Screening Tool (GFST)

Patients aged 65 years and older without both functional disability (Activities of Daily Living score ≥5/6) and current acute disease.
YESNO

Do not know

Does your patient live alone?







Has your patient involuntarily lost weight in the last 3 months?







Has your patient been more fatigued in the last 3 months?







Has your patient experienced increased mobility difficulties in the last 3 months?







Has your patient complained of memory problems?







Does your patient present slow gait speed (i.e., >4 seconds to walk 4 meters)?







Do you think your patient is frail?

YES 

NO 

If YES, is your patient willing to be assessed for his/her frailty status at the Frailty Clinic?

YES 

NO 

If you have answered YES to one or more of these questions:This article was published in the Journal of Nutrition, Health and Aging
Volume 17, Number 7, 2013
http://www.springer.com/medicine/internal/journal/12603

REFERENCES
1. Vellas B, Cestac P, Moley JE. Implementing frailty into clinicalpractice: we cannot wait. J Nutr Health Aging 2012; 16: 599-600.
2. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013; 381: 752-762.
3. Morley JE, Haren MT, Rolland Y, Kim MJ. Frailty. Med Clin North
Am 2006; 90: 837-847.
4. Cesari M. Frailty and aging. J Frailty Aging 2012; 1: 3-5.
5. Subra J, Gillette-Guyonnet S, Cesari M, Oustric S, Vellas B. The
integration of frailty into clinical practice: preliminary results fromthe gérontopôle. J Nutr Health Aging 2012; 16: 714-720.
6. Ferrucci L, Guralnik JM, Studenski S et al. Designing randomized,
controlled trials aimed at preventing or delaying functional decline
and disability in frail, older persons: a consensus report. J Am Geriatr Soc 2004; 52: 625-634.
7. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of
illness in the aged. The index of ADL: a standardized measure of
biological and psychosocial function. JAMA 1963; 185: 914-919.
8. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:
M146-56.

9. Morley JE, Abbatecola AM, Argiles JM et al. Sarcopenia with limited mobility: an international consensus. J Am Med Dir Assoc 2011;12: 403-409.
10. Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA.
Physical frailty is associated with incident mild cognitive impairment in community-based older persons. J Am Geriatr Soc 2010;
58: 248-255.
11. Avila-Funes JA, Pina-Escudero SD, Aguilar-Navarro S, Gutierrez-Robledo LM, Ruiz-Arregui L, Amieva H. Cognitive impairment and low physical activity are the components of frailty morestrongly associated with disability. J Nutr Health Aging 2011; 15:683-689.
12. Houles M, Canevelli M, Abellan Van Kan G, Ousset PJ, Cesari M,
Vellas B. Frailty and cognition. J Frailty Aging 2012; 1: 56-63.
13. Auyeung TW, Lee JS, Kwok T, Woo J. Physical frailty predicts futurecognitive decline - a four-year prospective study in 2737 cognitively
normal older adults. J Nutr Health Aging 2011; 15: 690-694.
14. Barusch A, Waters DL. Social engagement of frail elders. J Frailty
Aging 2012; 1: 189-194.
15. Gutierrez-Robledo LM, Avila-Funes JA. How to include the social
factor for determining frailty? J Frailty Aging 2012; 1: 13-17.

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THE INTEGRATION OF FRAILTY INTO
CLINICAL PRACTICE: PRELIMINARY RESULTS
FROM THE GÉRONTOPÔLE
J. SUBRA1,2, S. GILLETTE-GUYONNET2,3, M. CESARI2,3, S. OUSTRIC1,3,
B. VELLAS2,3 AND THE PLATFORM TEAM4

1 University Department of General Medicine, 133 route de Narbonne, 31062 Toulouse Cedex, France;
2 Gérontopôle, Service de médecine interne gériatrique. CHU Toulouse Hôpital Casselardit, 170 avenue de Casselardit, 31300
Toulouse;
3 Inserm 1027, F-31073 Toulouse; 4. Balardy L, Ghisolfi A, Bismuth S, Houles M, Hermabessière S, Cavaillon C, Jezequel F,
Pedra M, Soto ME, Rolland Y, Nourhashemi F.
Correspondence: Matteo Cesari, MD, PhD, Institut du vieillissement, Université de Toulouse, 37 allées Jules Guesdes, 31000
Toulouse, France, Phone : +33(0)561145628, Fax +33(0)5 61 14 56 40, e-mail : macesari@gmail.com

Abstract: Background: Disability is commonly considered
as an irreversible condition of advanced age. Therefore,
preventive actions need to be taken before the disablingcascade is fully established, that is in the pre- disability phase defined “frailty syndrome”. The complexity andheterogeneity of frailty requires a clinical approach basedon multidimensionality and multidisciplinary. In this paper,
we present the main characteristics of the newborn Platform for Evaluation of Frailty and Prevention of Disability (Toulouse, France). Intervention: Persons aged 65 years
and older screened for frailty by general practitioners in the
Toulouse area are invited to undergo a multidisciplinary
evaluation at the Platform. Here, the individual is multidimensionality assessed in order to preventively detect potential risk factors for disability. At the end of the comprehensive evaluation, the team members propose the patient (inagreement with the general practitioner) a preventive intervention program specifically tailored to the his/her needs
and resources. Results: Mean age of our population is 82.7
years, with a large majority aged 75 years and older. Most
patients are women (61.9%) Approximately two thirds ofpatients received any kind of regular help. Regarding levelof frailty, 65 patients (41.4%) were pre-frail, and 83 (52.9%)
frail. For what concerns the functional status, 83.9% of pa-

tients presented slow gait speed, 53.8% were sedentary, and57.7% had poor muscle strength. Only 27.2% of patients
had a SPPB score equal to or higher than 10. Autonomy
in ADL was quite well preserved (mean ADL score 5.6 ±0.8) as expected, suggesting that the patients of the platform have not yet developed disability. Consistently, IADL
showed a marginal loss of autonomy reporting a meanscore of 6.0 ± 2.3. About one third of patients (33.1%)
presented a MMSE score lower than 25. Dementia (measured by the CDR scale) was observed in 11.6% of theplatform population, whereas subjects with mild cognitive
impairment (that is CDR equal to 0.5) were 65.8%. New diagnosed depressive disorders were relatively rare with only
3.2% of patients showing signs of depression but somepeople were already treated. Numerous patients presented
vision problems with 10.4% having abnormal findings at
the Amsler grid. Finally, it is noteworthy that 9% of theplatform population presented an objective state of protein-energy malnutrition, 34% an early alteration of nutritional status, while almost everyone (94.9%) had a vitamin
D deficiency (partially explained by the period of the year,that is winter-spring, of most of the measurements). Conclusion: The Platform clinically evaluates and intervenes on
frailty for the first time at the general population-level. This

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THE INTEGRATION OF FRAILTY INTO CLINICAL PRACTICE: PRELIMINARY RESULTS FROM THE GÉRONTOPÔLE

model may serve as preliminary step towards a wider identification of early signs of the disabling cascade in order todevelop more effective preventive interventions.

Key words: Frailty, elderly, prevention, disability, evaluation.

