# Presentation: 007675

## The Continuum of Clinical Research and the Investment in Translational Research for Improved Patient Care

- Linda P. Fried, M.D., M.P.H.
- Professor and Director,
- The Johns Hopkins Center on Aging and Health
- And
- The Division of Geriatric Medicine and Gerontology

## Life Expectancy and Health Status

- At age 65, people can now expect to live another 15-20 years, on the average
- Health status during this time is of great importance:
- 30% robust
- 50% have 2 or more diseases
- 40% have difficulty walking or doing other essential activities
- 7-10% are frail

## Goal: Health in Aging

## Research on Health in Aging:  Where we stand

- Issues that affect health and well-being with aging
- Health needs of older adults differ from younger
- Substantial evidence: factors that may be responsive to prevention or treatment
- Evidence that prevention and treatment make a difference in health

## Disease Prevention with Aging

- Many of the “inevitable consequences of aging” in 1950 are not inevitable in 2003

## Chronic Diseases

- Most treatable; many preventable
- Prevention and treatment make BIG differences in patient outcomes and quality of life

## Impact of Effective Prevention: Change in U.S. death rates,1950-1997

|  | Age Group |  % change |
| --- | --- | --- |
| Heart Disease | 65-74 | -58% |
|  | 75-84 | -54% |
|  | 85+ | -31% |
| Stroke | 65-74 | -76% |
|  | 75-84 | -65% |
|  | 85+ | -46%  (Bureau       of the Census) |

## Explanation for Decline in Death from Heart Disease and Stroke

- Primary Prevention	                25%
- Exercise, diet, risk factor modification
- Secondary Prevention			29%
- Exercise, diet, risk factor modification
- Treatment					43%
- Medications, exercise, diet, angioplasty
- Optimal disease management
- Hunnink et al, JAMA 1997

## Heterogeneity of health with aging 

- Diseases
- Comorbidity/Multimorbidity
- Cognitive Impairment/Dementia
- Sensory impairments: vision, hearing
- Psychosocial factors
**Geriatric Conditions: Frailty, Falls**
**Disability and dependency**

## Disability: A 75 year old woman with arthritis of knees, fear of falling

- Difficulty:	Duration(yrs)	Response
- Walk 1⁄2 mi		10		Stopped
- Stairs 			  2-3		Hold rail
- Heavy housework       2		Stopped
- Light housework	   2		Do less
- Carry groceries	   1		Stopped

## Decline in DisabilityIndividuals 65 Years and Older1984 - 1993

- Percent Reporting Difficulty

- Source: Freedman & Martin, *Am.J.Public Health*., 88:1451-1462, 1998.

**Notes:**
Study from RAND analyzed trends during the period 1984 to 1993 in the prevalence of functional limitations within the 50 and over population.  The extent of improvement varied by age group, with the smallest gains occurring among 50-64 year olds and the largest among those 80 and over.  Data  from SIPP, nationally representative, household-based Survey of Income and Program Participation.  There were improvements across most subgroups, but the rate of functional limitations remained highest among the oldest, women, the unmarried, Hispanics, the least educated and those without liquid assets.  Blacks were more likely to report difficulty than whites.  For the 65+ age group there was :

A 4.9 percent point decline in difficulty seeing newsprint (from 21.7 to 16.8%)

A 7.2 percentage point decline in difficulty lifting and carrying a 10-pound weight, such as a bag of groceries (from 33.8 to 26.6%)

A 4.0 percentage point decline in difficulty climbing a flight of stairs without resting (from 34.9 to31.0%)

A 6.1 percentage point decline in difficulty walking a quarter mile, about three city blocks (from 37.6 to 31.5%)

## Frailty in Aging: Escalating Knowledge of a High Risk State

- 7-10% of community-dwelling older adults
- Weak, low energy, slow, low activity, thin
- Vulnerable – especially with stressors
- High risk for adverse outcomes
- Hospitalization, poor outcomes with hospitalization,
- falls,
- disability and loss of independence,
- death

## Likely Causes of Frailty, 2005

**Aging**

**Disease**

- Inflammation
-                                   hematologic
- musculoskeletal
- neurologic
-   Hormones

- Frailty

**Genetics**

## Discovery of causes of frailty – at all levels: biology, physiology, symptoms 

- Basis for discovering treatments, prevention
- Determine which most effective
- Applications to both clinical care, community health approaches
- On the near horizon: next 10 years

