Featured Article - Article de fond

Stress, Aging, and Resilience: Can Accrued Wear and Tear Be Slowed?
LOUISE C. HAWKLEY1,2 GARY G. BERNTSON3 CHRISTOPHER G. ENGELAND4 PHILLIP T. MARUCHA4 CHRISTOPHER M. MASI1,5 JOHN T. CACIOPPO1,2

Abstract
The impact of stress on age-related physiological capacities (i.e., resilience) is influenced not only by endowed genetic substrate, but also by individual differences, including the frequency of exposure to stress, the nature and intensity of psychological and physiological reactions to stress, and the efficacy of restorative processes that replenish physiological reserves and fortify against future stress (Cacioppo, Hawkley, & Berntson, 2003). This paper outlines a conceptualization of stress that acknowledges human susceptibility and resistance to the stresses of life and considers the net impact of human frailties and strengths on physiological resilience and health during the aging process.

Aging is inevitable. Indeed, one could say it is written into our genes. Cellular biological age is reflected in the gradual shortening of telomeres, the protective caps at the ends of chromosomes that normally prevent cell senescence (Frenck, Blackburn, & Shannon, 1998). Although the relationship between cellular and organismic age is not well understood (Chan & Blackburn, 2003), chronological age is inversely correlated with telomere length in adults across all age groups (Brouilette, Singh, Thompson, Goodall, & Samani, 2003; Cawthon, Smith, O’Brien, Sivatchenko, & Kerber, 2003; Epel et al., 2004). Moreover, stress
1 Chicago Center for Cognitive and Social Neuroscience, University of Chicago 2 Department of Psychology, University of Chicago 3 Department of Psychology, Ohio State University 4 Department of Periodontics, University of Illinois at Chicago 5 Department of Medicine, University of Chicago

Canadian Psychology/Psychologie canadienne, 2005, 46:3, 115-125

appears to contribute to cellular aging. For instance, among 20- to 50-year-old mothers who had been caring for a chronically ill child, telomere length in peripheral blood mononuclear cells was inversely related to the duration of caregiving (Epel et al.), even after controlling for mother’s age. This finding lends credence to the notion that stress is bad for the organism, and that it contributes to the wear-and-tear on the organism that marks the aging process. The thesis here is that aging is not simply equivalent to accrued exposure to stress, however. In the study referred to above, telomere length did not differ between the group of caregiving mothers and the group of control mothers not subjected to this chronic stress. However, telomere length was inversely related to perceived stress in both groups (Epel et al., 2004). Using established age-related means of telomere length, and controlling for chronological age and body mass index, the authors estimated that the lymphocytes of those in the highest perceived stress quartile were 9-17 years older than those in the lowest stress quartile (Epel et al.). Importantly, however, telomere length is insufficient to index cellular age. Telomere length is regulated by the telomere-protective and lengthening actions of telomerase, a cellular enzyme (Chan & Blackburn, 2003) whose activity decreases under conditions of repeated exposure to antigenic stimuli and with the approach of cellular senescence (Weng et al., 1997). Notably, then, caregiving and control mothers whose perceived stress scores were in the highest quartile not only had shorter telomeres, but also had significantly lower telomerase activity than those in the lowest stress quartile (Epel et al., 2004). These data suggest that, across the spectrum of stressful experiences, the impact of stress on age-related physiological capacities (i.e., resilience) is influenced not only by individual differences in exposure to stress, but also by individual differences in responses to and recovery from stressful experiences. In addition, we maintain that stress effects are influenced by the efficacy of restorative (e.g., anabolic) processes that serve to replenish physiological reserves. Our goal in this paper is to outline a conceptualization of stress that acknowledges not only human susceptibility but also human resistance to the stresses of life, and to consider the net impact of these frailties and strengths

The normalizing forces that constitute physiological responses to acute stress (i. in press. adaptation. increases in sleep. Very intense acute stressors (e. Marucha. inhibition of pathogen growth. For instance. stress in the form of exercise is encouraged precisely because exercise exposes the myocardium to a brief period of ischemia that elicits compensatory cardioprotective actions and decreases the risk of coronary artery disease and subsequent cardiac ischemia or infarction (Eisen et al. and Cacioppo on physiological resilience and health during the aging process. having a bear wander into your campsite will result in activation of the sympathetic nervous system and the release of the neurotransmitter norepinephrine. In animal models. a cytokine that plays a prominent role in mediating the effects of the acute phase response. restraint) have been shown to cause fever and to increase quantities of circulating leukocytes.116 Hawkley. and motor responses that support the behaviours necessary to survive a threat (i.g. and be more likely to survive. Tilg. 2003). immune... 2003). Cacioppo & Berntson. is to limit the tissue damage that excessive inflammation typically incurs (Barton). Dinarello. neuroendocrine.g. like that of other protease inhibitors. 1990). discrete stress of relatively short duration) evolved because there were reproductive benefits to being able to respond to disturbing environmental forces (i. 1997). 1988). Stressors and stress responses are neither inherently good nor inherently bad. these changes serve largely to limit pathogen growth. Sympathetic activation of the adrenal medulla prompts the release of hormonal epinephrine to further support demand for increased heart rate. In addition. heart rate and blood pressure increase). autonomic. Bosch. Marucha. stressors). and with higher rates of morbidity and mortality. For instance. a fight or flight situation). however. & Mier. and resilience – especially if the resources that can be marshaled are sufficient to meet adaptive demands and the associated restorative processes promote adaptive responding to future similar demands. when induced by acute stress.. Masi. activity. & Cacioppo. This makes sense from an evolutionary perspective because an organism with a primed immune system would mount a more efficacious response to.. Taylor & Starnes. Other acute stressors (e. Engeland. is elevated in response to inflammation and appears to have largely anti-inflammatory systemic actions (reviewed in Hawkley et al. Vander. The immune system also becomes involved in responses to acute stress. Instead.e. inescapable tail shock) are sufficient to produce a full complement of prototypical sickness behaviours (i. Short-Term Benefits of Acute Stress In general. with some types of immunity being suppressed and other types enhanced. 2004. however. exposure to acute stress elicits central. acute stress appears to have beneficial effects over the short-term by priming the immune system and placing it into a state of readiness to combat potential injury and infection.. but its function. IL-6. placing a rodent in an unfamiliar open-field causes a rise in both core body temperature and circulating levels of IL-6 (LeMay. elevated blood pressure. its actions at the heart and in the vasculature support the demand for increased blood supply (i. the functions of APPs include removal of cellular debris.e. decreases in food/water intake. 1996. of which C -reactive protein is an exemplar.e.e.” Numerous studies have shown that stress is associated with acute responses that mimic pathophysiological states (e. acute phase proteins (APPs). in press)... The short-term benefits and longterm costs of stress are perhaps best illustrated by examining the effects of acute and chronic stress on physiological functioning (see also. Engeland. in press). Thus. and activation of the hypothalamic pituitary adrenocortical (HPA) axis results in the release of cortisol to support increased metabolic needs.. and promotion of bacterial destruction by the activation of complement (Barton. infection and tissue damage in the event of injury suffered in a fight or flight situation.e.. Consistent with the priming hypothesis of acute stress. and social interactions). For instance. We turn to the immune system to illustrate how the acute stress response is adaptive and promotes resilience. Importantly. Protease inhibitors are one class of APPs with helpful actions.g. diminished lymphocyte proliferation). and these effects may last for days (reviewed by Maier. Importantly.. acute stress elicits immune changes consistent with sickness. Berntson. Hawkley. homeostatic processes can also promote growth. buffer inflammation. These homeostatic processes can have long-term costs. For example. an oral wound-healing study in humans showed that individuals with higher anticipatory stress (of the wounding procedure) healed significantly faster than individuals who were less stressed at the time of . foot shock. & Kluger. Acute stress also shifts enzymatic activity in blood to a state that is less conducive for bacterial growth/replication (Hart. activation of these immune components alone does not signify that sickness or inflammation will occur. and minimize damage to the organism in the event of infection. and IL-6. Stress is Neither Good Nor Bad The central dogma of stress research has long been that stress is “bad. C-reactive protein is frequently used as a marker of heightened inflammation.