INTRODUCTION

On the basis of this novel concept, the heterogeneous older population was subsequently categorized into three subgroups to better design and develop person-tailored interventions: Older persons were then considered “disabled” ifneeding assistance in the accomplishment of basic activities
of daily living, “frail” if presenting limitations and impairments in the absence of disability, and “robust” if no frailty
or disability were present.
To translate the theoretical concept of frailty into practice,Fried et al. (3) proposed a model combining the evaluation of the following five criteria: sedentariness, involuntary weight loss, fatigue, poor muscle strength, and slow
gait speed. According to this instrument, an older person
is considered “frail” if presenting three or more of thesedefining criteria.
The identification of a pre-disability state (i.e., frailty) allows
the detection of older persons at risk of negative events
that may still benefit from preventive interventions against
disability. This new concept of frailty modifies the common
geriatric approach by leading it towards the importance ofprevention, a field that was not possible to adopt in the pastwhen only irreversible conditions came to the geriatrician
evaluation. At the same time, the definition of a biologicalage provides the basis for identifying persons who indeed
need the evaluation of a geriatrician, redirecting to the different specialties those who can be followed and treatedusing standard protocols because only an graphically old.
The “gold standard” intervention adopted in geriatric medicine is surely represented by the comprehensive geriatricassessment (CGA). The CGA consists of a global evaluation of the older patient performed by a multidisciplinary
team finally resulting in the design of a person-tailored
preventive or therapeutical intervention. Since the CGA isconducted using standardized scales and instruments, thereis the possibility to evaluate the efficacy of the proposedinterventions over time and more efficiently follow-up thepatient.
In 1984, Rubenstein et al (4) first showed that CGA had
a beneficial impact on institutionalization and mortality ofolder persons. Few years later, the meta-analysis by Stuck etal. (5) on 28 clinical trials confirmed such positive results
extending them on multiple outcomes, including mortality,
hospital admissions, cognitive decline, and functional impairment. In 2004, a randomized trial studied the effectsof CGA (and CGA- derived interventions) in individuals
aged 74 years and older in primary care (6). Interestingly,
the study confirmed the idea that frailty is a reversible con-

Since the beginning of the 20th century, when first Nascher
proposed the birth of the novel medical discipline, geriatrics has been specifically focused at taking care of older persons experiencing the heavy burden of age-relateddiseases (1). Up to few years ago, the geriatrician was incharge of assisting (i.e., evaluating and treating) those patients which could not be adequately followed in any otherspecialty due to their comorbidities, polypharmacy, social
issues, and functional impairment. In particular, the average geriatric patient has commonly been for a long time anolder person at advanced age already presenting relevant
disabling conditions, significantly impairing his/her capacity to conduct an autonomous life. In other words, geriatricpatients frequently experienced those conditions and/or
clinical outcomes for which they were automatically excluded from standard interventions proposed at younger ages.
Moreover, the primary outcome of disability significantly
differentiates geriatric medicine from other specialties. This
end-point (also considering the characteristics of the subjects at risk of developing it) imposes the adoption of alternative approaches and choice of different interventions,
often in contrast with the so-called “evidence-based medicine”.
Disability is commonly considered an irreversible conditionin older persons. It is a clinical issue representing a priority
for public health systems of developed countries. In fact,
besides of posing severe burdens to the patient’s quality oflife, disability is associated with high healthcare costs (2).
The detrimental effects (at both person- and society-level)of disability should be considered in the wider scenario of
our aging societies. In this way, it becomes clear why wecannot anymore wait for assessing the standard geriatric patient already disabled, but we should preventively act before
the irreversible disabling cascade is in place.
For this reason, during the last two decades, a growing bodyof literature has been specifically focused at exploring the“frailty syndrome”. Frailty is commonly defined as a geriatric syndrome characterized by the reduction of physiological reserves and capacities of an individual needed toadequately face exogenous and endogenous stressors. Such
condition poses the subject at increased risk of negative
health-related events, including hospitalization, institutionalization, and disability. In particular, frailty is usually considered as a pre-disability state which, differently from disability, is still amenable for interventions and reversible (3).

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dition (27.9% of frail individuals were no longer frail after
the intervention).
Despite the importance of preventing disability, the implementation of frailty in the clinical setting is still limited. Major difficulties at preventively act against disability reside in:
1-The need to design a different geriatric approach to theolder patient. In fact, as above-mentioned, the geriatrician
cannot anymore wait to visit the (already disabled) patient,but preventively evaluate the health status of the older
subject. This implies the need of a close collaboration between family physicians and geriatrics facilities in order topromptly detect the early signs of the disabling cascade andpreventively act at the general population-level (7). In otherwords, the frailty detection and treatment are directed towards community- dwelling older persons which are not yet“medicalized” and may even not feel the immediate need ofa clinical assessment.
2-The still limited recognition of frailty as a valid clinicalcondition (thus, to detect, measure, and treat). The noveltyof frailty has raised intense debates about its nature andoperational definition. Nevertheless, its theoretical background is today sufficiently strong to recommend the assessment of frailty in the clinical practice (8, 9).
In these last years, the French government has defined a
new policy for preventing disability in older persons. To
address this national (but even wider) public health issue,
the geriatric center of Toulouse (i.e., the Gérontopôle of
the Centre Hospitalier Universitaire de Toulouse) in association with the university Department of General Medicineof Toulouse (DUMG) and the regional health authority(Agence Regionale de Santé -ARS- Midi-Pyrénées) designed
and developed an innovative Platform for the Evaluationof Frailty and the Prevention of Disability. Such platform
is specifically aimed at supporting the comprehensive andmultidisciplinary assessment of frail older persons. The
identification of the specific causes of the increased statusof vulnerability allows the multidisciplinary team to designa patient-tailored preventive plan of intervention against
disability. In the present paper, we describe the platform
structure and organization, and provide the main characteristics of the first 160 patients evaluated during the firsteight months of operation.
THE STRUCTURE OF THE PLATFORM

The Platform for the Evaluation of Frailty and the Prevention of Disability was started in October 2011 as a separate
activity of the geriatric day hospital unit of the Gérontopôle of Toulouse. It is currently hosted in four rooms(two clinical offices for the evaluation of patients and blooddrawn, a waiting room and an administrative office) locatedat the Hospital Garonne (Toulouse, France). The platform
currently accommodates up to four patients per day, fivedays per week. However, starting from January 2013, theplatform will be able to evaluate up to eight patients perday, five times per week, at the new site of the Hospital La
Grave (Toulouse, France).
Each patient evaluated at the platform must be referred bya physician detecting signs or symptoms of frailty in him/
her. This service is paid by the social security health system
to the hospital. As we can see in the results sections, thefrail older adults referred to the platform have already someunderlying diseases witch really need to be diagnosed. The
platform provides the patient’s assessment, treatment, andfollow-up in close connection with family physicians. Afterone and three months from the evaluation, the platform
staff contacts the patient (or his/her proxies) to make surethat the proposed interventions have been adopted and to
estimate possible modifications of his/her health status.