## Factors Influencing the Decline in Disability Rates – Could also decrease frailty

- Education
- Declines in the prevalence of several chronic diseases
- Changes in nutrition and public hygiene
- Improved health promotion and medical therapy

**Notes:**
Source:  Manton, Chronic disability trends in elderly United States populations: 1982-1994, PNAS 94:2593-2598, 1997.
Education- better educated persons tend to more readily adopt healthy behaviors, are more likely to have had better medical care , are better equipped to comply with complex and long-term medical treatments (e.g., hypertension, diabetes), more likely to exhibit fewer disabilities even with chronic conditions, and possible association with decreased risk of AD.
Declines in prevalence of chronic disease - declines in cardiovascular disease, cholesterol levels, and smoking for individuals 65 - 74.
Improvements in public hygiene and sanitation - decrease in Helicobacter pylori tied to long-term declines in gastric cancer and changes in peptic ulcer prevalence thru improvements in water quality.  Long-term declines in stroke and gastric cancer tied to reduced use of salt as a food preservative as refrigeration became more widely used.  Better regulation of commercial food processing and livestock management including thermal processing of meats, may have reduced the prevalence of food-borne pathogens possibly contributing to atherosclerosis.  Food supplementation - vitamins. Changes in lifestyle - reduced smoking rates in successive birth cohorts.
Impact of medical therapy on disability prevalence is hard to assess because many treatment innovations for chronic diseases are recent.  Exogenous estrogens were used in 1985 by 3 million U.S. postmenopausal women.  In 1995, nearly 10 million are taking estrogens, with benefits for osteoporosis, cardiovascular disease, and possibly AD.  Aspirin may reduce the risk of colorectal cancer and recurrences of stroke and heart disease. NSAIDS & AD, etc. may contribute to future decline.

## Potential for Translation of Research into Health Benefits

- Multiple levels:
- Designing communities to support successful aging
- Roles to remain productive, socially engaged,  maintain activity: “use it or lose it”
- Improved physical activity, nutrition
- Targetted therapies:  depending on health status and risk

## Potential for Prevention and “Compression of Morbidity”

## Research on Health in Aging

- Challenges
- Multiple causes; many systems affected
- Older adults are heterogeneous
- Changing biology closely tied to clinical well-being
- Social factors matter

- SOLUTIONS
- Multidisciplinary teams
- Research & translation to match complexity of health in aging
- Continuum of research: basic and clinical discoveries needed to improve health
- Social factors/ environment matters

## Aging Research: future directions

- From systems biology to clinical symptoms: frailty, dependency, delirium, dementia
- Community-based research:  how to keep aging population (20% >65) healthy, independent
- Outcomes: clinical trials for prevention and/or treatment
- Multidisciplinary teams organized around problems
- Population-based research can evaluate how decreased function in multiple systems leads to bad outcomes - together
- Basic mechanisms: mitochondrial dysfunction with aging?
- Clinical research: improving strength, well-being if frail
- Health Services research: caring for frail people
- Implementation to improve health

## Translation: Continuum of Research

**2. What are the important health issues?** Population-based and Clinical Evidence

**3. ** **Population-based and clinical evidence**
-  - Potential for prevention; keys to causes, targets for treatment

**4. Laboratory:**
-  -Physiology: subclinical components and mechanisms
-  -Biology: Ultimate cause

**5. Many causes, many systems involved:**
- Modifiable Pathways
- Population              Laboratory

**6. Ultimate Causes:**
- Genetics – Environment
- Laboratory        Populations
- -- Modifiable Pathways --

**Translation: Continuum of Research**

**Clinical Trials**

## Science of translation: poised to be worked out in multidisciplinary teams in aging research

*Phase I Translation:*
- from bench to therapeutics
- Translation between research disciplines to understand mechanisms of disease, frailty, disability
*Phase II Translation: of research into *_*practice:*_* *
- Improved care (eg: frailty: from therapeutics to hospital design to improve safety);
- Science of criteria for implementation
- How to get older adults to utilize discoveries: health behaviors, health management

## Research on Health in Aging: On the cusp of a new era

- Scientists are learning how to work in translational teams
- Knowledge of health issues in aging mature
- BUT:
**NOT ENOUGH CLINICAL AND POPULATION-BASED RESEARCHERS ON AGING**
**NO ORGANIZATION RESPONSIBLE FOR - AND WITH RESOURCES - TO ADDRESS THE FULL PICTURE:  WHAT PROBLEMS MUST BE SOLVED**
**NIA FUNDING AT AN ALL-TIME LOW: 15****th**** percentile**
**THE NEXT FRONTIER: LEARNING **_**HOW**_** TO TRANSLATE DISCOVERIES INTO IMPROVED HEALTH – BUT LITTLE FUNDING TO DO THIS**

