# Behavioral and Social Research Program

# National Institute on Aging

# National Institutes of Health

# NIA Exploratory Workshop on Allostatic Load

**Washington, DC, November 29-30, 2007**

Background Materials and Statements from November 2007 Workshop
Participants

Compiled November 19, 2007

Lis Nielsen, Ph.D.

Psychological Development and Integrative Science

Telephone: 301-402-4156

Email: [nielsenli@nia.nih.gov](mailto:neilsenli@nia.nih.gov)

Teresa Seeman, Ph.D (UCLA)

Consultant to BSR

Email: <TSeeman@mednet.ucla.edu>

Anneliese Hahn, M.S.

Research Program Analyst

Telephone: 301-402-4447

Email: <hahnan@nia.nih.gov>

**Background Statement for NIA Exploratory Workshop on Allostatic Load**

**Lis Nielsen, NIA/BSR**

**Teresa Seeman, UCLA**

## Introduction

The concept of allostatic load has served as a framework for a large
body of research on the integrative health psychology, epidemiology, and
demography of aging. It is based on the hypothesis that there is a
cumulative physiological risk associated with exposure to psychosocial
stressors over the life-course. Among the attractions of such a concept
is the existing body of evidence indicating that many psychosocial
stressors appear to have small to modest associations with multiple
different biological risk factors, reflecting links to most of the known
major regulatory systems (e.g., cardiovascular, immune, HPA, SNS)
Initial empirical work based on various cumulative indices of
physiological risk has provided evidence consistent with the idea that
greater cumulative dysregulation is associated with significantly
greater risks for subsequent disease (cardiovascular disease), declines
in physical and cognitive functioning and overall mortality (Seeman et
al, 1997; Seeman et al, 2001; Karlamangla et al, 2002; Geronimus et al,
2006). Research has also documented that psychosocial conditions
previously associated with greater morbidity and mortality (e.g., lower
socio-economic status and poorer social engagement) are also associated
with greater cumulative burdens of physiological dysregulation in
multiple systems (Seeman et al, 2002; Seeman et al, 2004 Kubzansky et al
1999; Hu et al, 2006). Cumulative indices of allostatic load have also
been positively related to measures of psychosocial stress in young
adolescents (Evans et al, 2007) as well as symptoms of post-traumatic
stress disorder (PTSD) in mothers of pediatric cancer survivors (Glover
et al, 2006) and adverse perinatal outcomes (Shannon et al, 2007).

## 

## Workshop Goals

Important questions remain, however, regarding the conceptualization and
operationalization of allostatic load as well as the overall utility of
the concept in efforts to better understand trajectories of health and
aging. The Behavioral and Social Research Program (BSR) at the National
Institute on Aging seeks to advance research on biopsychosocial pathways
of resilience and vulnerability to late life disease through a workshop
on conceptual and methodological issues surrounding the concepts of
allostatic load and cumulative physiological risk more generally. The
goal of the 2007 workshop is to bring together scientists from diverse
disciplines who share an interest in understanding stress-health
relationships from a life-course perspective, but who may differ in
their approaches and commitment to the allostatic load model. We
conceive of this group as a collaborative team whose interests are
focused on what is needed to advance behavioral and social research on
aging within this topic area.

The output of this workshop should include widely distributed
publications that will serve as references for established and new
researchers in the fields of behavioral and social aging research along
with recommendations regarding needed research to advance our
understanding of the biological pathways through which our life
experiences impact on health and aging.

## 

## Background

*Aging and allostatic load*

Aging is associated with increased risk for most forms of disability and
chronic disease, with the majority of older adults experiencing two or
more chronic conditions by the time they reach old age (Singer, Ryff, &
Seeman, 2004). It has been hypothesized that cumulative lifetime
exposure to social, psychological or environmental stressors increases
the risk of multiple age-related health problems by disrupting the
physiological regulatory systems that mediate the stress response.
Allostatic load has been put forth as a model for how features of the
psychosocial environment "get under the skin" and give rise to disease.
The model (based on the concept of biological adaptation to duress first
proposed by Cannon (1932) and Selye (1956, 1974), developed by McEwen
and colleagues (McEwen and Stellar, 1993; McEwen, 1998; McEwen and
Seeman, 1999; and elaborated most recently in a volume edited by Jay
Schulkin, 2004) proposes that a key mediator of increasing risk for
disease is the dysregulation of systems designed to balance the
organism's responses to environmental demands. Exposure to stress
elicits adaptive physiological responses in regulatory systems including
the hypothalamic pituitary axis (HPA), the sympathetic (SNS) and
parasympathetic (PNS) branches of the autonomic nervous system, and the
cardiovascular and immune systems. Allostasis (related to homeostasis)
is the adaptive maintenance of vitality in these systems via
neuromodulation of motive states and behaviors in response to changing
environmental circumstances. Allostatic load refers to the cumulative
biological wear and tear that can result from excessive cycles of
response (i.e., too frequent and/or of inappropriate duration or scope)
in these systems as they seek to maintain allostasis in the face of
environmental challenge. According to the theory, as these systems
become taxed and dysregulated, they begin to exhibit imbalances in the
primary neural mediators of the stress response, such as
glucocorticoids, catecholamines and proinflammatory cytokines.
Dysregulation is evidenced in both basal levels of system parameters -
including circulating baseline levels of these hormones - as well as in
patterns of dynamic response to stimuli. Chronic dysregulation is
believed to confer cumulative physiological risk for disease and
disability by causing damage to tissues and major organ systems.

*Mechanisms and measurement*

At the level of mechanisms, it is well known that a host of stressors --
social and environmental elicitors of negative emotions, pathogens,
physical challenges - lead to activations of physiological systems
designed to maintain balance (McEwen & Stellar, 1993). Moreover,
accumulating evidence supports the notion that stressors such as lower
socioeconomic status, early exposure to abuse, diminished social
support, and conflictual relationships (to name a few) are associated
with increased risks for poor mental and physical health outcomes and
mortality (Taylor, Repetti, & Seeman, 1997).

As an initial attempt to operationalize the concept of allostatic load,
Seeman, McEwen, and colleagues used existing data from the MacArthur
Study of Successful Aging to develop an initial measure of allostatic
load that represented a simple count of the number of critical
biomarkers of cardiovascular, immune, and HPA axis dysfunction on which
an individual is in the highest risk quartile. The biomarkers included
in this summary measure were derived from available data from the
MacArthur Study that represented parameters of major regulatory systems
with known or hypothesized links to various major health endpoints,
including disease, disability and mortality (Seeman et al, 1997).
Population-based survey research, where much attention has focused on
identifying biological markers that index risk for late life disease
outcomes, has provided evidence that higher levels of allostatic load
are associated with increased morbidity and mortality (Seeman et al,
1997; 2001) and that higher educational attainment and better social
relationships are associated with lower levels of allostatic load
(Seeman et al, 2002; 2004). Alternative measurement models for
allostatic load (canonical correlation, recursive partitioning) have
yielded findings consistent with earlier approaches (Karlamangla et al,
2002; Gruenewald et al, 2006).

*State of the evidence*

Current evidence, however, does not provide definitive support for the
proposed relationships between psychosocial stressors and dysregulation
of biological systems supporting allostasis. Many biological regulatory
systems appear to show age-related increase in levels of dysregulation,
but age related changes are not uniform within populations. It is
unknown what determines who exhibits such age-related changes and who
manages to avoid them though a growing body of evidence points to
socio-economic differences in rates of accumulation (those of lower SES
exhibiting earlier and larger accumulations of AL; Crimmins et al, 2003;
Seeman et al, 2004; Geronimus et al, 2006; Seeman et al, in press) as
well as differences relating to socially supportive qualities of one's
relationships with others (Singer & Ryff, 1999; Seeman et al, 2002). In
addition, there is a growing body of correlational evidence indicating
that individuals vary in their response to stressors based on
differences in personality, coping and emotional regulatory styles, and
social and cultural environments (e.g., Ryff, Singer, & Love, 2004).
Thus some individuals seem resilient to diseases of aging and present
with a profile of positive health and well-being that may protect stress
regulatory systems from dysregulation. Questions remain as to whether
some people are genetically disposed to greater resilience to stress, or
whether life-style, psychosocial, and socioeconomic factors are
responsible for these differences.

Not all scientists are convinced that biological measures have added
significantly to our understanding of risk and resilience pathways. Some
have questioned whether biomarkers actually measure, as hypothesized,
the mediators of psychosocial impacts on health. Even among social and
behavioral researchers committed to employing biomarkers and
physiological measures in their research, there is an awareness of
serious gaps in the theoretical model and needs for refinement of
methodologies and analytical strategies. Much more needs to be known
about which biomarkers (and/or combinations of biomarkers) are most
useful in predicting health outcomes in older age, and which
psychosocial factors are the key predictors of change in these
biomarkers over time. These researchers continue to wrest with
measurement issues around "allostatic load" as they strive to keep apace
of findings emerging from the biological literature on disease markers
and key indicators of age-related physiological decline. The current
workshop will focus on these pressing conceptual and measurement issues.

While the allostatic load model places emphasis on the biological
pathways through which psychosocial factors have their effects on health
outcomes, it should be emphasized that the fully integrative
biopsychosocial model is recursive, with numerous and complex
hypothesized bidirectional causal pathways. Real progress in integrative
physiology requires the development of new analytical techniques that
enable exploration of these multiple causative links, as well as
advances in measurement at the level of the physical environment, the
social context, the psychological subject, and the biological markers
and mechanisms underlying health and disease.

## 

## Topics to be addressed in the workshop and papers

### *Conceptual and theoretical issues*

Allostatic load is both a theoretical construct and a measure of
cumulative wear and tear on physiological symptoms due to chronic
stress. As a theoretical construct, it is a preliminary attempt to
formulate the relationship between environmental stressors and disease,
by hypothesizing mechanisms whereby multiple kinds of stressors confer
risk simultaneously in multiple physiological systems (Singer & Ryff,
2001). Important questions surrounding the concept of allostatic load
concern (1) the relationship of diverse research findings to the overall
theory, (2) the distinction between primary mediators of disease and
secondary outcomes, (3) the links between allostatic load and specific
disease outcomes, i.e., does allostatic load represents a unique
"syndrome" or an early stage on the pathway to multiple diseases, and
(4) whether there are different allostatic load pathways, and if so, how
do these differ from unique disease pathways?

### 

### *Methodological: measurement of allostatic load*

*Which biomarkers?* The currently available assortment of biomarkers for
measuring components of allostatic load is extensive and includes:
anthropometric, cardiovascular and metabolic measures, inflammation
markers, measures of HPA axis and SNS activity, measures of renal
function, lung function, bone density, immune functioning, antioxidants,
genetic markers, and adiposity. One of the aims of this workshop is to
encourage researchers to move beyond examination of how a single
psychosocial factor influences a single biological system or health
outcome and toward a more comprehensive view of the various profiles of
dysregulation that may develop. Greater attention needs to be paid to
primary mediators that can affect multiple other regulatory systems
(e.g. cortisol, inflammatory cytokines, catecholamines) as well as to
anabolic hormones that may mediate resilience (e.g. Igf-1, DHEA,
testosterone).