Identification of the frail elderly person
Numerous screening tools are currently available to detect
frailty in older persons, most of them primarily used in clinical research (10). Although several operational definitions
have been developed over the last decade to support clinicians and researchers at objectively screening older persons
for frailty, a controversy exists about the optimal instrument
to be adopted (11). The major reason for such difficulties
at reaching an agreement probably resides in the multidimensional nature of the frailty syndrome (12). This has led
to the proposal of multiple tools, each one constitued by
specific sets of items or tasks providing different phenotypes of frailty. For example, a panel of experts proposed
gait speed as a possible parameter to screen frailty in older
persons. After all, its predictive value for adverse outcome
is widely demonstrated (13, 14). The adoption of physicalperformance tests in the screening of older persons at riskof health-related events has been proposed as preliminary
step towards a structural reorganization of healthcare provision (15).
In a previous study, we explored the feasibility of a questionnaire screening frailty among general practitioners. The
instrument was based on the gait speed test and proposedby 50 physicians of the Midi-Pyrénées region (France). The
instrument was largely well accepted. However, two difficulties were mainly reported in the implementation of the
instrument: finding a 4-meter track in the physician’s office
to measure gait speed, and the addition of a novel screening
tool in the already busy practice (due to the complexity ofpatients) (16).
Taking into account data from literature and results fromsuch preliminary survey, we developed a questionnaire to
be used by general practitioners for screening frailty. In
particular, it takes into account the physician’s subjective
perception of the patient’s frailty status together with functional, social, cognitive, nutritional factors (Table 1). The

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THE INTEGRATION OF FRAILTY INTO CLINICAL PRACTICE: PRELIMINARY RESULTS FROM THE GÉRONTOPÔLE

questionnaire was design to highlight the importance of thegeneral practitioner in the definition of the frailty status of
the individual. This was done by rendering of primary importance the clinical subjective feeling of the physician in
the definition of the questionnaire result.
Table 1
Questionnaire for the detection of frail older patients used by generalpractitioners
Patients aged 65 years and over, independent (ADL 6/6), with nocurrent acute disease
SCREENING
YES

NO

DON'T
KNOW

Does your patient live alone?







Has your patient lost weight in
the last 3 months?







Has your patient felt more tiredin the last 3 months?







Has your patient found it moredifficult to go around in the last
3 months?



Does your patient complain ofmemory problems?







Does your patient have a slow
gait speed (more than 4 seconds
to walk 4 meters)?







=> If you have answered YES to one of these questions:
Do you think your patient is frail?:

 YES

 NO

If YES, does your patient agree
to evaluation of his/her frailty in
day hospital?

 YES

 NO

– Sedentariness is assessed by administering the following
question to the patient: “What is your current level ofphysical activity?”. The patient can answer: No physicalactivity (confined to bed); Rather sedentary, some shortwalks or other exercise of very light intensity; Light intensity exercise (walking, dancing, fishing or shooting,shopping on foot) at least 2 to 4 hours a week; Moderate intensity exercise (running, walking uphill, swimming,
gardening, cycling) for 1 to 2 hours a week, or light intensity exercise (walking, dancing, fishing or shooting) for
more than 4 hours a week; Moderate intensity exercise
more than 3 hours a week; Vigorous exercise several
times a week. By answering the question, the participant
is instructed that light intensity exercise does not cause
sweating and does not prevent conversation, moderateintensity exercise causes sweating and conversation is notpossible, and vigorous exercise involves maximum effort.
Although this specific question is not validated, it has
previously been used in literature to define sedentarinessand physical activity levels in older persons (17, 18).
– Slow usual gait speed is measured after testing the patient
over a 4-meter long track. Slow gait speed is considered aspresent if the patient takes more than 4 seconds (i.e., gait
speed slower than 1 meter/second) to complete the task.
– Poor muscle strength is measured by a hand-held dynamometer. The gender- and body mass index-specificcut-points originally provided by Fried and colleagues (3)are used to identify subjects presenting this criterion offrailty.
The patient is considered frail if he/she presents three ormore of these criteria, pre-frail if only one or two criteria
are present.

The definition of frailty
Consistently with its wide use, the primary instrument tomeasure frailty at the platform is the operational definition
proposed by Fried and colleagues and validated in the Cardiovascular Health Study (1). In particular, we define its five
constituting criteria as follows:– Involuntary weight loss is detected by asking “Have you
involuntarily lost weight during the past months?” Current weight and self-reported usual weight are also recorded.
– Fatigue is defined by the patient’s answers “often” or“most of the time” to the following two items, part of
the CES-D scale: “During the last two weeks I felt thateverything I did was an effort”, and “During the last two
weeks I felt that I could not get going”.

Causes of frailty
The evaluation of the patient at the platform is primarily
conducted by the geriatrician (or a general practitioner specifically formed in geriatrics) and a nurse. Sociodemographic (including living environment), anthropometric, and clinical (medical and surgical history, current treatments andallergies) are recorded. Moreover, all patients undergo ablood drawn for standard laboratory assessment (including
vitamin D concentrations, and special tests if required by
the patient’s clinical conditions) and an electrocardiogram.
The evaluation includes the administration of the following
questionnaires/scales objectively measuring the specific capacities of the person:– Cognition: Memory Impairment Screen (free and delayedrecall), AD8 Dementia Screening Interview (19), Mini
Mental State (MMSE) (20), Clinical Dementia Rating(CDR) (21);135WHITE BOOK

– Physical function: scales of disability in basic Activities of
Daily Living (ADL) (22) and Instrumental ADL (IADL)(23), measures of physical performance (Short Physical
Performance Battery, SPPB (24), Pepper Assessment
Tool for Disability, PAT-D (25);– Nutritional status: Mini Nutritional Assessment (MNA) (26);– Mood: the Covi and Raskin scales for anxiety and depression (27, 28);
– Vision and hearing: Parinaud’s scale (near vision), Monoyer’s scale (distant vision), Amsler grid (detection ofage-related macular degeneration, AMD), and the Hearing Handicap Inventory for the Elderly - Screening version (HHIES) (29).
The platform will soon receive a retinal camera to allow amore accurate detection of AMD and to screen other vision conditions (such as glaucoma). Moreover, a last generation dual energy X-ray absorptiometry (DXA) device, an
I-DXA for the study of body composition and bone mineral density will be shortly implemented in the daily practiceof the platform.
According to the results of the screening questionnaires/
scales and the geriatrician clinical visit, additional evaluations might be proposed. For example, according to thepatient’s needs, a neuropsychiatrist, an ophtalmologist, anutritionist, a physical therapist, a dentist, or a social assistant may be directly and promptly involved to complete theassessment and improve the definition of the subsequent
plan of intervention.
At the end of the multidisciplinary evaluation, the geriatrician of the platform summarizes the results of all the performed evaluations to prepare a personalized intervention
plan for the patient. The family practitioner of the patientis also immediately informed about the results of the visits
to share with him the visit conclusions. Moreover, in the attempt of increasing the patient’s adherence to the intervention and facilitate the follow-up, an appointment is readilytaken for the patient with his/her own general practitioner
within the following 15 days.

Interventions proposed
The plan of intervention proposed by the platform are specifically designed and adapted to each patient’s resources
and needs according to the results of the multidisciplinary
evaluation. The comprehensive evaluation of frailty leads
to the identification of potential risk factors for negative
health- related events in different domains of the older patient’s health. In particular, the possible causes for the increased vulnerability may consist of undiagnosed diseases
or risk factors (at least partially linked to the aging process).
When an unknown disease is detected, the patient is directed towards the specialist’s evaluation for further investigation (if needed) and/or a specific treatment proposed.