active versus passive coping).g. & Maier. and processes whose functions are to support resilience (Berntson & Cacioppo. 1999). previously stressed with inescapable tail shock and then challenged with lipopolysaccharide (LPS). weaken physiological resistance to stress and further diminish resilience.g. Instead. in preparation). . chronic stress affects the very homeostatic structures.. Fleshner. exercise) not only reduce the impact of stress on resilience..g. O’Connor. setpoints. and an augmentation of both fever and sickness behaviours (Johnson. is influenced by stress appraisals (e. feedback mechanisms (not illustrated) link peripheral physiological processes to the central nervous system to further modulate physiological resilience and aging. Similar stressors also activate the acute phase response (Deak et al.Stress.. however. smoking). Other studies have shown that animals. Hansen. & Maier. This appeared related to higher circulating levels of glucocorticoids (GCs) at the time of wounding and decreased inflammation in the wound tissue 24h postwounding (Engeland. and Resilience: Can Accrued Wear and Tear be Slowed? 117 Figure 1. on the other hand.g. Salubrious health behaviours (e.. In addition. Watkins.. Taken together. in turn. Aging. displayed an enhanced induction of proinflammatory cytokines (Johnson et al. Stress.. wounding. 2003). Nguyen. 2002). Cacioppo.g.. Poor health behaviours (e. and resilience: The impact of stress on age-related physiological capacities (i. reflecting genetic and environmental influences. controllable versus uncontrollable) and coping responses (e. which contribute to differential exposure and differential reactivity to stressors. These influences are evident across the central nervous (e. but also fortify the body against future stress. The stress response. Long-Term Costs of Chronic Stress The adaptivity of responses to acute stress does not extend to chronic forms of stress. for example. acute stress can both prime and increase the effectiveness of the immune response against antigenic challenge and injury. 1997) and enhance recovery from bacterial challenge (Deak. Watkins.. over the short-term.e. resilience) is influenced by individual differences. these findings indicate that. 2000). & Marucha. The efficacy of sleep. influences the maintenance and enhancement of physiological reserves that are needed to withstand stress demands. aging. Recuperative processes are also important for resilience.