*Multi-system approaches.* It is inherent in the hypothesis that a
lifetime of exposure to stressors of diverse origin will have cumulative
effects on multiple biological systems that we must be interested in
change in multiple systems over time. A limitation of most prior work on
allostatic load model is that it has been based on measures of
biomarkers from only one point in time. However, if chronic stress
disrupts allostatic load component systems sequentially, it may be more
appropriate to look first at early alterations in neuroendocrine
systems, later at elevations in inflammatory markers, and even later at
markers of metabolic syndrome. One key question to be addressed by the
workshop will be what the proper models are for looking at this.
Longitudinal measurements of biomarkers may provide critical information
about the pathways of cumulative dysregulation that lead to disease.

*Biological aging as the background.* The impact of chronic and daily
stressors on regulatory systems occurs against a background of normal
age-related declines in immune function, and the interaction of these
factors may pose additional health risks. Older adults appear to show
even greater immunological impairments associated with stress or
depression than young adults, making factors that are associated with
greater stress potentially more lethal to the elderly (Kiecolt-Glaser &
Glaser, 2002). It will be important to understand how accumulation of
allostatic load interacts with "normal" age-related dysregulation in
each of the systems that modulate stress responses.

*Multiple levels of analysis.* Additionally, this workshop should
explore research strategies that permit the examination of these
relationships at multiple levels (from more molecular up through more
macro-level assessments of social conditions) by offering models for
exploring pathways between levels and examples of successful research
that has adopted this approach. Importantly, measurement of biological
dysregulation requires both an examination of differences in basal
activity as well as and examination of system dynamics in response to
challenge.

*Measures of reactivity in systems.* While measures of stress reactivity
tend to be of higher cost, they are ultimately important for testing the
concept of allostatic load, since patterns of reaction in these systems
may be the earliest signs of dysregulation. Research is needed to
clarify where in system dynamics dysregulations are most evident or most
consequential, e.g. in response versus recovery parameters. A variety of
challenge paradigms exist for studying the effects of stress on
regulatory systems, including wound healing, vaccination response, and
social and cognitive stress paradigms designed for use with measures of
psychophysiological reactivity. What do the findings from these sorts of
studies tell us about individual differences in stress responsivity,
links between dysregulation and specific psychosocial factors and health
outcomes, and relationships between dysregulation on the various
measures? Emotional reactivity plays a pivotal role in the response to
stress. How much of emotional reactivity is biologically, genetically or
environmentally determined? What are the current measures of emotional
reactivity to stress, and what is known about how these develop and vary
over the life course?

*Lab-survey linkages.* Importantly, links need to be forged between
studies that focus on detailed evaluations of biological mechanisms in
the laboratory or field and population-based studies with greater
generalizability that don't allow for such detailed physiological
assessment. Given the complementing strengths of laboratory and
ambulatory research it is now possible and fruitful to extend
traditional laboratory studies with experience sampling methodologies
and corresponding ambulatory physiological, behavioral, and
endocrinological assessments. Such studies would provide insight into
the possibility that dysregulation is initially most evident in patterns
of response, while more basal activity is less easily affected and may
only show age-related changes relatively late in the process of
development of disease and dysregulation. Participants are encouraged to
envision ideal research designs that would provide insights on changes
in regulatory systems and their association with past and current
psychosocial factors. The workshop should provide a picture of state of
the art research in this area, and point to potentials for and obstacles
to improvements in research designs.

*Genetics.* As we learn more about the composition of the genome and
mechanisms controlling gene expression, and as inexpensive methods for
measuring DNA develop rapidly, it will be possible to integrate genetic
data with more comprehensive models that include information on
behavioral, social and other characteristics of individuals, and
allowing study of gene-environment interaction. Additionally, there is
an emerging interest in studying the genetic basis for individual
differences in response to or susceptibility to stress, a more nuanced
appreciation of the specific psychosocial phenotypes that play a role in
health outcomes and the underlying genetic and gene by environment
interactions that determine their expression.

*Additional measurement issues include:*

-   What selection of currently available biomarkers are most predictive
    of specific health outcomes, and which are indicative of health
    status not revealed by self-report? What are the criteria by which
    new biomarkers should be evaluated for inclusion in research on
    cumulative physiological risk?

-   What cumulative measures of allostatic load show most promise? How
    are they best analyzed? How should measures be combined to best
    clarify processes of change in health?

-   Do different biomarkers mean different things at different times in
    life, and if so, which measures are meaningful at which ages?

-   For different regulatory systems that change over time, how does one
    model the interrelated effects of these systems on outcomes?

-   What needs to be done to clarify the links between primary mediators
    and secondary outcomes (e.g., inflammation, antioxidants and
    hormones as primary, bone health and hypertension as secondary)?

-   How do measures of allostatic load relate to indices such as
    Metabolic Syndrome and the Framingham Risk Score?

-   How reliable are existing biomarker measures of cumulative risk? How
    reliable are measures of the individual components of cumulative
    risk scores?

-   Relatedly, explorations of variability in primary mediators over
    time are needed, as little is known about this. Is variability on
    specific measures itself an outcome of potential significance? Are
    individuals who show greater variability at greater risk than those
    who are relatively stable on measures?

-   Are different physiological systems more or less vulnerable to
    different types of psychosocial stressors (financial, social
    isolation, interpersonal conflict) and what are the implications for
    disease outcomes?

-   Is there more than one allostatic load profile, e.g. hypocortisolism
    vs. hypercortisolism; hypercholesterolism vs. hypocholesterolism,
    and do the health consequences of these profiles change with age?

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-   What is the relative importance of early life exposures to stress,
    versus later life exposures? Are there paths of no return, critical
    periods? Are effects of stress reversible? Does this vary by life
    period exposure?

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-   How do profiles of allostatic load differ by ethnicity and gender?

-   How should we account for individual differences in responses to
    stress?

-   What kinds of studies could be envisioned that would permit both
    pre- and post-stress biological measures, as well as measures of
    individual difference characteristics that may modify patterns of
    physiological response?

**REFERENCES**

> Cannon, W.B. (1932). The Wisdom of the Body. New York: Norton. Cited
> in Schulkin J. Allostasis, Homeostasis, and the Costs of Physiological
> Adaptation. Oxford: Cambridge University Press, 2004
>
> Crimmins EM, Johnson M, Hayward M, Seeman T. Age differences in
> allostatic load: an index of physiological dysregulation. Experimental
> Gerontology. July 38: 731-734, 2003.
>
> Evans GW, Kim P, Ting AH, Tesher HB, Shannis D. Cumulative risk,
> maternal responsiveness and allostatic load among young adolescents.
> Dev Psychol 43:341-51, 2007.
>
> Geronimus A.T., Hicken, M., Keene, D., Bound, J. "Weathering" and age
> patterns of allostatic load scores among Blacks and Whites in the
> United States. AJPH 96, 826-33, 2006
>
> Glover DA, Stuber M, Poland RE. Allostatic Load in women with and
> without PTSD symptoms. Psychiatry, 69:191-203, 2006.
>
> Gruenewald TL, Seeman TE, Ryff CD, Karlamangla AS, Singer BH.
> Combinations of Biomarkers Predictive of Later Life Mortality.
> Proceedings of the National Academy of Sciences, 103(38):14158-14163,
> 2006
>
> Hu P, Wagle N, Goldman N, Weinstein M, Seeman TE. The Associations
> between Socioeconomic Status, Allostatic Load and Measures of Health
> in Older Taiwanese Persons: Taiwan Social Environment and Biomarkers
> of Aging Study. Journal of Biosocial Science, Oct 20;:1-12, 2006.
> \[Epub ahead of print\].
>
> Karlamangla, A.S., B.H. Singer, B.S. McEwen, J.W. Rowe, and Seeman TE.
> Allostatic lead as a predictor of functional decline: MacArthur
> Studies of Successful Aging. Journal of Clinical Epidemiology, Vol 55,
> No. 7, 696-710, July 2002.
>
> Kiecolt-Glaser JK, Glaser R. Depression and immune function: central
> pathways to morbidity and mortality. Journal of Psychosomatic
> Research, 2002 Oct;53(4):873-6. []{.mark}
>
> Kubzansky LD, Kawachi I, Sparrow D. Socioeconomic status, hostility,
> and risk factor clustering in the Normative Aging Study: any help from
> the concept of allostatic load? Annals of Behavioral Medicine
> 1999;21(4):330-8
>
> McEwen BS. Protective and damaging effects of stress mediators. New
> England Journal of Medicine 1998;338:171-9
>
> McEwen BS, Seeman TE. Protective and damaging effects of mediators of
> stress. In Socioeconomic Status and Health in Industrial Nations:
> Social, Psychological and Biological Pathways, Adler NE, Marmot M,
> McEwen BS (eds), NY: NY Academic of Sciences, 896:30-47, 1999.
>
> McEwen BS, Stellar E. Stress and the individual: mechanisms leading to
> disease. Archives of Internal Medicine 1993;153:2093-101.
>
> Ryff CD & Singer B (eds), Emotion, Social Relationships and Health.
> New York: Oxford Press, pp189-209, 2001.
>
> Ryff CD, Singer BH, Dienberg Love G. Positive health: Connecting
> well-being with biology. Philos Trans R Soc Lond B Biol Sci.
> 359:1383-94, 2004.
>
> Schulkin J. Allostasis, Homeostasis, and the Costs of Physiological
> Adaptation. Oxford: Cambridge University Press, 2004
>
> Seeman TE, Singer B, Horwitz R, McEwen BS. \"The Price of Adaptation
> \--Allostatic Load & Its Health Consequences: MacArthur Studies of
> Successful Aging\" Archives of Internal Medicine 157:2259-2268, 1997.
>
> Seeman TE, Singer B, Rowe J, McEwen B. Exploring a new concept of
> cumulative biological risk \-- Allostatic load & its health
> consequences: MacArthur Studies of Successful Aging. Proc Nat Acad Sci
> USA 98(8): 4770-4775, 2001.
>
> Seeman TE, Singer B, Ryff C Levy-Storms L. Psychosocial factors and
> the development of allostatic load. Psychosomatic Medicine 64:395-406,
> May/June 2002.
>
> Seeman TE, Crimmins E, Bucur A., Huang MH, Singer B, Bucur A,
> Gruenewald T, Berkman LF, Reuben DB. Cumulative Biological Risk and
> Socio-Economic Differences in Mortality: MacArthur Studies of
> Successful Aging. Soc Sci & Med 58, 1985-1997, 2004
>
> Seeman TE, Merkin S, Crimmins E, Koretz B, Charrette S, Karlamangla A.
> Education, Income and Ethnic Differences in Cumulative Biological Risk
> Profiles in a National Sample of US Adults: NHANES III; Social Science
> and Medicine, in press.
>
> Selye, H. (1956). The Stress of Life. New York: McGraw-Hill. Cited in
> Schulkin J. Allostasis, Homeostasis, and the Costs of Physiological
> Adaptation. Oxford: Cambridge University Press, 2004
>
> Selye, H. (1974). Stress without Distres. New York: New American
> Library. Cited in Schulkin J. Allostasis, Homeostasis, and the Costs
> of Physiological Adaptation. Oxford: Cambridge University Press, 2004
>
> Shannon M, King TL, Kennedy HP. Allostasis: a theoretical framework
> for understanding and evaluating prenatal health outcomes. J. Obstet
> Gynecol Neonatal Nurs. 36:125-134, 2007.
>
> Singer B, Ryff C, Seeman TE. Operationalizing Allostatic Load. *In
> Allostasis, Homeostasis, and the Cost of Physiological Adaptation*. J.
> Schulkin (ed). Pp 113-149, 2004
>
> Singer B, Ryff CD. Hierarchies of life histories and associated health
> risks. Annals of New York Academy of Sciences 1999;896:96-115.
>
> Taylor SE, Repetti RL, Seeman TE. \"What is an Unhealthy Environment
> and How Does It Get Under the Skin?\" Annual Review of Psychology,
> 48:411-47, 1997

# Charge to Participants in the NIA Workshop on Allostatic Load

In preparation for the upcoming **NIA Exploratory Workshop on**
**Allostatic Load**, participants were asked to prepare a short (2-4
pages) statements outlining their views on how research on allostatic
load and the study of cumulative risk more generally can be most
fruitfully advanced in the behavioral and social sciences.  These
statements are intended to set the foundations for dialogue, at the
workshop, on research and resource needs for achieving this goal.