Differently, if a risk factor is found, it is discussed with thepatient to make him/her aware about its possible consequences. Such education of the patient is parallel with theplan of intervention that will be proposed. In fact, it will include behavioural and therapeutical suggestions to correct
the specific risk factor according to the clinical priorities
given by the physician. For example, if a risk of malnutrition is detected by the MNA at the preliminary assessment(i.e., frailty in the nutritional domain), the nutritionist (alsoon the basis of the objective data collected during the preliminary visit) may provide the patient with specific recommendations to improve his/her dietary intake. Similarly, incase of issues in the physical domain of the patient (e.g.,sedentariness), the physical therapist may simply suggest
specific exercises that can easily increase the physical activity level of the patient as well as fitness centers in thepatient’s neighbourhood. In the same way, a person withsocial issues may find specific support and information to
reduce the barriers at the basis of his/her frailty status. In
this context, it is noteworthy that the close relationship established between the platform with the administrative andhealthcare authorities has allowed the creation of multiple
possible alternatives in order to offer preventive protocols
against disability.
The approach of targeting the specific issues of the patients raised at the end of a comprehensive geriatric assessment performed by a multidisciplinary team mirrors what
has been previously shown to be particularly beneficial infrail older persons (5, 30, 31). Nevertheless, this is the firsttime that this model is exported and officially implemented
in the primary prevention of disability.

Patients’ follow-up
To make sure that the proposed recommendations arefollowed and to also determine their efficacy, a close follow-up is organized for all the patients undergoing theplatform assessment. First, a phone contact is made thesame day of the evaluation with the general practitioner
to briefly explain the proposed plan of intervention anddiscuss possible therapeutical modifications. The general
physician will also receive a detailed letter with all the results of the platform evaluation. An appointment is alsoorganized for the patient with his/her own general practitioner within two weeks. One month after the platform
evaluation, a nurse phones the patient to verify the put inplace of the recommendations and facilitate the solutionof possible issues. This first phone contact is also important to boost the attitude of the patient at improving his/her health status through the adoption of the proposed
healthier lifestyle habits. At three months from the initial
evaluation, a specifically trained nurse carries out a second
phone evaluation. This is specifically focus at administering
the PAT-D scale (25). This is a 23-item validated instrument

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THE INTEGRATION OF FRAILTY INTO CLINICAL PRACTICE: PRELIMINARY RESULTS FROM THE GÉRONTOPÔLE

measuring the physical function of older persons. It has
already been adopted in several trials with special focus on
disability prevention. The patient rates his/her ability ona six-point Likert scale, ranging from ‘able to perform anactivity without difficulty’ to ‘unable’. If the physical function of the patient is deteriorated compared to the baseline
evaluation, specific actions are taken from a new contact
with the general practitioner to discuss the case, to the reservation of a out-patient clinical visit for the re-revaluationof the patient. Throughout the follow-up, the patient willcontinue having the general practitioner as primary referent
for his/her health status.

Table 2Socio-demographics characteristics of the first 160 patients evaluatedduring the first 6 months of operation of the platform

Clinical research
Elderly persons who are frail and pre-frail often present
aging-related disorders that are still at an early stage. Thus,
as mentioned above, they can still benefit from early, innovative interventions. In this context, the platform plays animportant role for research. In fact, the standardized andobjective assessment conducted in the platform patientsmakes possible the creation of a unique database of community-dwelling older persons to study the biological andclinical foundations of the frailty syndrome. Moreover, thestructured follow-up of patients allows the evaluation overtime of the efficacy of the innovative interventions (e.g.,novel medications, biotechnologies, telemedicine…) thatwill be made available. The conduction of clinical studies
is also facilitated because the cohort of patients evaluatedat the platform will allow the creation of ancillary projects
testing specific hypotheses in a very cost-effective fashion.
Finally, the detailed database of patients will constitute animportant resource to easily find and contact possible candidates to future clinical trials.

Characteristics

Mean (SD) or n (%)

Gender, n=160
Woman

99 (61.9)

Man

61 (38.1)

Age (years), n=160

82.7 ± 6.1<75

14 (8.7)

75-84

92 (57.5)>85

54 (33.7)

Education, n=158
Higher education

44 (27.8)

Senior high school

30 (20.9)

Junior high school

13 (8.2)

Primary school

64 (40.5)

No school attendance

4 (2.5)

Marital status, n=160
Single15 (9.4)

Divorced

11 (6.9)

Married67 (41.9)

Separated

2 (1.2)

Widowed63 (39.4)

Living with partner

2 (1.2)

Living environment, n=160
Assisted living facility

6 (3.8)

Nursing home for dependent elderly

5 (3.1)

At home (communal home)

61 (38.1)

At home (individual home)

88 (55.0)

Help at home, n=160

THE PLATFORM POPULATIONYes

The description of the main characteristics of the first 160
patients recruited during the first months of activity of theplatform are reported in Table 2 and Table 3. Mean age ofour population is 82.7 years, with a large majority aged 75
years and older. Most patients are women (61.9%) Approximately two thirds of patients received any kind of regularhelp. Only 14.1% received old age allowance.

137

106 (66.2)

Kind of help, n=106
Home help

55 (51.9)

Visiting nurse

12 (11.3)

Physical therapist

7 (6.6)

Old age allowance

15 (14.1)

Other

17 (16.0)

WHITE BOOK

Table 3Clinical characteristics of the first 160 patients evaluated during the

Nutritional status (MNA), n=157

first 6 months of operation of the platform
Characteristics

Mean (SD) or n (%)

89 (56.9)

Good (MNA ≥24)

54 (34.2)

Risk of malnutrition (MNA 17 to 23.5)

14 (8.9)

Malnourished (MNA <17)

Frailty status (according to Fried criteria), n=158

Vitamin D status, n=157

14.8 ± 10.1 (4-59)

Not frail

9 (5.7)≤ 10 ng/ml

73 (46.5)

Pre-frail (1-2 criteria)

65 (41.4)

11-29 ng/ml

76 (48.4)

Frail (≥3 criteria)

83 (52.9)≥ 30 ng/ml

8 (5.1)

Frailty criteria (according to Fried criteria)
Recent weight loss, n=158

52 (32.9)

Feeling of exhaustion, n=157

49 (31.2)

Decreased muscle strength, n=156

90 (57.7)

Slow gait speed, n=155

130 (83.9)

Sedentarity, n=158

85 (53.8)

MMSE score (/30), n=154

25.4 ± 4.2 (12-30)<20

19 (12.3)

20-24

32 (20.8)

25-27

41 (26.6)>=28

62 (40.2)

CDR score, n=155
035 (22.6)

0.5

102 (65.8)

1

14 (9.0)24 (2.6)

MIS score (/8), n=157

6.4 ± 1.9 (0-8)

MIS-D score (/8), n=155

5.5 ± 2.6 (0-8)

AD-8 score (/8), n=157

3.3 ± 2.3 (0-8)

ADL score (/6), n=159

5.6 ± 0.8 (1-6)

IADL score (/8), n=159

6.0 ± 2.3 (0-8)

SPPB score (/12), n=157

7.4 ± 2.9 (0-12)

Good (score 10-12)

43 (27.2)

Medium (score 7-9)

53 (33.7)

Poor (score 0-6)

61 (38.8)

Gait speed (m/sec), n=155

0.8 ± 0.2 (0.2-1.3)<0.6 m/sec

38 (24.5)

0.6 to 0.79 m/sec

43 (27.7)

0.8 to 1.0 m/sec

49 (31.6)> 1.0 m/sec

25 (16.1)