We turn to coping as a factor contributing to individual differences in physiological stress responses that influence resilience and health.g. however. Using this approach. it was found that SDR stress induces a strong HPA activation in the defeated animals (Padgett et al. 1998. and in stress-related syndromes such as vital exhaustion and depression (Bauer et al. O’Connor et al. Malkoff... and slowed healing of experimental cutaneous and mucosal wounds (Kiecolt-Glaser.g.).. The research reviewed above (Engeland et al. vasomotor) activation (Light. In human studies. Sheridan. sympathetic system. 2001). How can these outcome differences be explained? Certainly. Llabre. & Schneiderman. Marucha. 2000). & Sheridan. 1998. to explain diverse outcomes among individuals confronting comparable stressors. and simultaneously leads to glucocorticoid resistance in splenocytes that have been activated with LPS (Stark et al. & Sheridan. 2001). 2003).. Quan et al. Stress is Neither Good Nor Bad.118 Hawkley. genetic endowment contributes. protracted) stress involves a lasting dysregulation of the HPA axis. 1998). & Ritchey. LPS) or a mitogen (e. et al. Klein. McCalla. repeated and/or intense bouts of acute stress can push the organism beyond its ability to meet the challenges. Saab. animal and human research each suggest that chronic stress has long-term costs evident in down-regulated glucocorticoid sensitivity of immune cells that leave the organism at risk for inflammatory disease (e. Hinderliter.. 1998). & Glaser. with some individuals showing greater cardiac reactivity and others greater vasomotor reactivity to the same stressor (Kasprowicz. 1999. metabolic syndrome. whereas passive coping tasks tend to elicit alpha-adrenergic (e.. Pariante. & Favagehi. Thus. 1990. & Light. 2002). cold pressor). Next. Kiecolt-Glaser. Beta-adrenergically mediated increases in blood pressure that characterize an active coping response are adaptive in the sense that task-related demands are most efficiently achieved . studies have found a reduced glucocorticoid sensitivity of immune cells in spousal caregivers of dementia patients (Bauer et al. Consistent with the glucocorticoid sensitivity hypothesis.g. Although acute stress tends to elicit an adaptive physiological response. 2000). But Coping Can Make It So One of the helpful distinctions in research on coping is that of active versus passive coping. Manuck.. Marucha. excessive fighting re-establishes the social hierarchy. the pervasive and ongoing demands of chronic stress change the character of the physiological response in ways that contribute to diminished physiological resilience and poor health. In addition.g. in parents of children undergoing cancer treatment (Miller. stress appraisals. Studies in humans confirm and extend the results of animal experiments. and coping responses.. 2001.g. Summary The differential effects of short.g. and immune systems (Maier & Watkins. Cohen. 1990). This distinction between acute and chronic stress is insufficient. Wirtz et al. Malarkey.. glucocorticoid sensitivity is measured ex vivo.. & Krantz. and colleagues have demonstrated that active coping tasks tend to elicit beta-adrenergic (e. Girdler. Masi. Das. Marucha.. In this experimental model. McEwen. leading to increased mortality from experimental influenza infection and septic shock in mice (Padgett. Berntson. autonomic nervous (e. this time to illustrate the detrimental effects of chronic stress. Stark. mental arithmetic).. Miller. cardiac) activation and increased blood pressure. Marucha. 2000). Girdler. & Sherwood. Cacioppo et al. an aggressive intruder is introduced.e.. 1998.. and Cacioppo hippocampus.. PHA) in combination with varying concentrations of GCs (e. Turner. at which time. Chronic (i. In a series of studies. Sherwood.g. 1994. but individuals also differ in their social systems.. dexamethasone). 2000). & Sheridan. Engeland. Stark et al. Dolan. Active coping refers to the individual’s efforts to achieve actual or perceived control over the outcome of a stressful situation or task (e.g. We again focus on the immune system. 1996). These differences could have implications for physiological resilience and health. 1998. in press) and increased blood pressure.. & Pearce. 1995.. male mice are housed in groups of five until a stable hierarchy develops.. 2004) and other chronic diseases. whereby immune cells are incubated with bacterial endotoxin (e. reduced response to vaccination (Kiecolt-Glaser. whereas passive coping requires only that the individual endure the stress (e. the SDR-induced reduction in glucocorticoid sensitivity results in greater likelihood of hyperinflammation. 1997. Gravenstein. 2003. and the consequences include suppressed cellular immunity (Lupien & McEwen. Padgett. Light. However. & Hinderliter. Light. in preparation) indicates that proper HPA functioning largely prevents overactivation of the inflammatory cascade following acute stress (Nguyen et al. Recent studies have revealed that HPA dysregulation may also be marked by cellular resistance to the immunosuppressant effects of GCs on proinflammatory cytokine release (Avitsur. cardiovascular response differences have been found. 2003). Glaser. Mercado.g.. Sheridan. 1998.. This phenomenon has been well-demonstrated in animal studies that employ social disruption (SDR) as a stress model. 1998). Malarkey.and long-term stress outlined above illustrate the principle that stress is not inherently bad.

Serotonin also plays a prominent role in depression and anxiety (Graeff. Stress: Take a Bad Thing and Make It Better Although stress is not necessarily bad. unreasonable bosses. and in social behaviour (Insel & Winslow. if the individual faces a stressful situation over which he or she has some control (e. and immune activation can diminish health across time. produces its physiological benefits. Add to that the adverse physiological consequences of chronic stress. Sheridan. were the ventral medial prefrontal cortex (mPFCv). Aging.6 If an individual has no potential for control over the outcome of a stressful situation (e. On the other hand. and coping actively in response. in some cases. and a flood of serotonin is released that contributes to autonomic activation and failure to learn to escape in a new situation. Physiological activation in response to stressors is beneficial up to a point. The metabolic requirements posed by psychological stressors in today’s society (e. traffic congestion. that seeing a stressful situation as controllable. found that uncontrollability defines the default stress circuitry in the brain: A stressful circumstance elicits activation of the DRN neurons. Similarly. but these physiological changes can have long-term consequences in risk for disease (Cacioppo et al. Malarkey. GuimarÇes.Stress. 1998). but excessive autonomic. a brainstem nucleus that provides most of the serotonin input to cortical and limbic structures that play a role in regulating autonomic and neuroen6 Endler (1997) outlined a similar multidimensional model in which coping strategies interact with the type of stress to predict outcomes. 2005). an area of the brain implicated in executive function and affective processing. and the dorsal raphe nucleus (DRN).. unrelenting stressful situations. 1998). The foregoing evidence suggests that neither active nor passive coping is necessarily optimal. in some cases.. then active coping (arguing with the police about the validity of the charge) may elicit more physiological activation than is warranted by the type of situation. at least in part. 2003). personal affronts. facing a deadline for a manuscript). Amat et al. those who had experienced severe chronic stressors (mostly involving employment problems or interpersonal difficulties) were at significantly greater risk of developing the disease (Cohen et al. particularly in the context of chronic stress. and Resilience: Can Accrued Wear and Tear be Slowed? 119 by increasing cardiac output and blood flow. passive coping can be adaptive in situations in which the stressor must be endured and cannot be actively controlled.and avoidance-oriented coping. On the other hand. 2000). and the accompanying physiological activity could work to the detriment of physiological resilience and health.g. & Kiecolt-Glaser. Recent research has identified critical components of the central circuitry underlying responses to controllable versus uncontrollable stress (Amat et al. as well .. the chronic stress of caring for a spouse with dementia resulted in a significantly smaller antibody response to pneumococcal bacterial vaccine in caregivers than in controls or former caregivers (Glaser. Lundberg & Frankenhaeuser. Given that humans continually confront daily stressors and. 1998). For instance.g. 1996). MacCallum.g. from diminished autonomic and neuroendocrine activity subsequent to inhibition of the DRN. and it seems inevitable that health should decline over the years. although his focus was on task-oriented versus emotion. Bianchi. 1978. On the other hand. pressing deadlines. & Birkenhaeger. during controllable stressors. but the alpha-adrenergically mediated increases in blood pressure that characterize a passive coping response can have damage potential because increased vascular resistance and the structural vascular changes that ensue contribute to the development of essential hypertension (Staessen. the consequences could be maladaptive if the reduced autonomic activation is inadequate to endure and survive the uncontrollable stressor. there is empirical support for its adverse effects on physiological functioning. Passive coping in these circumstances would be less than optimal because the stressful situation would persist and fester. and physiological reactions in response to these events can substantially exceed metabolic requirements. when individuals inoculated with rhinovirus were subsequently monitored for development of a cold. in that coping strategies appear to interact with the nature of the stressor to influence outcomes. then active coping (setting aside time and actually writing the manuscript) is desirable because it increases the likelihood that the stress will be resolved.. perceived injustices) are often minimal.. Of course. Controllability has for some time been recognized as an important stress dimension to predict consequences of stress exposure (e. De Andrade. Maier & Watkins. Wang. thereby reducing autonomic activation and preserving escape learning. public-speaking engagements. 1995). The accrued wear-and-tear on the organism takes its physiological toll on resilience.. neuroendocrine.g. namely. & Deakin. This elegant study raises an interesting possibility for human research on stress and coping. if the stressor is perceived as controllable but is actually uncontrollable. docrine functioning. how is it that humans survive as long and. the mPFCv inhibits activation of the DRN. being caught by police for speeding). The two areas of the brain studied by Amat et al..