As described in the foregoing background document, there are a number of
conceptual and methodological issues that could be addressed at the
workshop. Participants were asked to offer creative, well-informed input
on where the emerging research opportunities and needs lie within thier
own and related fields.  

Participants were asked to consider the following when preparing their
statements:

(1) How has the concept of allostatic load had a positive (or negative)
    impact on work in your field? Are there more valuable alternative
    approaches to the study of cumulative physiological risk, and if so,
    what are they and what is their relative advantage?

(2) What could be done to make this concept more valuable to research on
    social and behavioral factors in aging?

(3) What are the most critical measurement issues, in your view? Are
    there specific data needs for addressing these questions?

(4) What would be the most important \"next steps\" in moving research
    on allostatic load, or cumulative physiological risk more generally,
    forward?

Statements from invited participants follow.

**John Cacioppo**

**University of Chicago**

What is adaptive or maladaptive, healthy or unhealthy, depends on
context, and what may be good for one tissue may be life saving, but may
have negative impact on another tissue with mortal consequences in the
long run. The regional positioning of immunocytes in response to acute
stress may provide the host with a selective advantage should aggressive
behavioral interactions lead to cutaneous wounding and the possibility
of infection (Dhabhar & McEwen, 1997). The selective advantage that may
accompany acute stress does not extend to chronic forms of stress,
however, as the prolonged activation of the HPA axis and sympathetic
nervous system seen in chronic stress tends to suppress cellular
immunity (Lupien & McEwen, 1997; Sheridan, 1998), reduce response to
vaccination (Kiecolt-Glaser et al., 1996), and slow the healing of
experimental cutaneous and mucosal wounds (Kiecolt-Glaser et al., 1995;
Marucha et al., 1998; Padgett, Marucha, & Sheridan, 1998). These
complexities underscore the interdependence between organisms and their
physical and *social* environments. Restorative mechanisms such as a
balanced diet, moderate exercise, sleep, and rich social connections may
have the salutogenic (e.g., stress buffering) effects, whereas a diet
high in fat, the use of tobacco and alcohol, a sedentary lifestyle, and
hostility and isolation exacerbate the deleterious effects of chronic
stress. Our understanding of the complex regulative and restorative
processes of the organism -- and the balance within --is therefore
fostered by a multi-level integrative analysis.

Although the biological substrates for the etiology and course of
chronic disease are influenced profoundly by the physical and social
world, it remains to be determined to what extent these influences
result in individual differences in allostatic load as a consequence of
differential exposure to stressors, differential reactivity to
stressors, or differential recovery from stressors -- and why.

Second, a good deal is now known about stress physiology (e.g.,
Chrousos, 2001), but the rostral neurobehavioral systems that
orchestrate organismic-environmental transactions (Berntson et al.,
1998, in press) and the psychological transduction mechanisms (e.g.,
health behaviors, health utilization, stress buffering) remain only
partially mapped. "Stress" has been assigned a special role in the
development of allostatic load, but the concept of stress itself is
often vaguely (or circularly) defined. Operationalizations and measures
across studies, especially across animal and human studies, were
regularly so different (e.g., restraint, hypoglycemic, orthostatic,
mathematic stressors) that results are sometimes difficult to compare or
reconcile.

Third, stressors are not always negative, either, as positive as well as
negative events are considered stressors in studies focused on
predicting health (Holmes & Rahe, 1967). Further complicating matters,
the measurements of stress within a given study are often so weakly
correlated that they provide poor convergent validity for the construct
of stress (e.g., Lacey, 1959; Johnson & Anderson, 1990). In short,
neither stress nor health is a simple, unitary concept, and the search
for a singular universal mechanism relating stress to health is doomed
to failure. The concept of allostatic load, too, while useful at a molar
level of analysis, is misleading if applied to specific underlying
mechanisms as if there were a single cause of wear and tear. The concept
is useful because it represents a broad and multifarious category of
specific and largely unrelated transduction mechanisms that contribute
to the wear and tear on the organism.

Why not simply ignore the molar constructs of integrative physiology and
focus on the details of the cellular machinery? As Claude Bernard
(1878/1974) opined over a century ago and Lewontin (2000) has echoed
more recently, the organization and function of the elemental parts of
an organism can be understood comprehensively only within the context of
its transactions with its physical and social environment. Lewontin's
(2000) analysis suggesting that the reduction in mortality from
infectious diseases during the late 1800's and early 1900's is
attributable to a general trend of increases in real wage, an increase
in the state of nutrition, and a decrease in the number of hours worked
-- that is, a decrease in the wear and tear on the organism and improved
opportunities for the organism to heal itself -- hints at causal factors
and targets of interventions to which we would be blind by focusing on
cellular mechanisms alone. Although we are beginning to understand how
the brain integrates the regulatory and restorative forces of the body
to foster health and adaptation to environmental challenges, it is clear
that health psychology will have much to contribute to this
understanding for a long time to come.

The theory of allostasis remains to be fully delineated. Improvements in
operationalizations and construct-valid measures would promote
theoretical tests and refinements. Specification of the neurobiological
basis of allostasis would advance our understanding of the functional
system. Collaborative studies involving animal models and longitudinal
human studies would promote a mapping of CNS-PNS orchestration and the
decay of this orchestration.

**Sheldon Cohen**

**Carnegie Mellon University**

**Allostatic Load/Cumulative physiological risk**

This is a quick list of my thoughts about Allostatic Load (AL) Theory
and primarily about AL measurement. I should say that while I have been
involved multiple discussion about AL that occurred in the MacArthur SES
network and in various other forums starting when Bruce first drafted
the NEJM paper, I do not carefully follow research in AL or changes in
its conceptualization or measurement. Hence I hope you will excuse any
issues raised below that may have been addressed more recently as the
theory and measurement of AL has grown.

**General Opinion**: I like the AL heuristic, I don't like the way it
has been operationalized. McEwen's NEJM paper suggests that enduring
chronic stressors can result in the disturbance (dysregulation) of
multiple systems. Dysregulation can mean that the system overreacts,
underreacts, overreacts but cannot return to normal, etc. The
application of this idea to the study of specific systems can be
powerful. For example, chronic stress influences how effectively we
regulate our immune response, it does not just cause immunosuppression.

Which system is influenced in an individual presumable would be
moderated by individual vulnerabilities, e.g., genetic, previous
illness, etc. Less clear (and in my recall not a part of the original
theory) is the hypothesis that chronic stress disrupts multiple systems
and *consequently aggregating across systems* is an appropriate way of
measuring AL. However, this is how AL is generally measured.

I think there have been two underlying weakness in AL measurement. The
first, as suggested above, is aggregation across multiple systems
without adequate consideration of the possibility that a single or
specific sets of individual systems are what is important. The second is
that it is based on what has been (and in some cases can easily be)
measured rather than *what needs to be measured* to provide an
assessment of dysregulation. (This includes CARDIA at 15 years where
pretty much every standard measure that might assess AL and was
practical was selected, rather than asking what is the *minimum
requirement for assessing dysregulation across multiple systems*.)

**Up or Down or in the Middle?** Clearly a problem with many attempts to
assess AL is that they don't focus on regulation but rather on markers
moving in what is considered a direction of pathogenic risk based on
standard risk factor type analysis (e.g., high blood pressure is bad). A
measure consistent with the theory would focus on dysregulation whether
assessed as low, high, over and under reaction to stress, or inability
to return baseline after stress.

**Apples and Oranges?** Many of the studies presumed to measure
"allostatic load" aggregate across biomarkers representing a range of
different physiological systems. Interestingly, they generally unit
weight biomarkers, not systems. Many of the biomarkers are measures of
various cardiovascular functions and metabolic functions. As a
consequence, if the measure is related to something (e.g., measure of
SES or chronic stress or disease risk) it could be entirely due to its
influence on a single system. If an association is not found, there may
be relationships with individual systems, but the overall effect is
wiped out (or the effect size is reduced) by randomness across other
systems.

If one believes that aggregating across systems is important, than one
should 1) define the important systems to measure (e.g., ANS, SAM, HPA,
Cardiovascular, Immune, etc.); 2) develop adequate measures of the
REGULATION of each of these systems; and 3) equally weigh systems or
determine weights based on a theoretical basis in creating an aggregate.

**Specificity or generality?** There are reasons to think that specific
biomarkers used in assessing AL should be associated with specific
disease outcomes. (For example, cardiovascular system markers are
associated with cardiovascular disease risk). Comparisons of additional
variance accounted for after controlling for the system that one expects
to predict would be helpful. For example, it is possible that failure in
one system drives (or is otherwise correlated with) failure in another.
This doesn't mean that you need failure in both to influence a specific
disease outcome, although aggregation of system failure may make it look
this way.

**Does it depend when it happens for whether it counts toward AL?** AL
measures also tend to include both what McEwen called primary and
secondary mediators. Primary measures are immediate nonspecific
biomarkers of stress, e.g., catecholamines and cortisol. Anything
further downstream is considered secondary. Current work does not
differentiate between secondary measures that are markers of disease
risk versus disease pathology.

More recently, inflammation has been considered part of the primary
mechanism (see background statement). Although inflammation may play an
upstream role in disease progression (as hypothesized for coronary
artery disease), it clearly is a measure of underlying inflammatory
processes. Inflammation occurs in response to tissue damage. Therefore
it is a marker of an ongoing (although sometimes premorbid) disease
process. Hard to see it as a primary mediator...

**Should dysregulation be assessed as a process?**

Maybe we should consider an assessment of AL that addresses HOW FAR DOWN
STREAM the dysregulation has moved. For example, the difference between
a person with elevated cortisol and one with elevated cortisol and
inflammatory markers?

**NEXT STEPS**

1.  Develop the measures as assessments of *dysregulation* (not just
    convenient measures of risk). This would include some thought about
    the nature of dysregulation and assessments of reactivity and
    recovery as well as the usual basal measures.