Abnormal distant vision, n=140

107 (76.4)

Abnormal near vision, n=129

42 (32.5)

Abnormal Amsler grid, n=153

16 (10.4)

HHIES score (/40), n=152

7.1 ± 10.1 (0-40)

No disability

106 (69.3)

Moderate disability

26 (17.0)

Severe disability

21 (13.7)

Raskin score (/12), n=155
Signs of depression

7.4 ± 2.9 (0-11)
5 (3.2)

Regarding level of frailty, 65 patients (41.4%) were pre-frail,
and 83 (52.9%) frail. The fact that 93.3% of the subjects
addressed in the platform are frail or pre frail implies the capacity of the screening questionnaire of adequately detect
true positives in the general population.
For what concerns the functional status, 83.9% of patients
presented slow gait speed, 53.8% were sedentary, and 57.7%
had poor muscle strength. Only 27.2% of patients had a
SPPB score equal to or higher than 10. Autonomy in ADL
was quite well preserved (mean ADL score 5.6 ± 0.8) as expected, suggesting that the patients of the platform have notyet developed disability. Consistently, IADL showed a marginal loss of autonomy reporting a mean score of 6.0 ± 2.3.
About one third of patients (33.1%) presented a MMSE
score lower than 25. Dementia (measured by the CDR
scale) was observed in 11.6% of the platform population,
whereas subjects with mild cognitive impairment (that is
CDR equal to 0.5) were 65.8%. New diagnosed depressive
disorders were relatively rare with only 3.2% of patients
showing signs of depression but some people were alreadytreated. Numerous patients presented vision problems with
10.4% having abnormal findings at the Amsler grid. Thirteen percent of patients had a hearing loss.
Finally, it is noteworthy that 9% of the platform population
presented an objective state of protein-energy malnutrition,
34% an early alteration of nutritional status, while almost
everyone (94.9%) had a vitamin D deficiency (partially explained by the period of the year, that is winter-spring, ofmost of the measurements).
CONCLUSION

To prevent disability, frail older patients need to be identified and specifically evaluated starting from the general
population through a close collaboration between general practitioners and ad-hoc geriatric infrastructures. The
platform we designed and developed at Toulouse proposespreventive and therapeutical interventions, supports families and caregivers, and interacts with the general practitioners in order to optimize the management of the frail
older patient. Our next objective will be the evaluation of
the cost-effectiveness analysis of the platform and the evaluation of its clinical effectiveness over the long-term, in

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THE INTEGRATION OF FRAILTY INTO CLINICAL PRACTICE: PRELIMINARY RESULTS FROM THE GÉRONTOPÔLE

particular for the primary outcome of physical disability
prevention.
Our preliminary results from the first 160 patients we assessed should encourage the promotion of frailty to thelevel of a clinically relevant condition. The identificationand management of frail elderly is nowadays a clinical priority, which can no longer wait.
This article was published in the Journal of Nutrition, Health and Aging
Volume 16, Number 8, 2012
http://www.springer.com/medicine/internal/journal/12603

REFERENCES
1. Clarfield AM (1990) Dr. Ignatz Nascher and the birth of geriatrics.
CMAJ 143(9):944-948.
2. Fried TR, Bradley EH, Williams CS, Tinetti ME (2001) Functional
disability and health care expenditures for older persons. Arch Intern Med 161(21):2602-2607.
3. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al (2011) Frailty in older adults: evidence for a phenotype.
J Gerontol A Biol Sci Med Sci 56(3):M146-156.
4. Rubenstein LZ, Josephson KR, Wieland GD, English PA, Sayre JA,
Kane RL (1984) Effectiveness of a geriatric evaluation unit. A randomized clinical trial. N Engl J Med 311(26):1664-1670.
5. Stuck AE, Siu AL, Wieland GD, Adams J, Rubenstein LZ (1993)
Comprehensive geriatric assessment: a meta-analysis of controlled trials. Lancet 342(8878):1032- 1036.
6. Monteserin R, Brotons C, Moral I, Altimir S, San José A, Santaeugenia S, et al (2010) Effectiveness of a geriatric intervention inprimary care: a randomized clinical trial. Fam Pract 27(3):239-245.
7. Vellas B, Cestac P, Moley JE (2012) Editorial: implementing
frailty into clinical practice: we cannot wait. J Nutr Health Aging
16(7):599-600.
8. Rodríguez-Mañas L, Féart C, Mann G, Viña J, Chatterji S, Chodzko-Zajko W, et al. (2012) Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The
Frailty Operative Definition-Consensus Conference Project. J Gerontol A Biol Sci Med Sci.
9. Cesari M (2012) Frailty and Aging. J Frailty Aging. 3-6.
10. De Vries NM, Staal JB, van Ravensberg CD, Hobbelen JSM, Olde
Rikkert MGM, Nijhuis-van der Sanden MWG (2011) Outcome instruments to measure frailty: a systematic review. Ageing Res Rev
10(1):104-114.
11. Pel-Littel RE, Schuurmans MJ, Emmelot-Vonk MH, Verhaar HJJ(2009) Frailty: defining and measuring of a concept. J Nutr Health
Aging 13(4):390-394.
12. Cesari M (2011) The multidimentionality of frailty: many faces of
one single dice. J Nutr Health Aging 15(8):663-664.
13. Abellan van Kan G, Rolland Y, Andrieu S, Bauer J, Beauchet O,
Bonnefoy M, et al (2009) Gait speed at usual pace as a predictorof adverse outcomes in community- dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J
Nutr Health Aging 13(10):881-889.
14. Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, et al(2011) Gait speed and survival in older adults. JAMA 305(1):50-58.
15. Lafont C, Gérard S, Voisin T, Pahor M, Vellas B (2011) Reducing« iatrogenic disability » in the hospitalized frail elderly. J Nutr
Health Aging 15(8):645-660.
16. Subra J, Rougé-Bugat M-E (2012) Gait speed: a new « vital sign »for older persons in primary care. J Frailty Aging 1(2):50-58.
17. Patel KV, Coppin AK, Manini TM, Lauretani F, Bandinelli S, Ferrucci L, et al (2006) Midlife physical activity and mobility in older age:
The InCHIANTI study. Am J Prev Med 31(3):217-224.