and suppressed immune function (Baum. cardiovascular disease. 2002a). and Cacioppo as they do? The answer to this question lies not only in the human body’s innate restorative processes. stress can activate maladaptive behaviours that reflect attempts to cope with negative emotional responses. Whether stress contributes to poor sleep quality or vice versa (or both) remains an important question for future research examining the health consequences of loneliness. Indeed. These effects mirror what is seen in normal aging. greater daytime dysfunction was reported by lonely than by nonlonely individuals. quantity of sleep did not differ. Thus. sleep. et al. if he/she is not getting sufficient nutrition and rest to allow her body to repair as a result of the catabolic costs of the practice . although a certain minimal quantity of each nutrient category is required. and increased sympathetic tonus. and well-being.. A weakened antigen is inserted to immunologically challenge the body to produce the antibodies needed to eradicate the pathogen and repair the body. sleep. Masi. and benefit from. these findings support the notion that sleep may contribute to poorer health among lonely than nonlonely individuals.. moderate exercise..). mild bout of the illness. however. as indicated by reports of greater daytime dysfunction (Cacioppo. Office of Disease Prevention and Health Promotion. is not the only means to undo the ravages of daily life. individuals differ in the nutritional complexes in which these nutrients are consumed. On the other hand. if appropriate repair and maintenance processes also unfold. Indeed. fruits. Hawkley. and these behaviours may foster accidents. and humoral immunity are illustrative of the empowering aspects of the restorative powers of the body in response to stress. leading the authors to conclude that sleep debt may increase the severity of age-related chronic health disorders. 2005). As noted above. physiological functioning. for example. Moreover.that is. To the extent differences in sleep quality contribute to differences in physiological functioning. despite equivalent hours of nightly sleep (Cacioppo et al. The same performance expectations. In our study of young adults differing in degree of loneliness. Learning. Conversely. muscular development. Crawford. 2005). others by behaviours that enhance the organism’s capacity to engage in. Cohen. and vegetables). 1994. 7 If the pianist noted above overtrains . or in some cases reversed. and Van Cauter (1999) found that a sample of 11 young men restricted to four hours sleep per night for six nights exhibited lowered glucose tolerance.. arm.7 Sleep has taken on increasing importance as a mechanism by which some of the detrimental effects of stress are undone. not eating or sleeping properly. 2000. physical activity. A student pianist who makes the transition from graduate school to the realm of professional performances may initially be overwhelmed and fatigued by the amount of practice needed to accommodate scheduled performance events.g. Health behaviours are known to influence physiological robustness. the salubrious consequences afforded by health behaviours may also be distinguished along these dimensions.g. and not exercising. at least some long-term costs of stress may be minimized. 2003) and the United States (e. tobacco) being examples of lifestyle factors currently being addressed by national health oversight committees in Canada (Minister of Public Works and Government Services Canada. 1991). Bernstson. may engage in unhealthy practices such as smoking. become less and less demanding as the pianist’s back. Berntson. and substance use (e. For instance.g.. An individual who is vaccinated may suffer a brief. 53-78 yrs. In an illustrative study. some individuals do not appear to derive equivalent benefits. but given the same amount of sleep. There is no question that adequate sleep is necessary to optimize physiological functioning. et al. just as individual differences in sleep can be distinguished along the orthogonal dimensions of quantity and quality. 2002. Persons experiencing psychological stress. Marucha. 2002) among lonely compared to nonlonely individuals. but subsequently have an effective immune response in the event of exposure to a strong dose of the antigen. fats. if deprived of adequate opportunities to rebuild physiological resources. Spiegel. elevated evening cortisol concentrations. but also in individual differences in the efficacy of these processes. health. Hawkley. and hand muscles have time to repair and grow following each practice. with dietary choices (e. and deficits in sleep quantity or quality have stunning consequences for learning. alcohol. a balanced diet. Engeland. and in . too. resilience diminishes and risk of disease increases.then the practice will not provide the same physiological growth or resilience.120 Hawkley. In a small convenience sample of older adults (n = 25. Some of these differences may be determined by inherited physiological competencies. although potent in its salubrious effects if sufficient in quantity and quality. Leproult. These results have been replicated in a population-based sample of 229 urban adults enrolled in the Chicago Loneliness Study (Hawkley & Cacioppo.. and rich social connections can have beneficial and rejuvenating effects. 2002) and more frequent micro-awakenings (Cacioppo. innate restorative processes. vaccinations work in this way. but the quality of sleep did.