2.  Develop measures of *individual systems*. This requires a clear
    conceptualization of each system and preliminary empirical work to
    see how measures cluster. For example, Steve Cole did some initial
    work with measuring the ANS that was successful in linking social
    inhibition to HIV progression.

3.  Consider the individual variables that might predict individual
    differences in what system(s) would show vulnerabilities under
    stress.

4.  Consider an assessment of AL that addresses HOW FAR DOWN STREAM the
    dysregulation has moved. For example, the difference between a
    person with elevated cortisol and one with elevated cortisol and
    high blood pressure, and one with elevated cortisol, high blood
    pressure and inflammatory markers...

5.  Studies that focus on the stability/changes in the stress (social
    and physical) environment over time.

**Steve Cole**

**UCLA**

**Background:**

I study social regulation of gene expression. My work maps the "social
signal transduction pathways" by which socio-environmental processes
regulate broad patterns of gene transcription across the entire human
genome (and across viral and tumor genomes). This work is generally
molecular biological and computational/bioinformatic, with a concrete
focus on neuroendocrine receptors, intracellular signal transduction
pathways, transcription factor activation, and other aspects of gene
regulation. My lab focuses on the subset of gene regulation pathways
that are empirically responsive to social inequality, social isolation,
and "stress". We are not concerned with the activity of any individual
gene, except insofar as it provides a good generalizable example of how
social regulation of gene expression takes place. Our primary objective
is understanding the higher logic of a socio-environmentally responsive
genome, including:

1\) Which broad groups of genes are sensitive to social factors?,

2\) Which signal transduction pathways mediate those effects?,

3\) Which genetic polymorphisms moderate those effects?, and,

4\) What teleologic purpose is served by socially responsive genome?

I was trained as a social psychologist (Stanford), am employed as a
molecular biologist (UCLA School of Medicine and HopeLab Foundation),
and do most of my work with math and computers. I began this work as a
virologist, detailing the molecular processes by which psychosocial
factors drive the HIV-1 virus. We eventually determined that HIV-1, and
most other successful human viruses, have evolved to take advantage of a
biochemical "stress niche" in their hosts (us). My work now focuses on
understanding that human genomic niche, and ameliorating its impact on
viral infections and cancer.

**(1) How has the concept of allostatic load had a positive (or
negative) impact on work in your field? Are there more valuable
alternative approaches to the study of cumulative physiological risk,
and if so, what are they and what is their relative advantage?**

I believe the general theory of Allostatic Load is likely correct,
potentially quite useful, and not currently being operationalized in
ways that are scientifically helpful. My inclination would not be to
seek other theories, but to seek better biological (and behavioral)
measures of cumulative biological "wear and tear" and health risk. It
would be helpful if researchers maintained a clearer distinction between
the hypothesized mediator (allostatic load) and the outcomes it is
invoked to explain (e.g., disease biology).

**(2) What could be done to make this concept more valuable to research
on social and behavioral factors in aging?**

The concept of allostatic load is valuable, but most biomarkers
currently used as measures of allostatic load do not fit the bill. Many
biomarkers offered as measures of allostatic load may actually be
measures of the chronic disease processes that allostatic load is
invoked to explain (e.g., cytokine levels) or measures of transient
states rather than cumulative states (e.g., hormone levels). Telomere
length is, in principle, a good biomarker of cumulative challenge
because the state of the biological "analyte" (the thing being measured)
is known to change in a cumulative fashion with stimulation (i.e., cell
turn-over progressively shortens the terminal chromosome cap, though
telomerase introduces complications). Glucocorticoid resistance in
leukocytes may also reflect cumulative exposure, and it is conceivable
that flattened diurnal cortisol slopes might also (more longitudinal
work is needed to validate the later). Current hormone or cytokine
levels do not have that cumulative property and thus cannot serve as
measures of a cumulative process. Any biological parameter that does not
show a monotonic change in value over time must indicate something else
instead of (or in addition to) cumulative biological challenge.

**(3) What are the most critical measurement issues, in your view? Are
there specific data needs for addressing these questions?**

a\) Better biomarkers of cumulative biological effects,

b\) better behavioral/neurobiological measures of cumulative risk
exposure, and

c\) a clear distinction between measures of cumulative challenge and
measures of current disease biology.

Neural proxies for cumulative challenge should be developed more fully
(e.g., functional neural imaging responses to targeted probe stimuli,
progressive innervation or denervation of solid tissues, epigenetic
regulation of neural genomes or neurally-responsive cells such as
leukocytes, etc.). Much of this biological "history" may be encoded in
the internal regulatory structure of cellular response to environmental
stimulus (e.g., glucocorticoid resistance) rather than in the
extracellular parameters released from cells (e.g., circulating hormone
levels).

**(4) What would be the most important \"next steps\" in moving research
on allostatic load, or cumulative physiological risk more generally,
forward?**

a\) A greater focus on biological parameters that are truly cumulative
(e.g., more the quality of telomere shortening) or are functionally
historical (e.g., glucocorticoid resistance)

b\) treatment of "state" parameters (e.g., hormone levels, cytokine
levels, CRP levels, etc.) as outcomes to be explained rather than
cumulative mediators, and

c\) a greater understanding of cumulative neurobiological allostasis,
and its biomarkers. This would provide measurement advantages (relative
to self-report) and fill in an important missing piece in the basic
theory of how historical environmental stimuli alter the current
functional activity of the body.

I believe the later concept represents the most significant contribution
of Allostatic Load theory. How is it that past events can affect the
functional characteristics of the present body? To answer this question,
it might be helpful if Allostatic Load theorists borrow more deeply and
directly from developmental biology and psychology. Telomeres are clever
in this regard. What else might we borrow from the biology of life-span
development?

**Eileen Crimmins**

**University of Southern California**

Re: Relevance of Allostatic Load to Measuring Risk in Large Populations

How has the concept of allostatic load had a positive (or negative)
impact on work in your field? Are there more valuable alternative
approaches to the study of cumulative physiological risk, and if so,
what are they and what is their relative advantage?

The work on allostatic load has been central in promoting the idea that
the body has a set if integrated physiological systems. The
demonstration that large components of allostatic load can be measured
in community settings, has led to the incorporation of many of these
indicators in population level surveys. All of this has been extremely
valuable and changed the world of data collection very rapidly

However, the measurement to date still has limited physiological
coverage in populations because of difficulty of measuring some
physiological systems. So the theoretical idea may not be fully
addressed. In addition while allostatic load has an emphasis on reaction
to stress, there is a category of markers of organ reserve that might be
more appropriate for use as an indicator of "frailty" or loss of
function that is appropriate for evaluating population health change. In
general a separation into indictors of early and late trajectory
physiological change would be useful.

What could be done to make this concept more valuable to research on
social and behavioral factors in aging?

Review of conceptual issues to clarify how empirical tests are able to
address theoretical ideas.of allostatic load and integration of this
concept with ideas of population health change.

What are the most critical measurement issues, in your view? Are there
specific data needs for addressing these questions?

In population studies, the use of new methods has increased the data
collection more rapidly than the development of assays using non
invasive collection methods such as saliva and blood spots.

What would be the most important \"next steps\" in moving research on
allostatic load, or cumulative physiological risk more generally,
forward?

Most immediately, the large national samples are not measuring stress
indicators. This seems essential to test the most important hypotheses
about stress and discrimination as factors in health differentials.

**Elissa Epel**

**UCSF**

**Influence of Allostatic load (AL), Allostasis and health.**

The concept of allostasis and allostatic load have had a large impact on
my research. AL model promotes a developmental model of disease
progression, toward general pathways, across systems, away from single
biomarkers. It is important in stress mechanism research both to
understand general pathways of chronic disease (AL, met syndrome) as
well as specific pathways (ie, Lutgendorf's model of ovarian cancer,
Dhabhar's model of skin cancer).

To understand health, not disease, it is helpful to measure allostasis
(albeit a moving target) and, further, whether 'enhanced allostasis'
exists (functioning above baseline, characteristic of youthful systems)
(See Bower et al, 2007). Examples of enhanced allostasis may be the high
levels of variability (heart rate variability, hormonal pulses) in
youthful systems, which degrade over time. The concept of recovery is
crucial to understanding allostasis. Most reactivity studies do not
examine longer term recovery from acute stressors. This may be one
critical period during which emotional regulation and cognition
(positive appraisals vs. rumination) are more closely tied to
physiology/states of arousal. My preliminary data (that I will show)
suggests that emotional reactivity and rumination during recovery are
linked to cellular aging markers. **High variability** and **rapid
recovery** may represent enhanced allostasis, which may be predictors of
longevity. This is mere speculation, but to understand aging, we need
studies that test whether there are unique mechanisms that predict
longevity, which may be different than those that predict early disease.
The AL model provides hypotheses or phenotypes about healthy vs. aged
profiles of arousal during acute and chronic stress states. The concept
is clarifying, the operationalization of both allostasis and AL is
challenging (below).

*What could be done to make this concept more valuable to research on
social and behavioral factors in aging?*

**It would be helpful to have better measurement of primary mediators,
which is challenging.** We need better identification of the key
measures in an allostatic load battery, and which aspects are most
closely tied to behavior, stress, and genetics. One long standing
obstacle in stress research, only recognized more recently, is that
primary mediators such as cortisol levels are a dynamic measure, and
dysregulation can lead to both hyper or hypocortisolemia. Researchers
need better statistical models to deal with 'bimodal' variables of
dysregulation, and to use variance like this as a way to understand
different phenotypes of dysregulation. We need markers of chronic stress
that don't depend on how stressful one's day was. **For example, imaging
measures of adrenal volume, thymus involution, and possibly
dexamethasone nonsupression, should represent a history of chronic
stress arousal, at least ACTH or cortisol.**

**It would be helpful to develop better measurement of chronic stress**.
One might wonder why AL is not related to distress in several population
based studies. Often we are trying to link a 'state' measure available,
like depression over the last two weeks with what may be largely a long
term reflection of lifestyle and wear and tear. Why should recent mood
be strongly linked to long standing footprints of dysregulation? We need
**cumulative models of distress.** We are currently trying to measure
lifetime histories of depression better. Measuring stress
retrospectively is even more problematic. Measurement of **emotional
reactivity** may be more closely linked with allostasis than trait
measures of negative affect or depression. What types of stress are most
damaging, and what does this look like in the brain? Studies linking
brain chemistry and activity with peripheral biomarkers would be
invaluable. However, we are limited by our inability to measure
important central peptides in humans peripherally (eg, NPY, oxtytocin,
opioids in the VTA) and there is a lack of ligands that would allow us
to see PET scan activity.

**Given the central role that chronic stress plays in accelerating
aging, we need a better multilevel understanding of stress vulnerability
and stress resistance**. The problem becomes obvious when we realize
that there is no agreed upon operationalization of either term. What is
stress vulnerability or stress resistance, psychologically or
physiologically? Many of us have answers to that, from our individual
paradigms, but they probably have little "shared variance." It is
imperative to identify the most common phenotypes of a maladaptive
stress response---including whatever components are most important in
the pathway toward aging\-\-- affective, cognitive, genetic, and in
terms of neural activity and biochemical substrates centrally and
peripherally.