18. Cesari M, Leeuwenburgh C, Lauretani F, Onder G, Bandinelli S,
Maraldi C, et al (2006) Frailty syndrome and skeletal muscle:
results from the Invecchiare in Chianti study. Am J Clin Nutr
83(5):1142-1148.
19. Galvin JE, Roe CM, Powlishta KK, Coats MA, Muich SJ, Grant E, etal (2005) The AD8: a brief informant interview to detect dementia.
Neurology 65(4):559-564.
20. Folstein MF, Folstein SE, McHugh PR (1975) « Mini-mental state ».
A practical method for grading the cognitive state of patients forthe clinician. J Psychiatr Res 12(3):189-198.
21. Morris JC (1997) Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type.
Int Psychogeriatr Suppl 1:173-176; discussion 177-178.
22. Katz S, Ford AB, Moskovitz RW, Jackson BA, Jaffe MW (1963)
Studies of Illness in the Aged. the Index of Adl: A Standardized
Measure of Biological and Psychosocial Function. JAMA 185:914919.
23. Lawton MP, Brody EM (1969) Assessment of older people:
self-maintaining and instrumental activities of daily living. Gerontologist 9(3):179-186.
24. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF,
Blazer DG, et al (1994) A short physical performance battery assessing lower extremity function: association with self-reported
disability and prediction of mortality and nursing home admission. J Gerontol 49(2):M85-94.
25. Rejeski WJ, Ip EH, Marsh AP, Miller ME, Farmer DF (2008) Measuring disability in older adults: the International Classification
System of Functioning, Disability and Health (ICF) framework.
Geriatr Gerontol Int 8(1):48-54.
26. Guigoz Y, Vellas B (1999) The Mini Nutritional Assessment (MNA)
for grading the nutritional state of elderly patients: presentation of
the MNA, history and validation. Nestle Nutr Workshop Ser Clin
Perform Programme 1:3-11; discussion 11-12.
27. Lipman RS, Covi L (1976) Outpatient treatment of neurotic depression: medication and group psychotherapy. Proc Annu Meet
Am Psychopathol Assoc (64):178-218.
28. Raskin A, Schulterbrandt J, Reatig N, McKeon JJ (1969) Replication of factors of psychopathology in interview, ward behavior andself-report ratings of hospitalized depressives. J Nerv Ment Dis
148(1):87-98.
29. Sindhusake D, Mitchell P, Smith W, Golding M, Newall P, HartleyD, et al (2001) Validation of self-reported hearing loss. The Blue
Mountains Hearing Study. Int J Epidemiol 30(6):1371-1378.
30. Stuck AE, Aronow HU, Steiner A, Alessi CA, Büla CJ, Gold MN,
et al (1995) A trial of annual in-home comprehensive geriatric assessments for elderly people living in the community. N Engl J
Med 333(18):1184-1189.
31. Stuck AE, Minder CE, Peter-Wüest I, Gillmann G, Egli C, Kesselring
A, et al (2000) A randomized trial of in-home visits for disability
prevention in community-dwelling older people at low and high risk
for nursing home admission. Arch Intern Med 160(7):977-986.

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WHITE BOOKFRAILTY AND NOVEL TECHNOLOGIES –A STEP AHEAD
E. KELAIDITI

Gérontopôle, Centre Hospitalier Universitaire de Toulouse, France.
Correspondence: Dr Eirini Kelaiditi, PhD. Institut du Vieillissement, Gérontopôle. Université de Toulouse III-Paul Sabatier.
37 Allées Jules Guesde, 31000 Toulouse, France. Faculty of Health and Social Sciences (HSS), Royal London House, R312,
Bournemouth University, Christchurch Road, Bournemouth BH1 3LT, UK
Email: e.kelaiditi@gmail.com

Abstract: Dependence and disability are almost inevitableconsequences of population aging. As these conditions are
considered irreversible, a growing interest has been directed
towards the identification of related conditions that are still
amenable to preventive interventions. In this context, frailty
has attracted an increasing scientific interest. Frailty is characterized by decreased homeostatic reserves and diminished resistance to stressors. The frail elderly constitutes acomplex population in terms of assessment, monitoring,
adherence to recommendations, and follow-up. The use ofnovel technologies may be considerably helpful for bothclinical and research purposes. In particular, technologies

P

opulation aging is leading to a considerable increase in age-related pathological conditions, including dependence and disability. In 2010, morethan 3 hundred million persons were disabled worldwide,and such estimate is projected to almost double by 2050,
with considerable increases in costs for the healthcare system (1, 2). As dependence and disability are considered as
almost irreversible conditions, a growing interest has been
pointed to the identification of those health profiles that,
although characterized by increased risk of negative events,
may still be amenable to preventive interventions against
disability. In this context, frailty has attracted a significantly
increasing scientific interest (3).
Frailty is a multidimensional condition characterized by decreased homeostatic reserves and diminished resistance tostressors (4). It is also a consequence of cumulative decline
in multiple physiological systems, and is associated with amay support interventions preventing disability, improving the quality of life, and enhancing the wellbeing of frail
people. Traditional assessment instruments can be complemented or replaced by mobile devices measuring and monitoring frailty domains (e.g., physical performance, cognitive
function, physical activity, nutritional status). Novel technologies have indeed the potential to benefit, assess, monitor, and support frail older people to live independently andimprove their quality of life.
Key words: Aging, prevention, information and communication technologies, assessment, screening.

greater risk of adverse health outcomes, such as falls, hospitalization, institutionalization and mortality (5). This concept is frequently adopted to indicate a status of pre-disability, characterized by potential reversibility.
Frail elders constitute a complex population in terms ofscreening, assessment, monitoring, and follow-up. It is likely that technologies may indeed play a role in supporting
healthcare professionals and researchers in this context.
In other words, the questionnaires, scales, and assessment
tools usually completed by healthcare professionals may
be complemented and supported by the implementationof novel technologies. An overview with few examples ofnovel technologies that can be used for the screening, assessment and follow-up of frail older persons is presented
in this brief report. The list of examples is not exhaustive
but indicative, just an example for indicating the high potentialities of this innovative and promising field.

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FRAILTY AND NOVEL TECHNOLOGIES – A STEP AHEAD

The identification of frail older people in the routine clinical care and research is a difficult but important task. For
example, electronic screening may be supported by technologies using large healthcare databases and sources to identify frail older persons in primary care (6).
Current literature on the use of novel technologies for theassessment and follow-up of older people is exponentially growing. For example, a mobile device characterized
by a wide range of features (accelerometer sensors, wireless communication capabilities, and processing capacities
among others) has recently been developed in order to support the frailty assessment (7). It provides information on
anthropometric characteristics, nutritional, functional andcognitive status of the individual, potentially supporting
the assessment of the healthcare professional. Its objective
results are indeed shown to be consistent with results ofthe standard clinical evaluation. Another example of technologies used to measure physical performance may be
represented by electronic walk-ways (e.g., www.protokinetics.com), which provide objective measures of movement
patterns (i.e., gait analysis) and facilitate the identificationof age-related abnormalities. A development of traditional
instruments capturing some frailty criteria/domains (e.g.,
dynamometers for the measurement of muscle strength)
are also evolving into more informative devices (8).
The use of technologies has also been proposed during
the clinical interview of the older person for better understanding some specific features of his/her health status.
For example, Marsh and colleagues (9) have validated theuse of animation videos as examples for improving theassessment of mobility and activities of daily living. Thisapproach uses a computer- based program displaying video
clips constructed from computer animations. After viewing
each video clip of the animated task, participants are asked
a question about their ability to perform the same task. Thismethod appeared to have a significant impact at improving
the accuracy in the reporting of older adults’ self-reportingof ability related to mobility.
In relation to the assessment of physical activity, commercial mobile applications currently available to promote
physical activity among adults are numerous (10). These
applications are able to monitor physical activity on a daily
basis and even provide person-specific recommendations
for maintaining a good health status and a healthy bodyweight (11).
Assessment and monitoring of nutritional intake and status is also very important for the frail elderly. In this case,long food frequency questionnaires could be replaced bymobile devices using applications that take a picture of theconsumed meals. Then, through a dedicated online-based
service, an analysis of the food can be conducted by specific software, and images converted into nutritional data (i.e.,
macro- and micro- nutrients composition). This informa-tion can be made directly accessible to dietitians, which may
then provide personalized recommendations (12).
Furthermore, the improvement of domains other thanphysical function and nutrition may also positively affectthe health status of frail older persons. In other words,
multiple domains may generate and significantly enhance
the frailty condition (e.g., vision impairment, hearing loss).
In this context, visually impaired individuals could benefit
from mobile applications designed to read out the text ina document or an image (e.g., https://itunes.apple.com/
us/app/ saytext/id376337999?mt=8). Telephone devices
including a monitor, which “reads” the voice of the caller
and translates it to text, may reduce the isolation of individuals with hearing impairment (e.g., www.CaptionCall.com).
Once screening and assessment are complete, a main issue with frailty is the follow-up and the identification andevaluation of adherence to recommendations of the frail
elderly. New technologies could be particularly helpful inthis direction. An example of the use of novel technologies
in improving the adherence to recommendations during
the follow-up of patients is the use of a pedometer-based
behavioral change program, which appeared to increase
physical activity and performance of frail elders (13). Another example of how much technologies may help in thisfield, may be the use of mobile applications supporting themonitoring of compliance of older frail people to medications (e.g., http://seniornet.org/blog/). In addition, identification of adherence to recommendations with the use oftechnologies might be evaluated by the electronic check ofrenewal of drug prescriptions of pharmacies.
As a future perspective, the concept of a “smart home”(for example, equipped with sensors, actuators, and/or biomedical monitors) could be a promising way for improving
the assistance at home of frail and disabled elders, potentially allowing greater functional independence, maintaining
good health, and preventing negative adverse outcomes (including social isolation). In fact, these types of infrastructures usually operate in a network connected to a remote
data center, which may promote the early diagnoses andanticipate healthcare procedures (14).
The use of novel technologies for preventing disability infrail people is yet limited and challenging. Indeed, while
a lot of applications are targeted to younger populations,less are specific to older persons, especially if frail. Nevertheless, the aging population may represent an ideal target
group of persons, which may greatly benefit from scientific advancements in this field. By stating this, we are notunderestimating the costs and efforts of the extension oftechnologies to advanced age individuals. For example, randomized-controlled trials using technologies are particularly challenging due to the complexity of the population,
the reduced willingness of consider technological devices
as part of their daily life, lack of consensus on technology