under review). gender. individuals encounter numerous daily stressors as well as chronic stressors and lifealtering events. consistent with the notion that stress contributes to diminished resilience.. & Hawkley. an experience sampling component of the study showed that lonely and nonlonely young adults did not differ in the frequency or type of daily activities in which they engaged during everyday life. were independent of perceived stress. and less potent “uplifts” than nonlonely individuals (Cacioppo et al. Ability to compensate. social support. income. lonely individuals are vulnerable to a more rapid age-related decrease in physiological resilience. Not only does stress have a number of dimensions by which resilience is affected. Waite. Hughes. Social support has also been found to slow age-related SBP increases in chronically stressed individuals (Uchino. yet lonely individuals rated their daily circumstances as more stressful.). exposure. depressed affect. and the efficacy of restorative processes that replenish physiological reserves and fortify against future stress (Cacioppo. Correspondingly. but also in the frequency with which they are exposed to stress. and between loneliness and number of chronic health conditions and self-rated health (Cacioppo. because individuals differ not only in their endowed genetic substrate. age is an imperfect measure of total wear-and-tear on the organism. in turn. under review).. Schumm. & Garvey. Notably.e. physiologic decline. this rate of decline is con- . In contrast to the young adults. Concluding Remarks Over four decades ago. Whether increased exposure and/or reactivity to stress contribute prospectively to diminished resilience and increased health risk among lonely individuals is a topic of study in longitudinal research currently underway. Mathematical models and observational data showed that. and themselves as less capable of meeting those demands than did nonlonely individuals (Hawkley. the nature and intensity of their psychological and physiological reactions to stress. however. but stress dimensions may be differentially affected over the life course. and mortality. The cumulative load of these stressors differs across individuals. threatening.e.. under preparation). In our Chicago Loneliness Study. hostility. & Cacioppo. the human organism has an innate capacity to heal itself. & Cacioppo. an organism dies when stress magnitude exceeds capacity to compensate physiologically. & Berntson. 2003). education) (Hawkley. 2004). According to their theory. more serious hassles..Stress. & Cacioppo.. however. restoration). in which the authors presented a stochastic model to explain associations between aging.9 to 1. perceived stress was insufficient to explain loneliness differences in measures of health and physiology. the study of nutrigenomics. Barnes.g. general and life event-related perceptions of stress were higher among lonely than nonlonely individuals. Hawkley.85 mm Hg per standard deviation of loneliness for each additional year of age. 1992). stress perceptions were unrelated to measures of physiological functioning in these young adults. Berntson. Moreover. lonely and nonlonely college students did not differ in the number of major life events or traumas they reported. suggesting that loneliness accelerates typical age-related reductions in physiological resilience (Hawkley et al. Kiecolt-Glaser. and Resilience: Can Accrued Wear and Tear be Slowed? 121 their responses to these nutrients (e. as they were in young adults. the typical age-related decline in physiological resilience is not uniform across individuals but is influenced by individual differences in any or all of these dimensions of stress (i. associations between loneliness and SBP (Hawkley et al.). psychological surveys indicated that lonely individuals perceived higher levels of stress. 2000). As such. the journal Science published a “General Theory of Mortality and Aging” by Strehler and Mildvan (1960). Specifically.4%per year. Berry. Masi. in our study of college undergraduates. An important followup question to these cross-sectional results is whether loneliness is causal or consequential relative to increased stress exposure and (hyper)reactivity. loneliness interacted with age such that SBP was higher by 0. resilience) of 0. To the extent loneliness adds to the total stress load by one or more stress mechanisms. under review). and individual differences in the efficacy of these restorative processes are important to understanding the conditions under which physiological resilience is maintained or enhanced. Cao. & Cacioppo. reactivity. Allison. in older adults we found that perceived stress was associated with higher levels of systolic blood pressure (SBP). but as noted above. Nevertheless. 2003). In sum. Aging. Relevance for Aging Across the lifespan. ethnicity. and demanding. lonely older adults also reported a greater number of major life events in the past year than did their nonlonely counterparts (Hawkley. For instance. was postulated to be determined by initial physiologic reserves and by a linear decrease in physiologic reserves (i. However. we found that the effects of loneliness on SBP increases were independent of social support (Hawkley et al. and demographic characteristics. Burleson. at the population level. Indeed. In addition. independently of demographic characteristics (age.

