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.
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.
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:
How to incorporate severity of dysregulation? Should clinically recognized disease entities be treated as the most severe form?
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)?
How to incorporate past history of dysregulation (since a longer history of dysregulation is associated with poorer health outcomes)?
If some systems are better represented (by more biomarker measurements) than others, is weighting needed?
How to handle interactions between physiological systems (e.g., high blood pressure has worse implications in the presence of diabetes)?
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.
Does a high level of psychosocial well-being lead to better than normal regulation? If so, how to measure it?
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?
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
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
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.
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
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.
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.