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WHITE BOOK

definitions, and the poor standardization of the assessment
tools. However, despite of such evident barriers, it is noteworthy that the number of people aged 65 years and olderusing the Internet is rapidly rising (15). And, of course, thelarge scale implementation of technologies in the field offrailty is subject to still-to-come positive results (especiallyfor what concerns cost-effectiveness) from clinical trials.
In conclusion, frailty is a clinical condition determining an
increased risk of adverse health-related events and requiring a complex, multidimensional evaluation. Novel technol-ogies present interesting potentialities to support the complex research and clinical activities around this syndrome.
We are just at the very beginning of an exciting new field ofdevelopment for geriatrics and gerontology.
Conflict of interest: Dr. Kelaiditi has no conflict of interest
to declare.
This article was published in the Journal of Frailty and Aging
Volume 4, Number 2, 2015
http://www.jfrailtyaging.com

REFERENCES
1. World Alzheimer Report 2013. ADI 2013.
2. Fried TR, Bradley EH, Williams CS, Tinetti ME. Functional disability and health care expenditures for older persons. Arch Intern Med
2001;161(21):2602-7.
3. Cesari M, Abellan Van Kan G, Ariogul S, et al. The European Union
Geriatric Medicine Society (EUGMS) working group on “Frailty inolder persons”. J Frailty Aging 2013;2(3):118-120.
4. Rodríguez-Mañas L, Féart C, Mann G, et al. Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus
Statement. The Frailty Operative Definition-Consensus Conference Project. J Gerontol A Biol Sci Med Sci 2013;68(1):62-7.
5. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381(9868):752-62.
6. Drubbel I, Numans ME, Kranenburg G, et al. Screening for frailty
in primary care: a systematic review of the psychometric properties of the frailty index in community-dwelling older people. BMC
Geriatr 2014;14:27. doi: 10.1186/1471-2318-14-27.
7. Fontecha J, Hervás R, Bravo J, Navarro FJ. Mobile and Ubiquitous
Approach for Supporting Frailty Assessment in Elderly People.
J Med Internet Res 2013;15(9):e197.

8. Matsui Y, Fujita R, Harada T, et al. A new grip strength measuring
device for detailed evaluation of muscle contraction among theelderly. J Frailty Aging 2014;3(3):142-147.
9. Marsh AP, Ip EH, Barnard RT, Wong YL, Rejeski WJ. Using video
animation to assess mobility in older adults. J Gerontol A Biol Sci
Med Sci 2011;66(2):217-27.
10. Middelweerd A, Mollee JS, van der Wal C, Brug J, Te Velde SJ. Apps
to promote physical activity among adults: a review and content
analysis. Int J Behav Nutr Phys Act 2014;11(1):97.
11. Hebden L, Cook A, van der Ploeg HP, Allman-Farinelli M. Development of smartphone applications for nutrition and physical activity behavior change. JMIR Res Protoc 2012;1(2):e9.
12. Zhu F, Bosch M, Woo I, et al. The Use of Mobile Devices in Aiding
Dietary Assessment and Evaluation. IEEE J Sel Top Signal Process
2010;4(4):756-766.
13. Yamada M, Mori S, Nishiguchi S, et al. Pedometer-based behavioral
change program can improve dependency in sedentary older adults:
A randomized controlled trial. J Frailty Aging 2012;1(1):39-44.
14. Chan M, Campo E, Estève D, Fourniols JY. Smart homes - current
features and future perspectives. Maturitas 2009;64(2):90-7.
15. Macfarlane H, Kinirons MT, Bultitude MF. WWW. Do not forgetolder people. Age Ageing 2012;41(6):807-10.

142INNOVATIVE MEDICINES INITIATIVE: THE SPRINTT PROJECTINNOVATIVE MEDICINES INITIATIVE:
THE SPRINTT PROJECT

E. MARZETTI1, R. CALVANI1, F. LANDI1, E. HOOGENDIJK2, B. FOUGÈRE2,
B. VELLAS2,3, M. PAHOR4, R. BERNABEI1, M. CESARI2,3
ON BEHALF OF THE SPRINTT CONSORTIUM

1. Department of Geriatrics, Neurosciences, and Orthopedics, Catholic University of the Sacred Heart, Rome, Italy;
2. Gérontopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse, France;
3. Inserm UMR 1027, Université de Toulouse III Paul Sabatier, Toulouse France;
4. Department of Aging and Geriatric Research, University of Florida – Institute on Aging, Gainesville, FL, USA
Correspondence: Matteo Cesari, MD, PhD. Faculté de Medicine, Université Toulouse III – Paul Sabatier;
37 Allées Jules Guesde, 31000 Toulouse, France. Phone: +33 (0)5 61145628, Fax: +33 (0)5 61145640;
Email: macesari@gmail.com

Key words: Frailty, sarcopenia, disability, prevention.