Marucha. Medial prefrontal cortex determines how stressor controllability affects behaviour and dorsal raphe nucleus. Hawkley or John T. biological.. is to be able to derive rewards from these stressful experiences. S. Nutrition. Stark. Engeland. A. Weiss (Eds. and in truth. Personal growth and mastery. E. Zeus combined these gifts with the “blessing” of perpetual sleep. Berntson. J. thereby maintaining a resilient physiology and helping to ensure a long and healthful life. Reluctantly. Bauer. to age well.. J. 39. From homeosta- . P. K. L. Perks. although aging is inevitable. (1996). Bland.. Watkins. 940 E. The authors proposed that these differences can be attributed to. L. A. F. L. S. To live is to age. ex.. and Cacioppo stant across the decades after age 30. 28. Department of Psychology. In his recounting of this myth. she pleaded with Zeus to grant Endymion eternal life. T. painful. G. USA (E-mail: hawkley@uchicago. Bauer. fell in love with a handsome shepherd boy. PO1 AG18911. (2000). Medicinal Research Reviews. and environmental interactions in disease processes. Psychoneuroendocrinology. she also asked Zeus to grant him eternal youth. (2004). 84-92.. Cacioppo. This research was supported by the National Institute of Aging Grant No. Ces différences comprennent notamment la fréquence d’exposition au stress. and in part to efficient restorative processes that rebuild physiological reserves. These capacities are attributable in part to lifestyle choices that limit exposure to stress. & S. engaging human strengths in the face of contemporary stressors can considerably slow the accrual of bodily wear and tear.. Le présent article décrit une conceptualisation du stress qui reconnaît la susceptibilité et la résistance de l’humain aux stress de la vie et examine l’incidence des fragilités et des forces de l’humain sur la résilience physiologique et la santé au cours du processus de vieillissement. 103. & Cacioppo. Vedhara. Much to Selene’s dismay. Résumé L’incidence du stress sur les capacités physiologiques liées à l’âge (p. (2003). William Thomas (2004) concludes. When Selene. IL 60637. Wilcock. The multifaceted conceptualization of stress we have described above clearly has implications for the aging process. J. V. la nature et l’intensité des réactions psychologiques et physiologiques au stress et l’efficacité des processus réparateurs qui refont les réserves physiologiques et fortifient contre le stress futur (Cacioppo.. indeed. 6 February 2005. “Aging is part of what makes us human. and by a grant from the John Templeton Foundation. la résilience) est influencée non seulement par le substrat génétique légué. Barton. S. Baum. Avitsur. D. Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids. Strehler and Mildvan (1960) acknowledged that there is considerable variability in initial physiologic reserves and in rate of physiologic decline. It is perhaps appropriate to recall a Greek myth to illustrate this point. Improvement in any of these domains would be expected to have an impact on health and resilience. K. and then. Papadopoulos.. 49-65. The adage that it is better to have loved and lost than never to have loved at all reminds us that there are worse things in life than encountering stressors. Endymion never died. however. Washington. Perks. 1. 247-257. 1-7. & Berntson.. M.. humans have sometimes astonishing capacities to minimize or contain the long-term costs of stress. Zeus granted Selene’s request. To live long is to age much” (p.. G.. & Garvey. (1994). W. P.. (2000). et al. & Sheridan. At the individual level. 2003). Journal of Neuroimmunology. Baratta.122 Hawkley. & Maier.. N. 20. E. Advance Online Publication. The biological effects of interleukin 6. T. To live well. University of Chicago. G. and discouraging events and situations. Barnes. 16. S. Masi. S. Endymion.. Matthews. Social stress induces glucocorticoid resistance in subordinate animals. to make sure he would not succumb to eternal aging. Altered glucocorticoid immunoregulation in treatment resistant depression. E. Paul. Nature Neuroscience.. M. (2005). Hawkley. never lived either. Berntson. Although limited by genetically endowed physiology.. however. 87-109. Thus. New research frontiers in behavioural medicine: Proceedings of the national conference. References Allison. In S.edu). Foreword from the editors. T. Poon. 33). Checkley. S. J. mais aussi par les différences individuelles. meaningful close relationships.edu or cacioppo@uchicago. B. R. It has been the goal of the current paper to present stressrelated factors that contribute to these individual differences. M. Amat. & Shanks. Hormones & Behaviour. and opportunities to nurture the next generation are just some of the rewards experienced by individuals with a capacity to put their stressful experiences to good use. Behavioural. To live is also to experience difficult. L. B. The model outlined here suggests that human biology has evolved accordingly. DC: NIH Publications. 57th St.. Chicago. Blumenthal. R. in part to adaptive appraisal and coping strategies that reduce the impact of stress exposure.. K.).. a function of the interaction of genetic and environmental factors. (2001). never aged. Address correspondence to Louise C. Lightman. and modeled as. F.. Lightman.. L. the Moon.

S. (year). Biochemistry. 5607-5610. K. & Kiecolt-Glaser. 109-121. L. Z.. J. Oxford handbook of health psychology. Tenenbaum. K. A. 12. Malarkey. In G.. H. et al. M. Glaser. 6. Psychosomatic Medicine.. & Marucha. A. homeostasis. J. Psychosomatic Medicine. (Eds. (1988). E. Hillsdale. Plotnikoff et al. B. KiecoltGlaser.. Sgoutas-Emch. J. B. G. R.). Cacioppo. Singh. T. Blackburn. A. 359. Hawkley. S.Stress... (year). Role of 5-HT in stress. T.). and Behaviour. 101. & Glaser. (2004). B.. A. Frank. G. J. F.. T. R. Morrow. E. J. Frenck.. & Cacioppo. Cawthon. J. Ernst.). Hawkley. G. Aging. Karraker (Eds. et al.. E. K. Uchino. Dhabhar. 17312-17315. J. L. A. Life-span developmental psychology: Perspectives on stress and coping.. Malarkey. P.. Abouhamze. et al. 123137. B.. Adler. P. Acute stress may facilitate recovery from a subcutaneous bacterial challenge. Berntson. Brouilette. Stickgold. L. T. Burleson.. 64. Bosch.. W. M. White cell telomere length and risk of premature myocardial infarction. K.. 13. Annals of Behavioural Medicine. S.. S. W. G. T. Cohen. Neuroscience & Biobehavioural Reviews. Engeland. C. T. Hughes. Health Psychology. Deak. J. Arteriosclerosis. K. 393-395. Proceedings of the National Academy of Sciences. and health: Balancing demands of the internal and external milieu.. 129-141. M. & Kerber. Cacioppo. Thrombosis. R. B. The anatomy of loneliness. K.. et al... (2003). C.. Lonely days invade the nights: Potential social modulation of sleep efficiency. F. S. W. L. J. & K. S. anxiety. (2003). Cacioppo. . (2000). 459481). Heterogeneity in neuroendocrine and immune responses to brief psychological stressors as a function of autonomic cardiac activation.T. Canadian Psychology. Sheridan. New York: Oxford University Press. Hawkley. K. & Deakin. C.. L. Goodall. T. A. Ischemic preconditioning: Nearly two decades of research. C. N. G. D. Fleshner. FL: CRC Press. Sivatchenko... health behaviours and infectious disease. Telomeres and telomerase. Rubenfire. De Andrade. J. S. (1991). M... anxiety and coping: The multidimensional interaction model. Eisen. Philosophical Transactions of the Royal Society of London.. 23. L. et al.... neuroendocrine. Crawford.. W. 344-354. & Hawkley.. (2003). dysphoria.. Freimark. G. B. Graeff. J. & Berntson. D. A. 12. C. Social supports and physical health: Symptoms. A. J. Doyle. Blackburn. The brain. H. Psychological Science. J. Ernst. E. Current Directions in Psychological Science.. Biological basis of the behaviour of sick animals. Jr.. U. 214-23. In H. M. Fisman. 17. Meriwether.. (in press). Fleshner.. Thompson. 66-73. F. & Berntson. Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. (1995). 664673.. 804-807. 57. Gibbs. A. J. Proceedings of the National Academy of Sciences.. H. J. Kiecolt-Glaser. and depression. L. J. Berntson. et al. G.. 172. Skoner. Stress hormones modulate the healing rates of oral wounds. Stress. Nguyen. NJ: Erlbaum.. 840.. K. C.. T. J.. G. Metabolic syndrome X: An inflammatory condition? Current Hypertension Reports. & Maier. J. G. McKechnie. (1998). Deak. C. T.. G. The rate of telomere sequence loss in human leukocytes varies with age. R. (1998). (1997).. W. R. L. S. 136-153. J. N. Kiecolt-Glaser. 407-417. H. W. T. (1996). 154-164. & Samani. J. self-rated health.. Evidence that brief stress may induce the acute phase response in rats.. Manuscript in preparation. R. Types of stressors that increase susceptibility to the common cold in healthy adults. Cacioppo. R1998-R2004. Malarkey. (Eds. Moldawer. M. 22. Engeland. The Lancet. R. J. E. Spencer. (2002). (2004). Cohen Silver (Eds. M. Burleson. L. M.. R. N.. L.. G. Psychosomatic Medicine. S. (Manuscript under review) Cacioppo. Neuroimmunomodulation. J. 54. H.. Boca Raton..).. D. 273... Kowalewski. & Shannon. E. J. Hart.. 38-387. R. Ernst. F. F. 95. Berntson & J. Loneliness. P. C. C. Cacioppo... G. (1999). Accelerated telomere shortening in response to life stress.. L. Watkins. Poehlmann. (1998). M. J. Poehlmann. MacCallum. (2004).. M. In A. J. A comprehensive review. M... L. O’Brien. L. R. Cohen... Friedman & R. Hawkley. 71-74. 201-210. W. M.. In N. E. T. Cummings. R... 6. J. Handbook of psychophysiology (pp. Cytokines: Stress and immunity (2nd ed). K. E.. T. S. T. B. Burleson. C. Cacioppo. Pharmacology. Malarkey. 62. J. G. E.. R. M.. and immune responses to psychological stress: The reactivity hypothesis.. Chan. C. (in press). 361. Greene. K. R. H. N. L. T. J.. T. M. Loneliness and health: Potential mechanisms. stress and immunity: A role for cytokines. F.. et al... J. (1997). S... Smith. B. J.. S. W. 140-148. Sheridan.. J. R. Rabin. R. Loneliness and depressive symptoms. GuimarÇes.. Das. 38. Atherosclerosis. (2000). M. M.. E. and Resilience: Can Accrued Wear and Tear be Slowed? 123 sis to allodynamic regulation. & Gwaltney. Waite. N... Berntson. Hawkley. B. Cacioppo. Annals of the New York Academy of Sciences. Autonomic. and chronic health conditions: Evidence from two population-based studies. & Blackburn. T. Endler. L. Sheridan. F.. and Vascular Biology. H. 842846.. Marucha. Lin.. (2003). Association between telomere length in blood and mortality in people aged 60 years or older. G. G.. American Journal of Physiology. Cacioppo.. Epel. L. (2002). Cacioppo. Autonomic and neuroendocrine responses to mild psychological stressors: Effects of chronic stress on older women.