We need to move beyond tautological models -- eg, linking high blood
pressure to hypertension to CVD, to studies that point to mechanism.
This is where models of somatic cellular aging or immunosenescence, and
gene expression may be helpful. Focusing on cell based markers of
biological aging allows us to measure aging in youthful systems as they
develop, and allows examination of life course perspectives. Markers of
how cells age --such as telomere length---and the biochemical mediators
such as Insulin exposure, oxidative stress, and inflammation\-- may
reflect poor allostasis even in young people. However, mid life is a
time that a critical mass of mitotic cells become senescent and thus
biological aging becomes manifested in phenotypes of aging (graying,
wrinkling, clinically measurable disease). It is helpful to have aging
studies start at mid-life or earlier.

*What would be the most important \"next steps\" in moving research on
allostatic load, or cumulative physiological risk more generally,
forward?*

**There is a need for 'mechanistic' longitudinal studies.** Given the
nonlinearity of physiological processes (eg, bidirectional
relationships, webs of interconnections), cross sectional research can
lead to false assumptions. With limited resources, there should be more
focus on causal mechanisms. This includes longitudinal studies with
experimental studies embedded (like MIDUS). Well characterized samples
could be taken advantage of. The lack of investment in samples that
cannot be followed sufficiently, due to limited funds to extend research
longitudinally, is an obstacle to understanding the process of aging.

Once we have developed more advanced conceptual models of phenotypes of
"stress" --we need multilevel research examining how "stress
vulnerability" leads to transmission of disease risk and conversely, how
"stress resilience" may confer longevity. This might require
multigenerational studies that include prenatal conditions. Large
longitudinal studies that examine women and men in young adulthood, and
how they pass on traits such as emotional reactivity, stress hormone
reactivity, insulin resistance, and telomere length to their progeny,
and substudies to examine mechanisms in depth. Such studies require
multi level analyses, and need to include social factors, genetic,
behavioral phenotypes, neurobiology at least as well as it can be
measured in humans.

**Importance of health behaviors as moderators and mediators not
covariates.**

How much of AL is related to health behaviors, and how much of our
health behaviors are environmentally constrained or influenced by
genetic variations? Linear models are limiting, and the large effects of
stress may be in interaction with behavior. Health behaviors are often
used as covariates but actually affected by stress. Behavior can mediate
negative effects of stress (such as the interaction of high fat diet and
stress) or, in the case of exercise, can moderate and buffer impact of
stress. As an example, there have been many iterations of human studies
addressing relationships between stress and visceral fat in cross
sectional ways. Some studies find this relationship and others do not.
New rat research shows how chronic stress interacts with a high fat diet
to recruit and enlarge visceral fat cells through NPY. Chronic stress
alone did not significantly increase visceral fat (ie, no main effects),
but only in interaction with eating fat. The action was in the
interaction, and it required an animal studies to unravel the mechanism.
We need more animal studies addressing questions about behavior/stress
interactions.

**Lisa Fredman**

**Boston University**

1.  How has the *[concept]{.underline}* of allostatic load had a
    positive (or negative) impact on work in your field? Are there more
    valuable alternative approaches to the study of cumulative
    physiological risk and if so, what are they and what is their
    relative advantage?

> I am a psychosocial epidemiologist and my research focuses on the
> health effects of caregiving stress. I think that the concept of
> allostatic load has had a big impact, both positive and negative, on
> the field of psychosocial epidemiology, and little impact on
> caregiving research. It has had a huge impact on my own research: here
> is how.
>
> I have been conducting a prospective cohort study on a sample of
> elderly women caregivers and non-caregivers who are participants in
> the Study of Osteoporotic Fractures (aka Caregiver-SOF). Its
> theoretical framework is the stress and coping model. The
> Caregiver-SOF caregivers are more stressed than the non-caregivers,
> but have lower rates of functional decline and mortality. I could not
> explain this methodologically or theoretically until I read Teresa's
> studies of allostatic load. The strengths of the concept were that the
> "wear and tear of chronic stress" affected multiple, inter-related
> homeostatic systems, and that it predicted established measures of
> health decline in an epidemiologic study. High allostatic load could
> be the physiologic pathway between caregiving and health decline. I
> performed a cross-sectional pilot study: caregivers and non-caregivers
> did not differ on allostatic load, although the caregivers had more
> stress. Therefore, I theorized that a subset of caregivers -- those
> who were stressed AND developed high allostatic load -- would have
> higher rates of health decline, whereas those who were stressed but
> who did not progress to allostatic load would not differ from
> non-caregivers. The prospective study design would reveal the temporal
> relationships between chronic caregiving stress, development of
> allostatic load, and health decline.
>
> I submitted and resubmitted several proposals to test this hypothesis
> to NIH. Reviewers from multiple study sections criticized the concept
> and the measurement of allostatic load on the grounds that a single
> score was used to reflect a multidimensional concept, validity studies
> were lacking, and that the measure combined cardiovascular, metabolic,
> and neuroendocrine indicators which could mask the true physiologic
> mechanism.
>
> Based on these critiques and recent studies of stress-induced
> metabolic syndrome, I revised my conceptual model. Metabolic syndrome
> replaced allostatic load as the pivotal mediator between chronic
> caregiving stress and health decline. This new model incorporates
> theories that stress-induced disruptions in the neuroendocrine and/or
> immune systems may increase the risk of metabolic syndrome, leading to
> health decline. It is supported by epidemiologic studies (see Yaffe et
> al, 2004 on the combined effects of inflammatory markers and metabolic
> syndrome on cognitive decline). It is consistent with the theory of
> allostatic load. Moreover, data from Caregiver-SOF and our pilot study
> support this model.
>
> I revised my proposals, submitted them to NIH, and got funded! That is
> how allostatic load has influenced my research.
>
> In general, I think that the concept of allostatic load can give us
> tremendous insights into the physiological mechanism(s) by which
> chronic stress affects health. It would strengthen studies of
> caregiving outcomes which, with few exceptions (e.g., studies by Grant
> and by Vitaliano), focus on single biomarkers if they include
> biomarkers at all, and do not address effects on multiple
> physiological systems, or the downstream effects on physical or
> cognitive health decline.

2.  What could be done to make this concept more valuable to research on
    social and behavioral factors on aging?

> In epidemiologic research, the concept of allostatic load might be
> more valuable if prospective studies were designed to evaluate
> sequential changes in the components of allostatic load, and the
> subsequent effects on functional, cognitive, and disease outcomes.
> This would involve taking multiple measures of the components of
> allostatic load at multiple time points, such as annual or biennial
> followup interviews. Such studies would allow researchers to
> disaggregate the components of allostatic load, and to tie it to other
> theories of physiological responses to chronic stress. A limitation of
> many epidemiologic studies is that biomarkers of allostatic load are
> collected at only one or two time points, which prevents seeing how
> changes in one system lead to downstream changes in other, multiple
> systems.
>
> Secondly, since allostatic load is theorized to result from chronic
> stress, we need prospective cohort studies on populations exposed to
> chronic stress and comparable populations that are not exposed to that
> stress, to determine how chronic stress leads to allostatic load and
> components of allostatic load. Samples of caregivers and
> non-caregivers could serve this purpose, but the selection of
> non-caregiver comparison groups can introduce potential selection
> biases (ie, married non-caregivers are often healthier than
> caregivers, elderly non-caregivers are less physically active than
> caregivers). Other high-stress populations might include workers in
> high-stress occupations or spouses of veterans. I am concerned that
> some epidemiologic measures of "life course stressors" actually
> indicate non-stress risk factors for components of allostatic load:
> for example, low socioeconomic status may lead to metabolic syndrome
> through poor diet rather than through stress, so epidemiologic studies
> need to include measures of these confounders.
>
> Third, perform research on factors that may prevent or reduce
> allostatic load components in the face of chronic stress. For example,
> studies could evaluate how stress reduction programs affect allostatic
> load components and ultimately prevent chronic stress from progressing
> to allostatic load.

3.  What are the most critical measurement issues? Are there specific
    data needs for addressing these questions?

> Epidemiologists express the need for validity studies of allostatic
> load. In addition, there are questions about how to operationalize an
> "allostatic load" score. There are also questions about how to
> operationalize the components of allostatic load: as continuous
> variables, z-scores, or categorical measures. One concern is that
> studies that use categorical measures tend to base the cutpoint on the
> sample-based distribution (for example, top tertile of cortisol). But
> the cutpoints differ from study to study. Therefore, it would be
> helpful to compare measures of allostatic load and the distribution of
> its components in different samples and across multiple time points.

4.  What would be the most important "next steps" in moving forward
    research on allostatic load or cumulative physiological risk?

> Researchers are increasingly including biomarkers in their studies,
> often without a strong conceptual framework. Perhaps research would be
> moved forward if there were more articles in discipline-specific
> journals that emphasized the conceptual strengths of the allostatic
> load model or on models of cumulative risk.
>
> More research is needed on the points raised in the previous sections:
> the temporal relationships among the components of allostatic load;
> evaluating whether there are critical aspects of allostatic load, such
> as metabolic syndrome, that link chronic stress to disease outcomes;
> conducting parallel studies of allostatic load in different
> populations and high-stress groups to identify similarities and
> differences in the mediating role of allostatic load between chronic
> stress and health decline.
>
> A practical issue is how to get studies on allostatic load favorably
> reviewed by NIH study sections. This is important for advancing
> research in this area.

**Noreen Goldman**

**Princeton**

For the past eight years, I have been involved in a data collection
effort in Taiwan known as SEBAS.[^1] This survey, which took place in
2000 and 2006, includes home-based interviews, collection of blood and
12-hour urine samples, and physicians' health exams, from about 1000
middle-aged and elderly respondents who comprise a random subsample from
an ongoing, national longitudinal survey. The underlying objective of
SEBAS has been to examine the relationships among the social
environment, stressful experience and mental and physical health and to
identify the intervening physiological pathways. A subsidiary goal has
been to evaluate the utility of the allostatic load framework and
existing measures of allostatic load in elucidating the linkages between
stressful experience and health.

In the Princeton workshop last spring, I outlined five sets of questions
that have plagued analyses, including our own, that attempt to analyze
these relationships in broad (non-clinical) populations.

1.  How well have we measured (or can we measure) stressful experience
    in interview surveys? How should we measure stressful experience --
    e.g., traumatic events, major life events, short-term stressors,
    perceptions of stress?

2.  Are we obtaining the "correct" biomarkers from large-scale surveys?
    How do we determine whether a biomarker is a potentially important
    component of the allostatic load framework? How often should we
    attempt to measure these biomarkers? How can we best parameterize a
    large number of biomarker values in terms of variables or scores?

3.  How well have we measured (or can we measure) individual
    characteristics that may moderate the impact of stressful experience
    (e.g., personality, coping mechanisms, social position)? Can our
    statistical models and sample sizes support this type of complexity?

4.  Are studies such as SEBAS focusing on too old ages -- e.g., a period
    in the life span when the effects of social factors and challenge
    may be less important than earlier in life and when many persons at
    risk have already died?

5.  How much variation in these relationships do we expect to occur
    across populations (or across individuals within populations)? For
    example, is it reasonable to think that associations found in the US
    or other Western populations would be of a similar magnitude to
    those in Taiwan?