## Clinical Research on Health and Aging

- Potential: rapid translation into improved care
- BARRIERS/SOLUTIONS:
**Who is responsible for the big picture?**
**Make investment with 10-15 year horizon**
**Enhance funding to NIA NOW to reap benefits when baby boomers are getting Social Security; Charge NIA with developing the science of Phase II translation**
**Charge a research organization with responsibility for doing Phase 2 translation, prevention & care (AHRQ?)**
**Organization and financing of health care that matches the needs, health issues of older adults**

## People Now LIVE With Chronic Diseases

| AGE | 0 | 1 | >2 |
| --- | --- | --- | --- |
| 18-44 | 75% | 18% | 7% |
| 45-64 | 45% | 30% | 25% |
| > 65 | 20% | 28% | 52% |

- NHIS 2000

## Comorbidity Associated with Health Care Utilization and Cost: WHAS I

| # Diseases
(% of total) | Hospital’d
        % | Home Health Cost | Total health Costs |
| --- | --- | --- | --- |
| 0-1
       (13%) |        20% |    $ 352. |    $4,947. |
| 2
       (21%) |        27%        |    $ 290. |    $4,624. |
| 3-4
       (55%) |        28% |    $ 553. |    $6,492. |
| >4
       (12%) |        38% |    $ 826. |    $6,135. |

- Weiner, 2003

## Factors in Healthy Aging:Cardiovascular Health Study

- Older adults free of chronic disease (no CVD, COPD, Cancer) and alive after 7 years of follow-up:
- 	_Associated factors:_
- 	Behavioral:      Physical activity,
- 				No smoking
- 				No obesity
-    Disease management: HBP, DM, HDL
- 			Burke et al, J Amer Ger Soc, 2001

## Increasing heterogeneity with aging

- 65 years and older:
- Self reported health:
- Excellent/Very good: 	38%
- Good:			33%
- Fair:				22%
- Poor:			  8%
- Guralnik, Fried, et al
- Women’s Health and Aging Study
- Baltimore, MD

## Trajectories of change in health status vary with aging

- AGE

## Declines in strength with aging:15% per decade

- Etiologies:
- Sarcopenia (loss of muscle mass)
- Inflammmation
- Inactivity/disuse
- Disease
- Undernutrition

## Physical disability in community-dwelling persons 70 and older, U.S.

- Difficulty:		Men		Women
-       - walking		30%		   33%
-       - IADLs			13%                7%
-       - ADLs			22%		    17%
- 						NCHS, 1999

## Current Aging-related Research Activity(with caveats)

- Aging related research throughout both campuses; also GRC
- Basic Research: Basic biology of aging, frailty
- 		*e.g.: decreased telomere length with aging*
*	**	**         **oxidative stress with aging; DNA repair*
- Clinical and Population-based Research
*	**	**e.g.: congestive heart failure differs in old *
*	**	**	**preventive health care for older adults*
- Health Services Research/ Health care policy
*	**  **e.g.: Reimbursement; longterm care models*

## A new breed of aging-related research: premises

- Recognizes core issues in older people:
- _Heterogeneity_ of health status in people _>_65
- _Chronic_ *disease* is the norm, complicated by *frailty* and *disability, as well as dementia; *
- _Outcomes expand_*: disability as well as disease, mortality*
- Physiology, _Risk/vulnerability, _needs, and effective health care models vary with health status
- Health status – and care - inherently _multifactorial_
- On many important questions, research must be multidisciplinary to validly capture complexity

## Implications

- Effective prevention must be tailored to health status level and may vary by prognosis (2 75 y/o’s: 1 robust, 1 nh)
- Risk: emergence delirium after surgery; mortality
- To manage CHD/CHF (or any chronic disease) in older adults – have to understand competing risk from comorbidities, other treatments etc.
- Health care models that are tailored to health status are more effective

## Frailty: Silent and elusive –but important contributor to health outcomes as people age

## Current aging-related research:A new form maps to roadmap

- Example: Frailty in older adults: determining what it is, what causes it, risk and opportunities for intervention:
- Multidisciplinary questions,
- Multidisciplinary research will answer
- Aging research and training: inherently suited to roadmap