S. O’Connor. The neurobiology of stress: From serendipity to clinical relevance. J. ON: Health Canada. (2005. Girdler. G. M.. L. The multifarious nature of ubiquitous stress: Chicago Health. F. S. Malkoff... Cohen. Chronic stress alters the immune response to influenza virus vaccine in older adults. T. D. A. R. (in press). Hammack.. J. T. 207-219. (1998). (1998). Johnson. 27. 193-201. Berntson. (1998). & Cacioppo. Journal of Personality & Social Psychology.. L. E. 44. 105. & Frankenhaeuser. U. 461. (1990). 24. D. 531-41. B. B. The Lancet.. J. 28.. K. Lupien. Manuck. Hawkley. K. K. Pariante. Will. pituitary. LeMay. D.. K. L. M. Kasprowicz. K.. & Cacioppo.. & Watkins. Hawkley.. Slowing of wound healing by psychological stress. L. M. Ottawa. J. Kiecolt-Glaser. & Glaser. and cognition. Vancouver. Psychosomatic Medicine. Masi. S. Health Psychology. B..124 Hawkley. R. Serotonin and neuropeptides in affiliative behaviour. depressed affect. O’Connor. S. 69-85. C. Light. & McEwen. J. P. R. K.. 362-365. 481-500. Mucosal wound healing is impaired by examination stress. P. C. (2002). 229-246.. ON: Public Health Canada. F.. G. McEwen. 957-961.. Kiecolt-Glaser J. J. Anderson. Prior stressor exposure sensitizes LPS-induced cytokine production. Cardiovascular and endocrine functioning in an aging population: The effects of loneliness... S. Burleson. Brooks. Loneliness in everyday life: Cardiovascular activity. 284. Minister of Public Works and Government Services Canada (2003).. M. J. H39-429/1998-1E). Comparison of cardiac versus vascular reactors and ethnic groups in plasma epinephrine and norepinephrine responses to stress. Brain. M.. J. M. Expanding the boundaries of health: Bio-behavioural-social perspectives. Hansen. and hostility. S. C.. (2003). & Cacioppo. 859. Hansen. Saab. 17. Individual differences in behaviourally evoked cardiovascular response: Temporal stability and hemodynamic patterning.. L. J. M. C. G. J. M. A. In N. Physiology & Behaviour. J. et al. (1978). Miller. J. Effects of cytokines on glucocorticoid receptor expression and function.. & Maier. Proceedings of the National Academy of Sciences: United States of America.. T. . B. Light. G. Advances in Experimental Medicine & Biology. Marucha. Maier.. & Immunity.). R.. (in press). T. D. & Favagehi. Manuscript under review. 47. D. C. R. March). Sleep quality as a function of psychosocial risk factors in a populationbased sample of older adults: Loneliness as a proximal and distal predictor. 85. T. Effects of prior stress on LPS-induced cytokine and sickness responses. Nguyen. Glucocorticoid resistance and relevance to depression. M. L.. J. A. & Schneiderman. J.. L. H39-252/1992E).. Canada’s physical activity guide to healthy active living (Cat. No. A.. & Maier. T. A. Genetic and behavioural factors in combination influence risk of hypertensive heart disease. & Sherwood. & Pearce. P. S. S. Ottawa. & P. & Kluger. D. R.. Watkins. et al. N. Watkins. R. mood. S.. S. Psychophysiology.. Stark. 5. Masi. American Journal of Physiology. No. 1-27. J.. Kessel. Gravenstein.. Berry. (2003).. Cytokines for psychologists: Implications of bidirectional immune-to-brain communication for understanding behaviour.. B. S. (1990). S. C. A.. S. 172-189. N. R. O’Connor.. Biological Psychology. 886. perceived stress. L. Timecourse and corticosterone sensitivity of the brain.. K. K. social support. W. Behaviour. Malarkey. S. Klein. pain. Malarkey. F. Marucha. The effects of psychological stress on plasma interleukin-6 activity in rats. and serum interleukin-1beta protein response to acute stress. Glaser.. 3043-3047.. and Cacioppo Hawkley. Turner. L. Fleshner. M.. Engeland. T. Spencer. P. (in press). Rosenfield (Eds. 605-619. 16.. 83-107. Miller. B. L. M. J. Maier. Watkins. H. International Journal of Behavioural Medicine.. & Krantz.. Mercado. T. 11941196.. Aging and Social Relations Study (CHASRS). 107-116. & Ritchey. 3. F. Deak. S. (1997). Berntson... A. K. Psychoneuroendocrinology. (2002). Llabre. Brain Research.. A. and cognition. Cao. (1995). M. Deak. R... New York: Oxford University Press. International Journal of Behavioural Medicine. BC. B.. Manuscript in preparation.. T. G. L. C... 6. Chronic psychological stress and the regulation of pro-inflammatory cytokines: A glucocorticoid-resistance model. M. Behaviour & Immunity. Girdler. W. A. M. The acute effects of corticosteroids on cognition: Integration of animal and human model studies. (2003). 461-476. Poster presented at the annual meeting of the American Psychosomatic Society. (2003). J... Johnson. C. (1994). Biological Psychiatry. Psychophysiological reactions to noise as modified by personal control over noise intensity. L. (1999). Bi-directional immune-brain communication: Implications for understanding stress.. Vander. Inescapable shock induces resistance to the effects of dexamethasone. Classification of individual differences in cardiovascular responsivity: The contribution of reactor type controlling for race and gender. R. Psychological Review.. Kiecolt-Glaser. K. (2000). (2000). 346. & Hinderliter. 105-120. Lundberg. A. H. S. Brain Research Reviews. Marucha. & Cacioppo. Canada’s food guide to healthy eating (Cat. L... B. T. McCalla. psychosocial context. Insel. & Winslow. 21. Schumm. 93. T. and health behaviours. A. K. 51-59. Minister of Public Works and Government Services Canada (2002). (1996). M. S. Brain. L. R422-R432. Brain Research.. 213-229. K. B. & Sheridan. E.. Hawkley. Hunsaker. Hinderliter. 60. Johnson. B. (1998). J. F. D.