Although I continue to believe that these are pressing issues, I think
it would be useful to focus some of our discussion on a more basic
question:

> ***What types of findings would offer strong support (or a strong
> refutation) of the construct of allostatic load (in human
> populations)?***

I believe that some of the claims in the literature that purport to find
support for this construct are unfounded. For example, much of the
research to date on human populations that assesses the allostatic load
framework does so by examining the connection between an array of
biomarkers and a set of health (or survival) outcomes. Indeed, some
recent studies have included in an "allostatic load score" physiological
measurements that do not appear to be related to the stress response
(e.g., grip strength), but are known to be strong predictors of future
health status. Given the established associations between most of the
biomarkers used in population surveys and a multitude of mental and
physical illnesses, statistically significant associations between the
two should come as no surprise. That is, the links between these
physiological measurements and health may arise from numerous pathways,
many of which are probably not what we would think of as stress-related
mechanisms. Similarly, the demonstration that a score of allostatic load
(e.g., a summation of the number of these biomarkers that fall outside
normal operating ranges) has a stronger correlation with downstream
health measures than do individual markers is also an expected result in
light of potential measurement error and the fact that the sum of small
effects is typically a larger effect.

Thus, it seems that one needs to set a higher bar to evaluate the
construct of allostatic load, one that demonstrates linkages between
stressful experiences and poor physiological profiles (however defined).
There are two issues that require attention in this regard. One pertains
to how we define a "stressor." Physiologists often focus on
health-related mechanisms such as pain, pathogens, or lack of sleep.
Social scientists are apt to think instead of life challenges, such as
the death of a loved one, trauma, serious illness, loss of job,
financial hardships, discrimination, or repeated daily hassles. Perhaps
we need to distinguish here between the animal and human literatures.
The second point pertaining to the link between stressors and poor
physiological profiles concerns the role of socioeconomic status (SES).
Social epidemiologists have argued that the social gradients in health
come about in large part because persons of lower SES experience greater
stress than their higher status counterparts. This conclusion is
sometimes based on little more than statistically significant
associations between SES (typically measured by education, income or
occupational status) and a handful of biomarkers (e.g., blood pressure,
cholesterol level, BMI, or fibrinogen). Much more compelling evidence is
needed to identify the importance of "stress" in driving social
inequalities in health. Researchers also need to keep in mind that
"stress" can play two different roles in the SES-health link: persons of
lower SES may experience more (or more serious) stressful events and
they may be more vulnerable (have a greater physiological response) to
stressors. Researchers have rarely been explicit about these two
mechanisms and have generally not attempted to establish their veracity.

**Igor Grant**

**UCSD**

[1. How has the concept of allostatic load had an impact on work in your
field? Are there more valuable alternative approaches to the study of
cumulative physiological risk, and if so, what are they and what is
their relative advantage?]{.underline}

The concepts of allostasis and allostatic load derive from a long
tradition stretching back to Claude Bernard's observations on the
physiological necessity of the "fixite du milieu interieur" which was
then elaborated by Walter Cannon in the concept of homeostasis. To me,
the concepts of allostasis and allostatic load have been particularly
useful in their ability to unite notions of homeostatsis and acute and
chronic stress. Of particular heuristic importance has been the
elaboration of the notion of primary mediators (e.g., catecholamines and
glucocorticoids) and the categorization as effects of these mediators
into primary (cellular), secondary (e.g., downstream metabolomic
changes), and tertiary (actual organ disease).

These notions have been very useful in framing our own program of
research into the health effects on elderly spousal caregivers of being
married to and looking after a dementia husband or wife. Our overarching
concept is that the stresses associated with caregiving, which are both
chronic and punctuated by acute events, can lead to a state of
sympathoadrenal medullary (SAM) arousal characterized by greater fluxes
in circulating catecholamines, including norepinephrine and epinephrine.
Consistent with notions of allostasis, we measure not only basal and
stress-induced catecholamines, but also the receptor system upon which
they act (in our case we focus on beta adrenergic receptors and on
lymphocytes as a model of effects that may be occurring in other
tissues). We then attempt to link these changes to changes in molecules
such as D-dimer and IL6 (being examples of indicators of the coagulation
environment and inflammation), which would be examples of secondary
outcomes in the McEwen et al., model. Our work is now examining more
downstream outcomes which may be thought of as transitions from
secondary to tertiary outcomes --- for example, changes in baroreflex,
in endothelial function as measured by flow mediated dilation, and
evidence of early arteriosclerosis as determined through ultrasound.

Our model also examines the effects of resiliency factors such as coping
skills involving degrees of mastery, as these might moderate the above
relationships.

In sum, the concepts of allostasis and allostatic load very much map
onto the theoretical issues that concern us.

[2. What could be done to make this concept more valuable?]{.underline}

The first steps to improve the usefulness of the concept have already
been taken in the elaboration of concepts such as primary mediators and
primary, secondary, and tertiary outcomes. These help to frame what
groups of variables it would be useful to study and provide the
beginnings of a framework for interrelating them. In my view, these
"levels" could be refined further. For example, much of the focus in
secondary outcomes has been focused on measures relating to energy
metabolism (e.g., insulin, lipids, and other indicators of metabolic
syndrome). A second focus has been on immune dysregulation. Clearly,
both classes of events are of importance in various outcomes including
cardiovascular disease and possibly autoimmune diseases and cancer.
Additional classes of variables deserve study. One of these includes
inflammatory markers of various sorts (research on these is actually
underway). A second group of mediators concerns hemostasis. Allostatic
load in the hemostasis system may be indicated by increases in
"procoagulatory" markers such as D-dimer and fibrinogen. Markers such as
these have been linked to increased likelihood of cardiovascular disease
and stroke, but have not been very systematically studied among elderly
under chronic and acute stress. Other indicators of "vascular health"
such as responsiveness of the endothelium to baro or hypoxic stress are
also worthy of focus, since responsive endothelial functioning may
protect against the sorts of injuries to vessel linings that form the
precursors to arteriosclerosis.

The area of vulnerability and resilience also deserves better
conceptualization. As in inherent in models of allostasis, genetic
factors may predispose to chronic allostatic load in some but not
others. Studies on genetics, gene expression, proteomics, and
metabolomics should ultimately be done to clarify who under what
circumstances responds in what manner, and how such proteomic and
metabolomic changes influence downstream organ health and disease.

A great deal of work has been done in the fields of psychosomatic
medicine and behavioral medicine generally on resilience factors
including concepts like problem focused coping, mastery, etc. Better
linkage between these notions and studies of psychobiology of aging
under conditions of acute and chronic stress are needed.

[3. What are the most critical measurement issues?]{.underline}

Research into allostasis and allostatic load would be advanced by
developing normative data in regard to primary and secondary outcomes.
For example, what represents "normal" response to a stressor for men and
women of different ages, socioeconomic strata, educational levels, or
race/ethnicity? In neuropsychology a great deal of progress has been
made in the ability to detect and monitor change in neurocognitive
performance in respect to illness or aging by developing expected ranges
of performance on various neurocognitive tests with respect to age,
education, gender, and race/ethnicity. Such standards allow us to
determine whether responses of groups of interest are within the
expected range, or may represent maladaptive responses. Until we have
good data on how, for example, elderly men and women who are in
generally good health and not under conditions of severe stress respond
to acutely stressful circumstances in terms of catecholamines,
glucocorticoids, ACTH, etc., it will be difficult to explore notions of
change in "set point" that may be occasioned by chronic stress.

Related to this, several groups of investigators have attempted to
create overall measures of allostatic load. These have involved creation
of standard scores, counting of scores outside particular ranges, etc.
These are useful starting points, but if we had more data on "normals"
then it might be possible to generate Z or T-scores for the primary and
secondary outcome measures that are more reliable.

[4. What would be the most important \"next steps\" in moving research
on allostatic load forward?]{.underline}

Some of these notions have been covered in #3 above. Another useful
approach would be the design of experiments that are able to test the
theorized mechanistic pathways linking stress to primary, secondary, and
tertiary outcomes in a more precise way. From the example of hemostatic
variables mentioned above, can we, for example, link changes in basal
and/or stress induced hemostatic response to changes in endothelial
function, vascular response, or early indicators of arteriosclerosis?
Mapping these more fine-grained associations would permit moving us from
studies that are correlative in nature to those in which it may be
possible to test models of causality. Implied in this strategy is the
importance of examining people or animal models over time with a view to
accumulating sufficient longitudinal information to test such causal
models.

**Arun Karlamangla**

**UCLA**

## The Concept 

The concept of allostatic load originates from the idea that the
internal physiologic milieu adapts to environmental demands -- a
phenomenon referred to as *allostasis*. Allostasis is a dynamic
regulatory process, with continuous adaptation of physiology in response
to stressors. However, when adaptation efforts are excessive, in terms
of frequency, duration, and/or extent, it can lead to gradual loss of
the body's ability to maintain system parameters within normal operating
ranges. Allostatic load is the total accumulation of such dysregulation
across physiological systems, and was hypothesized to mediate the
effects of stress on health risks. There is now good evidence that
psychosocial adversity is associated with higher levels of dysregulation
in multiple physiological systems, or higher allostatic load. Higher
allostatic load (or larger number of systems that are dysregulated) is
in turn, associated with poorer health outcomes.

## Potential Use in Clinical Care

## In addition to the research role of allostatic load in understanding the mechanisms by which psychosocial influences on health risks play out, allostatic load can also be potentially used as a measure of total sub-clinical change in physiology, to assess risk for adverse outcomes. In young adults, it could be an early warning sign of health risks accumulating beneath the surface, which should trigger changes in health behaviors. Markers of sub-clinical changes are especially important in older adults: Many older men and women experience gradual declines in physical and cognitive abilities in the absence of a clinically manifest disease process, and sub-clinical measures such as allostatic load can identify the older adults at increased risk for such declines, and target appropriate interventions. 

## Operationalization

Initial operationalizations of allostatic load have used simple count
measures based on resting or baseline values of physiological parameters
from multiple regulatory systems. While the approach has served to test
the allostatic load concept, it likely does not adequately capture the
extent of dysregulation and is insensitive to changes in system dynamics
that do not affect resting values. To maximize the utility of the
allostatic load concept for both research and clinical uses, the
allostatic load measure has to reliably and reproducibly measure both
the extent/severity of dysregulation and aspects of the dynamics in
multiple physiological systems. Measurement questions that need to be
answered include:

1.  How to incorporate severity of dysregulation? Should clinically
    recognized disease entities be treated as the most severe form?

2.  How to handle use of medications that affect the measured biomarker
    (since medication use might modify the relationship between an
    affected biomarker and health outcomes)?

3.  How to incorporate past history of dysregulation (since a longer
    history of dysregulation is associated with poorer health outcomes)?

4.  If some systems are better represented (by more biomarker
    measurements) than others, is weighting needed?

5.  How to handle interactions between physiological systems (e.g., high
    blood pressure has worse implications in the presence of diabetes)?

6.  How to measure reactivity to challenge? How to measure recovery?
    Diminished reactivity and delayed recovery are both examples of
    dysregulation that are not captured by an index based only on
    measurement of resting/baseline values.