## ?

_**Outcomes**_
-  Falls
-  Disability
-  Dependency
-  Death

_**Syndrome**_
- Weakness
- Weight loss
- Slowed performance
- Exhaustion
- Low activity

_**Molecular       & Genetic**_
**      **
**?**

**Disease**

- Fried, et al., Gerontology 2001

- Walston, et al., Archives of IM 2002

- Leng, et al., JAGS 2002

- Leng, et al., Aging 2004

-  IL-6, CRP

-  Factor VIII
-  D-Dimer

- Glucose intolerance

- IGF-1,   DHEA-S

**    **_**Physiology**_

-  Cortisol

## Multisystem Alterations May Underlie Loss of Reserves, Frailty

- Altered hormones

-  SNS activity

-  Hematopoiesis

- Glucose intolerance

**PHYSIOLOGIC**

-  Free radicals

- Cellular senescence

-  DNA damage

- Altered telomeres

**>**

**>**

**>**

**MOLECULAR & GENETIC **

- Mitochondrial Dysfunction

**>**

- Genetic Variation

- Inflammation

- Altered hormones, Environmental factors

- Altered cellular metabolism

**Multisystem Alterations May Underlie Loss of Reserves, Frailty**

## •

- Weight Loss

- Sarcopenia

-  Strength
- Exhaustion/  exercise tolerance

-   Motor performance

-  physical   activity

**Clinical Presentation**

**•**

**•**

**•**

**•**

**•**

**>**

- >

**>**

**>**

**Physiologic Vulnerability**

**Physiologic Dysregulation**

**Cellular  Function, Molecular and Genetic Characteristics**

## Treating Frail Patients To Prevent Adverse Outcomes

- Prevention of frailty:
- Preventing onset
- Improving frailty
- Preventing outcomes

- Treating the frail patient at times of stressors to decrease risk

## 65

- 100

**Frailty as accelerated decline in anatomical integrity and function across multiple physiological systems. The “replacement therapy” approach is unlikely to be effective.**
**	**

## To figure out frailty:

- Physiologists and molecular biologists: many systems
- Quantitative, integrative biology:  dynamic responsiveness of system(s)
- Collaboration between:
- Population based scientists able to look at many systems at a time – plus:
- Basic scientists
- Physiologists
- Clinicians – to take back to bedside

## Treatments for Frail, Hospitalized Older Adults

- Minimize the stressors that worsen frailty:
- deconditioning, weakness, undernutrition
- dehydration
- isolation, sleep deprivation
- medication side effects
- consider risk for procedures
- 					(Tinetti, Inouye, Fiatarone, Evans)

## Treatments for Frail, Hospitalized Older Adults

- Prevent the adverse outcomes of frailty:
- confusion, delirium
- falls
- disability and dependency

## Institutional Approaches to Preventing Adverse Outcomes of Frailty in Hospitalized Patients

- Geriatric Consultation
- Inpatient Geriatric Assessment
- Rehabilitation; “prehab”
- ACE Units (Landefeld, Palmer et al)
- Hospital Elder Life Program (Inouye et al)
- Home Hospital (Burton, Leff)

## WHAT we DO Matters with aging: Improving Health Outcomes

- Physical Activity
- Cognitive Activity
- Social engagement:
- Meaningful, productive roles
- Leaving a legacy
- Social networks and support

## Lack of activity and engagement associated with adverse health outcomes for older adults.

- Social isolation
- Non-stimulating environments
- Sedentariness
- Little sense of purpose

## What people do affects their health outcomes: Experience Corps

- Improved strength, energy
- Decreased falls
- Improved cognitive functioning; executive function
- Less depression
- To be determined:
- Preventing frailty, disability
- Maintenance of independent functioning
- Fried, Rebok, Carlson, Glass, McGill et al, 2004

## Opportunities and challenges of an aging population

- Health promotion and prevention
- Creating images and roles of aging that are alternatives to “rocking chairs and decrepitude”
- Determining the societal benefits of having as many older adults as children
- Creating the knowledge and institutions to support healthy and successful aging of individuals and to evolve communities to support successful aging.

## Physical Disability in Older Adults

- Severe impact on individuals, families, society
- Crucial health outcome
- Understanding etiology would provide a basis for:
- Identifying those at high risk, screening;
-  Prevention and treatment
- Compression of morbidity
- (Katz 1983; Fries 1980)

## Performance Measures: Knee Extensor Strength

- Bed
- Transferring

- Dressing

- Walk Up 10 Steps

- Shopping

- Bathing

- Heavy housework

**kg**

***A**