Leproult. 63.... Quan. Essential hypertension. Bianchi. (1998).. et al. L. Weng. 001-000-04719-1). 18.Regulatory Integrative & Comparative Physiology. M.. W. J. Dinarello. R... Acta Physiologica Scandanavica. 14-21. Taylor.. Behaviour and Immunity. Avitsur. 43-54.. & Sheridan. Avitsur. J. Beck. 107-116. 27.. June. and aging. 280. D. Dolan. von Kanel. D. 672-8. and Resilience: Can Accrued Wear and Tear be Slowed? 125 Office of Disease Prevention and Health Promotion (2000). General theory of mortality and aging. DC: U. Social stress and the reactivation of latent herpes simplex virus type 1. H. E. J. A. Lancet. Ehlert. Berntson. T. & Light. F.. (2001). B. Lancet. G. A. Shah. Palmer. Journal of Personality and Social Psychology. J. J. R. (1998). N. J. Journal of Neuroimmunology. American Journal of Physiology .. R.. (1998). (1990).. 017-001-005509). A. J. 839-846. L.. C. Social stress induces glucocorticoid resistance in macrophages... 12. 1435-1439. Reduced glucocorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. R1799-R1805. Tales of tails: Regulation of telomere length and telomerase activity during lymphocyte development. L. Brain. B. J. (2001). Washington.. W. P. K.Stress.. A. P.. F.. (1960). 115. Impact of a sleep debt on metabolic and endocrine function. 65.. 95. F. 132. G. 160. differentiation. Healthy people 2010 (Stock No. . U. M. 16291641. IL-6 and APPs: Anti-inflammatory and immunosuppressive mediators..... Psychosomatic Medicine.. Frey. Caligiuri. & Birkenhaeger. Dorne. Psychophysiology. Sheridan. (1997). 7231-7235. MA: VanderWyk & Burnham. Sheridan. C. C. Government Printing Office. & Mildvan. R. R. Spiegel. J. Padgett. J. A.. Uchino. Hemodynamics of blood pressure responses during active and passive coping. & Hodes. A. J. Lane. Thomas. J. L. R. Age-related changes in cardiovascular response as a function of a chronic stressor and social support.S. Schnorpfeil. H. H. K... (2003). (1997). 178. Candelora. T. He. G. M. H. & Glaser. J.. A. Proceedings of the National Academy of Sciences of the United States of America. D. & Starnes. & Fischer. J. Padgett. & Van Cauter. & Sheridan. P. Age. Science. Acton. A. Behaviour and Immunity. Staessen. (2004). Campbell. What are old people for? How elders will save the world. 12. K.. F. S. Office of Disease Prevention and Health Promotion (2005). J. Aging. Washington. Social stress increases the susceptibility to endotoxic shock. L. R. 361. 428-432. Dietary guidelines for americans. E.. Brain. Government Printing Office.. 1-6. H... B. cell signaling and cardioprotection. Strehler. Padgett. K... (1999). Immunology Today. W. 656-668. (2003).. DC: U. D. F. 64-73. Sherwood. K.S. Stark. N.. Kiecolt-Glaser. activation. 354. Immunological Reviews. Stark. J. P. & Mier. N. (2003). 2005 (Stock No. 36-45. Stress-induced modulation of antiviral immunity. L. C. Tilg. Levine. Marucha. & Cacioppo. Wirtz.. Restraint stress slows cutaneous wound healing in mice. C. (1992). H. Wang. P.