7.  Does a high level of psychosocial well-being lead to better than
    normal regulation? If so, how to measure it?

8.  Validation: Should the allostatic load measure be validated w.r.t.
    prediction ability for health outcomes or w.r.t. dependence on
    psychosocial histories or both? Should mediation be the test of
    validation? If yes, what is the best way to test mediation?

.

**Dario Maestripieri**

**University of Chicago**

Interindividual variation in allostatic load:

Investigating the role of early experience with a nonhuman primate model

[Understanding interindividual variation in allostatic load]{.underline}

Allostatic load refers to the cumulative strain on the body produced by
the physiological costs of repeated adjustments to stressful
perturbations as well as the elevated activity of physiological systems
under challenge. Not all individuals are affected by allostatic load in
the same way. "There is a growing body of correlational evidence
indicating that individuals vary in their response to stressors based on
differences in personality, coping and emotional regulatory styles, and
social and cultural environments. Thus, some individuals seem resilient
to the effects of aging and present a profile of positive health and
well-being that may protect stress regulatory systems from
dysregulation. Questions remain as to whether some people are
genetically disposed to greater resilience to stress, or whether
life-style, psychosocial, and socioeconomic factors are responsible for
these differences" (Seeman & Nielsen, Background Statement for NIA
Workshop on Allostatic Load).

As a developmental scientist using a lifespan approach to address
questions regarding behavior, physiology, and health, I am interested in
understanding the effects of early experience, in conjunction with those
of genetic make-up and current environment, on the development of stress
vulnerability and resilience, including the accumulation of allostatic
load in aging individuals.

[Early exposure to stress and the development of stress vulnerability
and resilience]{.underline}

Exposure to stress early in life has long been known to increase
vulnerability to stress and stress-related diseases later in life.
Laboratory studies have repeatedly shown that the
hypothalamic-pituitary-adrenal (HPA) axis is involved in mediating this
link, as stressful early life events contribute to long-term changes in
both brain and neuroendocrine stress responsiveness in humans and
animals. It is now well established that severe stress experienced
during infancy or childhood impairs the acquisition of appropriate
coping skills, enhances stress-induced HPA axis activation, and
increases the risk for the development of mood and anxiety disorders in
adulthood, as well as other stress-related diseases.

Stress researchers have often assumed that stress vulnerability later in
life increases linearly as a function of the intensity of the early
stressor, so that individuals who are exposed to severe traumatic events
will exhibit later greater vulnerability than individuals exposed to
mild stressors, who in turn will be more vulnerable than individuals
exposed to little or no stress (Fig. 1a). Several studies, however, have
shown that prior stress exposure does not increase vulnerability in a
linear fashion, but according to a J-shaped curvilinear function (Fig.
1b). Whereas severe early life stress exposure generally undermines the
development of resilience and leads to vulnerability, mild early life
stress exposure may protect against these deleterious effects.
Specifically, milder forms of adversity may provide a challenge, that
when overcome, produces competence in the management of, and enhanced
resistance to, subsequent stressors.

![](media/image1.wmf){width="4.7291338582677165in"
height="4.384645669291339in"}

The idea that mild early life stress exposure may "inoculate" the
developing organism by permanently altering cognitive appraisal of, and
emotional and neuroendocrine sensitivity to subsequent stressors has
potentially profound implications for understanding the accumulation of
allostatic load and the occurrence of stress-related diseases late in
life. Early life stress inoculation may especially confer psychological
health benefits for women, who more often engage in maladaptive
ruminative coping strategies that increase negative emotional arousal
and exhibit greater HPA axis responses to pharmacological stimulation
and social rejection than men. Moreover, after puberty, women are twice
as likely as men to develop certain stress-related mood and anxiety
disorders.

As a comparative behavioral scientist working with animal models of
human behavior, development, and health, I am interested in developing a
nonhuman primate model to understand how early exposure to stressors of
different intensity affects the development of stress vulnerability and
resilience and the accumulation of allostatic load in aging individuals,
particularly females.

[A nonhuman primate model of early experience and allostatic
load]{.underline}

My model organism is the rhesus macaque and my model for studying
allostatic load is dominance rank, the equivalent of socioeconomic
status in humans. In rhesus macaques, baboons, and related species,
female dominance rank is acquired early in life and remains stable
throughout the lifespan. In these species, chronic stress associated
with low dominance rank has a number of adverse adrenocortical,
cardiovascular, reproductive, immunological, and neurobiological
consequences. Low ranking monkeys, particularly females, exhibit basal
hyperactivity of the HPA axis and cathecolaminergic systems, basal
hypertension and elevated heart rate, blunted cardiovascular stress
response after a challenge, pathogenic cholesterol profiles, increased
vulnerability to the atherogenic effects of a high fat diet, later
timing of puberty and decreased gonadal hormone levels in adulthood,
suppression of circulating lymphocyte numbers and blunted immune
responsiveness to a challenge, and a host of neurobiological changes
including inhibition of neurogenesis, dendritic atrophy, and impairment
of synaptic plasticity in the hippocampus. The deleterious physiological
consequences of chronic stress associated with low dominance rank should
be particularly evident in aging individuals, although few or no studies
so far have investigated allostatic load and aging in free-ranging
primate populations.

I am currently involved in two research projects investigating early
experience and allostatic load in aging monkey females at the Caribbean
Primate Research Center in Puerto Rico. My subject population is the
free-ranging rhesus macaque population (n= 850) on the island of Cayo
Santiago, which has been the subject of behavioral and biomedical
research since the 1960s.

The first project focuses on aging females (all of the oldest females in
the population) and involves the collection of multiple biomarkers of
allostatic load in these individuals. We expect that aging females of
low dominance rank will exhibit greater evidence of allostatic load than
same-aged females of high dominance rank, as well as than younger
females of both low and high dominance rank. We also expect that there
will be significant inter-individual variation in biomarkers of
allostatic load in all aging females, but especially in those of low
rank. We measure basal levels of glucocorticoid hormones in fecal
samples, and plasma HPA axis hormone concentrations in response to
various challenges. Peptide and monoamine metabolite concentrations in
the CSF are measured. Proinflammatory cytokines and other biomarkers of
health are measured in blood and CSF samples.

The second project is a prospective longitudinal study aimed at
investigating whether exposure to psychosocial stressors of different
intensity in infancy can account for a significant fraction of
interindividual variation in allostatic load among aging females of low
dominance rank. This project involves 2 phases: in the first phase, we
investigate whether exposure to stressors of different intensity in
infancy affects the development of behavioral and physiological measures
of stress responsiveness in the first 3 years of life (i.e. birth
through puberty). In a subsequent phase of the project, study subjects
will be followed into old age (15-25 years) to examine whether early
exposure to stress and individual profiles of responsiveness to stress
in the first 3 years of life predict differential accumulation of
allostatic load in old age, especially among females of low rank.

Two contrasting models of the relation between early stress and later
vulnerability/resilience will be tested: one in which there is a linear
relationship between intensity of early stress and later vulnerability
(Fig. 1a) and another in which this relationship is a J-shaped
curvilinear function (Fig. 1b). A crucial prediction of the second model
is that exposure to mild stress early in life will promote later
resilience and function as a protective factor against the accumulation
of allostatic load in females of low rank. Other risk/protective factors
being considered are genotype (the polymorphisms in the serotonin
transporter gene) and current environment (the availability or lack of
social support).

We use a naturalistic model of variable early stress exposure: naturally
occurring interindividual variation in maternal rejection behavior.
Mothers prevent their infants from making contact with them and nursing
by pushing them away, and occasionally hitting and biting them. Rejected
infants exhibit intense distress behavior including prolonged screaming
bouts and tantrums. There is great interindividual variability in
maternal rejection behavior. Although the general function of maternal
rejection is to encourage infant independence, some mothers exhibit
extremely high rates of rejection, often in conjunction with physical
abuse of their infants. Previous studies have shown that exposure to
variable maternal rejection in the first few months of life affects
behavioral reactivity to novelty and stress later in life, the
development of the HPA axis, and the development of the brain
serotonergic and dopaminergic system. Infants exposed to mild rates of
maternal rejection seem to benefit in terms of greater independence from
their mothers, while those who experience high rates of aggression
exhibit hyper-reactivity to stress, fear and anxiety, and associated
neuroendocrine and neurobiological alterations. The deleterious
consequences of early exposure to high maternal rejection appear to be
greater in individuals carrying the short allele of the serotonin
transporter gene, and in individuals lacking large and effective
networks of social support.

**Jan Moynihan**

**University of Rochester Medical Center**

Until relatively recently, our lab has focused on animal
psychoneuroimmunology, using rodent models to dissect out relationships
among stress, the central nervous system, and immune responses. The use
of mouse models has in general been a fruitful basic science approach
with important translational implications. Our science was originally
informed by the General-Adaptation-Syndrome theory of Hans Selye 1; to a
large extent, the concept of allostatic load can be argued to be the
updated version of this theory.

To summarize my own findings and those of others over the years, the
effects of stress over time (arguably synonymous with cumulative wear
and tear resulting in 'allostatic load') on immunity in genetically
inbred mice (as well as 'outbred' humans) are dependent upon at least
three sets of factors. The first concerns the experimental subject, and
includes: species and genetic strain; age and gender; previous life
history; and circadian rhythm (the time of day at which a stressor is
imposed). A second set of variables has to do with the stressor itself,
including: the intensity and duration of the stressor (acute versus
chronic); the timing of stressor in relation to (immunological)
challenge; and, perhaps most importantly, the subject's perception of,
and capacity to cope with, the stressor. Finally, the immunological (or
other physiological) measure of interest itself presents another
important set of factors in determining the outcome of stressful
encounters, including: the kinetics of the immune response, the nature
of the response (i.e., innate versus cell-mediated versus humoral); the
antigen used to elicit a response and its concentration; the site of
response (peripheral blood versus lymphoid organ); and the use of in
vitro versus in vivo measures or ex vivo measurements. The concept of
allostatic load provides us with a theoretical framework in which to
think about the dynamic nature of these interacting factors.

**Neuroendocrine responses to stressful stimuli may vary as a function
of the stressor.** The concept of allostatic load---cumulative wear and
tear on physiological systems and organs\-- raises the question of how
environmental stimuli are translated into physiological or immunological
changes. We understand that there are two important CNS-derived
responses to stressors: activation of the hypothalamo-pituitary-adrenal
(HPA) axis, and activation of the autonomic nervous system. With respect
to immune function, activation of these neurochemical pathways, and the
release of virtually every one of their hormones and transmitters, has
the potential to alter some aspect of immune response 2;3. Of all these
neurochemicals, adrenally-derived corticosteroids (corticosterone in
rodents and cortisol in humans) have received overwhelming attention
from investigators searching for the mechanism underlying
stress-mediated immune alteration. Certainly, there are data to support
the hypothesis that increased corticosterone levels, either alone or in
concert with other hormones, mediate altered immune function 4-6.
However, we should not forget older papers in the literature that have
convincingly shown that stress-induced changes in immunity can occur in
either adrenalectomized or hypophysectomized animals (e.g., 7-9).
Further, stress-induced elevations in glucocorticoid levels can occur in
the absence of detectable changes in immune function 10;11. Finally,
stress-induced immune alteration can occur in the absence of a
detectable, or perhaps biologically meaningful, change in glucocorticoid
levels 12-14. Thus, experimental designs that focus on a single
neurochemical mediator fall short of providing a complete understanding
of allostatic load. Further, pharmacotherapies that might target a
single "stress hormone" will be unlikely to rescue immune or other
physiological functions that are impaired by allostatic load.