T

he current healthcare systems are built around the
traditional paradigm of patients suffering from asingle acute illness. They are therefore largely unprepared to face the increasing demands for health services arising from the expansion of an older population withspecific medical needs related to multiple chronic disorders.
As a consequence, the medical conditions of a large andgrowing segment of the older European population are notefficiently managed by the available healthcare services (1).
Among these conditions, the geriatric syndrome of frailty
has emerged as a significant public health priority. It is defined as a multidimensional condition characterised by decreased reserve and diminished resistance to stressors (2).
Such extreme vulnerability exposes the older individual
to an increased risk of morbidity, disability, inappropriate
healthcare use, institutionalization, poor quality of life, anddeath. Early detection and prevention of frailty are thus
crucial to impede its progression and the development of
its detrimental clinical consequences, while ensuring sustainability of healthcare systems of the Member States (3).
Unfortunately, to date, no healthcare programmes or pharmacological treatments are available for frail older people.

This is largely due to the lack of a precise, universal definition of frailty, linked in turn to the multidimensional natureof the condition. Eventually, the existing gaps in knowledge are reflected by the absence of effective interventions.
Such a barrier may be overcome by developing and validating a robust conceptual framework to achieve a practicaloperationalisation of frailty. This should precisely define
its pathophysiological and clinical foundations, to assist in
the design and implementation of specific interventions
aimed at restoring robustness and delaying the onset ofadverse outcomes. The « Sarcopenia and Physical fRailty
IN older people: multi-componenT Treatment strategies »(SPRINTT) project is specifically designed to overcome theexisting barriers for an efficient public health intervention
against frailty, and promote the implementation of successful aging strategies across Europe. To reach such an ambitious goal, the actions of the SPRINTT Consortium are
directed towards the achievement of a consensus among
academia, regulators, industry (pharmaceutical and medical devices), and patients’ representatives over:
1. clear operationalisation of the presently vague conceptof frailty;

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2. identification of a target population with unmet medical
needs;
3. evaluation and validation of methodologies for implementing preventive and therapeutic strategies among frail
elders at risk of disability in the European Union;
4. d efinition of an experimental setting as a template forregulatory purposes and pharmaceutical investigations;
5. identification of biomarkers and health technology solutions to be implemented in clinical practice.
The SPRINTT project proposes a novel operationalisationof physical frailty recognising sarcopenia as its central biological substrate. This approach is based on the fact that thephysical frailty phenotype overlaps substantially with sarcopenia (4). Indeed, many of the adverse outcomes of frailty
are probably mediated by sarcopenia, which may therefore
represent both the biological substrate for the developmentof physical frailty and the pathway through which the negative health outcomes of frailty ensue. Although physicalfrailty encompasses only a part of the frailty spectrum, theidentification of a definite biological basis (i.e., skeletal muscle decline and loss of mobility function) opens new venues
for the development of interventions to slow or reverse theprogression of this condition. It is noteworthy that all of
the components describing the Physical Frailty and Sarcopenia (PF&S) model are measurable and quantifiable. It isthus anticipated that the implementation of such a model will allow the identification of a precise subset of frail
elderly citizens whose medical needs are presently unmet.
The ad hoc randomised clinical trial (RCT) resulting fromthe SPRINTT project will translate the PF&S model into a
multi-component intervention [combining physical activity,
nutritional assessment/counseling and implementation ofInformation & Communication Technology (ICT) solutions] aimed at preventing incident mobility disability andmajor negative health-related events.
The multi-component intervention proposed is original(such an intervention against the outcome of mobility disability has never been previously tested on a large scale,although built upon solid scientific background and data),
relevant (it targets conditions of high prevalence in European community- living older persons), pertinent (it isfocused on function, a primary component of quality oflife and the one of the most important outcomes in theelderly), feasible (it will be carried out by internationallyrecognised researchers with outstanding experience in thefield of PF&S), easily applicable at a population level (thusfacilitating the future clinical implementation of the project findings), and scalable (it will validate health technology
services and an ICT infrastructure that will enable optimaldata acquisition/analysis and clinical decision-making, as
well as ensure accessibility to the interventions from theuser’s home).

The RCT, based on a priori power calculation, plans to recruit 1,500 participants aged 70 years and older (750 per
treatment arm), distributed across seven regional coordinating site across Europe and involving nine European
Countries. The target population will be comprised of “reallife”, non-disabled older persons exposed to increased vulnerability to stressors.
The identification of such a population will rely on thethree key elements that are at basis of the PF&S operationalisation:• target organ deterioration (i.e., low muscle mass, measured by dual energy X-ray absorptiometry),• clinical manifestation of physical frailty (i.e., weakness,slow walking speed, and poor balance),• functional impairment [assessed using the Short Physical
Performance Battery (SPPB].
The main exclusion criterion will be the presence of mobility disability, that is the first step of the disabling cascade,at baseline.
Participants will be randomised to either a multi-component intervention or an educational control group. Both interventions will be administered for up to three years.
The primary outcome will be the incidence of mobility
disability, operationalised as incident inability to walk 400
metres. Secondary outcomes will include: changes in physical performance; ability of selected biomarkers to predictthe rate of change in muscle mass & functional capacity;changes in frailty status; changes in sarcopenia parameters;
incidence of falls and injurious falls; changes in nutritional
status; changes in physical function, cognitive function andmood; changes in utilisation of healthcare services; changes
in drug consumption and polypharmpacy; changes in quality of life; incident cognitive impairment; mortality rate.
To ensure the successful accomplishment of all SPRINTT
goals, a unique and robust Consortium has been established that convenes internationally recognised leading experts in the field of PF&S. The Consortium is organisedin multiple interacting work-package teams, reassembling
academia, members of the European Federation of Pharmaceutical Industries and Associations (EFPIA), and two
Small and Medium Enterprises (SMEs). Each participant
supports with its own specific expertise the conductionof the SPRINTT work-packages. Each leader/co-leader“tandem” will coordinate a group of experts in specific domains. The expertise of each partner will thus be valorised,
and the Consortium activities conducted in the most informed, shared, and appropriate way.
Conflict of interest: All the authors are investigators of the
SPRINTT project, an Innovative Medicines Initiative(IMI)- funded project (including partners from the European Federation of Pharmaceutical Industries and Aasso-144

INNOVATIVE MEDICINES INITIATIVE: THE SPRINTT PROJECT

ciations [EFPIA]). Matteo Cesari has received honoraria forpresentations at scientific meetings and/or research fundings from Nestlé, Pfizer, Novartis. Bruno Vellas has served
as consultant/advisor for Biogen, GSK, Lilly, Lundbeck,
Medivation, MSD, Nestlé, Nutricia, Pfizer, Roche, Sanofi,
Servier, TauRx Therapeutics, Novartis. The other authors
have no conflict of interest to disclose.

Funding: All the authors are investigators of the IMI-funded SPRINTT project. Marco Pahor is Principal Investigatorof the University of Florida Claude D. Pepper Older Americans Independence Center (NIH/NIA P30AG028740).
This article was published in the Journal of Frailty and Aging
Volume 4, Number 4, 2015
http://www.jfrailtyaging.com

REFERENCES
1. Vellas B, Cestac P, Morley JE. Implementing frailty into clinicalpractice: we cannot wait. J Nutr Health Aging 2012;16:599-600.
2. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet 2013;381:752-762.

3. Morley JE, Vellas B, Abellan van Kan G et al. Frailty consensus: acall to action. J Am Med Dir Assoc 2013;14:392-397.
4. Cesari M, Landi F, Vellas B, Bernabei R, Marzetti E. Sarcopenia
and physical frailty: two sides of the same coin. Front Aging Neurosci 2014; 6:192.

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