Another important question that arises from thinking about allostatic
load is: what is the nature of the relationship between an experimental
subject and an individual stressor as a function of time or aging? There
are some stressors that an experimental subject is likely to repeatedly
perceive as stressful (for scientists, a good example may be the process
of NIH grant submission). In contrast, there are some stressors to which
a subject will learn to adapt or habituate. Finally, there are some
stressors to which a subject learns maladaptive behaviors (e.g., learned
helplessness). How are these disparate behaviors related to, or perhaps
driven by, the neuroendocrine response to that stressor?

Escapable versus inescapable shock is a paradigm involving pairs of
rats, one of which learns to turn off electric shock (also called the
"executive animal"); the other, yoked control rat is not allowed to
learn, receiving an identical amount of shock that is inescapable. The
paradigm provides an interesting model for examining the neuroendocrine
mechanism(s) underlying a) the ability to control or cope with a
stressor (escapable stress), versus b) the induction of learned
helplessness (the subsequent inability to terminate or escape from the
stressor when given the opportunity to do so). Rodents subjected to
escapable versus inescapable shock differ in performance of a number of
subsequent behavioral tasks; as one example, yoked animals show a
decrease in social interaction compared to executive animals 15-17.
Despite these clear behavioral differences, however, the HPA axis
response of these two very different rats to the shock experience is
similar; that is, the magnitude and duration of the adrenocorticotropic
hormone (ACTH) and corticosterone response to shock does not
discriminate between the two groups 18;19.

In contrast to similar HPA axis hormone levels observed in executive and
yoked animals, Dr. Dana Helmreich (University of Rochester Center for
Mind-Body Research (RCMBR)) and her colleagues have observed
differential regulation of another relatively unstudied
stress-responsive pathway, the hypothalamo-pituitary-thyroid (HPT) axis,
in rats subjected to escapable or inescapable shock. That is, peripheral
T3 levels, which are critical for maintenance of homeostasis throughout
the lifespan, do differ between executive and yoked animals 20; T3
levels are decreased in rats subjected to inescapable shock. Dr.
Helmreich's results are similar to those reported by Josko 21; yoked
rats have a decrease in circulating thyroid stimulating hormone (TSH),
T3 and T4 levels compared to executive rats.

In humans, dysregulation of thyroid hormones is associated with mood
disorders, particularly depression 22. Recently, modest decreases in
thyroid hormones, yet still within clinical boundaries of euthyroidism,
have been correlated with increased incidence of post-partum depression
23, increased anxiety 24, decreased well-being and quality of life 25;26
and increases in metabolic syndrome 27. These results support the
conclusion that subtle changes in thyroid hormone levels have
quantifiable and significant consequences for mental health, and perhaps
immunological health as well.

These data suggest that different neuroendocrine pathways may be
activated by various stressful stimuli. These patterns of activation are
undoubtedly associated with differing patterns of, for example, immune
outcome measures. Thus, rather than examining a single biomarker or
immune outcome, our understanding of stress-induced changes in health
and disease (the consequence of allostatic load) will require the
examination of a combination of neuroendocrine and immunological outcome
measures.

**The role of genetics in the response to a stressor(s).** Even a simple
manipulation such as the differential housing of genetically inbred
strains of mice can illustrate the complex interactions among
environment, genetics and immune function. In one such experiment, we
housed male BALB/c and C57Bl/6 mice 1/cage versus 4/cage. Their
secondary antibody response following immunization with a novel protein
antigen was assayed. BALB/c mice responded with a robust antibody
response; no differences were observed between BALB/c mice housed 1/cage
versus 4/cage. C57Bl/6 mice responded to the same concentration of
antigen with a significantly lower antibody response than BALB/c mice,
regardless of housing condition. More importantly, C57Bl/6 mice housed
1/cage produced a significantly higher antibody response than C57Bl/6
mice housed 4/cage at all time points examined 28.

The direction of the difference in antibody titers between singly versus
group-housed C57Bl/6 mice may have seemed surprising to us initially;
perhaps we might have expected that mice housed alone would be
"isolated," and should therefore have lower, not higher, antibody
levels. The lack of an effect of housing for the BALB/c mice becomes
more interesting in light of a recent paper which suggests that compared
to C57Bl/6 mice, BALB/c mice are low in sociability 29. One might
speculate that for the BALB/c mouse, being housed 1/cage versus 4/cage
is much less "disturbing" than it is to the C57Bl/6, social animal.

**The role of epigenetics in responses to stressors.** A large body of
work from Michael Meaney and his colleagues documents that early
experiences, including the early rearing environment, can cause changes
in gene expression in stress-sensitive brain regions in rats that last
into adulthood 30-32. The implications of these changes in epigenetic
programming for neuroendocrine, and especially immune responses and
health, remain largely unknown. As the perinatal period is a period of
plasticity for both the nervous and immune systems, it is not difficult
to imagine that early events might also directly affect immunity, and/or
that altered central nervous system function, e.g., altered expression
of glucocorticoid receptors in the brains of adult rodents, would
influence immunity across the life course.

Clinical studies that examine early events, in this instance during
pregnancy, are ongoing in our Laboratory for Mental Disorders at the
University of Rochester Medical Center, under the direction of Thomas
O'Connor, PhD. Dr. O'Connor has shown an association between maternal
stress and anxiety during pregnancy with long-term cortisol
dysregulation and behavior problems in offspring, who are now 10-12
years of age 33;34. Dr. O'Connor extends these findings in a new study,
Prenatal Anxiety and Its Effects on Child Development, which will
examine the effects of anxiety during pregnancy on child outcomes in
infancy, including the immune response to hepatitis B vaccination.

In addition to these human studies, my colleagues in Rochester are
conducting rodent experiments to determine (1) how early life
experiences influence developmental and long-term behavioral,
neuroendocrine and immunological processes, and how changes in function
might be influenced, positively and negatively, by subsequent
experiences to alter the development and/or progression of disease
throughout the life span; and (2) the developmental and long-term
psychophysiological and health effects of immunological challenges
experienced during early life. This work is conducted by my colleague in
the RCMBR, David Parfitt, PhD, who is particularly interested in
neonatal rearing and adult stress reactivity in C57BL/6 mice. We are
proposing longitudinal studies in rodent models that test hypotheses
about early life events across the lifespan in ways that cannot be
studied in humans.

**Conclusions.** One approach to understanding allostatic load and aging
utilizes translational studies in animals that inform the process of
"wear and tear" and aging in humans. While the complexity of interacting
variables---not to mention the redundancy that is built into many of our
systems (such as is exhibited in the proinflammatory cytokine
cascade)---may appear daunting, it is important to understand how a
lifetime burden of stressors impacts the aging process. In tandem,
studies should consider ameliorating these potentially deleterious
effects, either pharmacotherapeutically or via psychological or physical
(e.g., exercise) interventions.

**Reference List**

1\. Selye H. Stress. Montreal: ACTA, 1950.

2\. Levite M. Neuropeptides, by direct interaction with T cells, induce
cytokine secretion and break the commitment to a distinct helper
phenotype. Proc.Natl.Acad.Sci. 1998;95:12544-49.

3\. Khansari DN, Murgo AJ, Faith RE. Effects of stress on the immune
system. Immunol.Today 1990;11:170-75.

4\. Dobbs CM, Feng N, Beck M, Sheridan JF. Neuroendocrine regulation of
cytokine production during experimental influenza viral infection:
effects of restraint stress-induced elevation in endogenous
corticosterone. J.Immunol. 1996;157:1870-77.

5\. Coe CL, Rosenberg LT, Fisher M, Levine S. Psychological factors
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**Julian Thayer**

**The Ohio State University**

The Allostatic Load Model has been important in focusing researchers on
the concept of cumulative physiological risk. Of special note is its
attention to the temporal dimension. In our own work we have proposed
the Prolonged Activation Model with an emphasis on anticipatory stress
and delayed recovery, in the context of our broader Neurovisceral
Integration Model. Similar to the Allostatic Load Model, our Prolonged
Activation Model seeks to identify the pathogenic state that leads to
organic disease. We feel that the cumulative load put on the system is a
critical factor on the path from psychological stress to morbidity and
mortality.

There are several areas where our models have focused that may be
under-represented in the Allostatic Load Model. One area is individual
differences. Whereas the Allostatic Load Model uses individual
differences in allostatic load scores to predict morbidity and
mortality, we use individual differences in heart rate variability
(HRV), for example, to predict differences in stress reactivity per se
including anticipatory stress and delayed recovery. Thus we are able to
look at individual differences in the regulation of allostatic systems
at a more fine grained level than is common in the Allostatic Load
Model. This has implications for the understanding of gender and ethnic
differences in the accumulation of risk.

A second area is the relationship between the central nervous system and
the peripheral nervous system. Our studies of simultaneous measurement
of cerebral blood flow or other indices of CNS function and peripheral
measures such as HRV allow us to make inferences about the central
concomitants of the regulatory processes being indexed by our peripheral
measures. We are also able to show how these central and peripheral
interactions might be changing with aging or as a function of genotype.

A third area involves the cognitive processes that lead to prolonged
activation. In this context our Perseverative Cognition Hypothesis
provides insights into the toxic cognitive mechanism that leads to
prolonged stress responses and thus the excess wear and tear (cumulative
load) on the system. What is actually going on inside the heads, as it
were, and how to modify those thought processes represent potential
avenues of intervention to decrease cumulative risk.

A fourth area is the use of nonlinear dynamical systems theory and
especially the role of inhibitory processes. The interplay of excitatory
and inhibitory processes is essential for the proper functioning of a
nonlinear dynamical system. Importantly, a little bit of inhibition at
the right place and/or the right time can be a critical factor in stress
responsivity and whether it leads to prolonged activation or not.
Nonlinear dynamical systems theory also provides a broader perspective
for the generation of testable hypotheses about the pathways and
mechanisms associated with cumulative physiological risk. From a
measurement perspective the integration of indices of the
parasympathetic nervous system should enhance the measurement of
allostatic load.

A fifth area involves possible interventions that could help to reduce
cumulative risk. We are currently testing both psychological (e.g.,
worry reduction and CBT) as well as behavioral (dietary e.g., omega-3
and exercise) interventions to decrease markers of cumulative risk.
Interventions aimed at improving allostatic load scores might be
fruitfully employed to reduce cumulative risk as well.

And finally, the next steps for moving research on cumulative risk
forward include funding mechanisms that allow for such interdisciplinary
research to take place. The current disease specific funding mechanisms
can not accommodate the type of integrative models that the allostatic
load model exemplifies. Further incorporation of these ideas into the
allostatic load concept could make it more valuable to researchers.

[^1]: The Social Environment and Biomarkers of Aging Study (SEBAS) is
    collaborative with the Bureau of Health Promotion in Taichung,
    Taiwan and includes Maxine Weinstein, Dana Glei, and myself as
    leading investigators.