Does cellular aging relate to patterns of allostasis?: An e`xamination of basal and stress reactive HPA axis activity and telomere length
Highlights
► Allostatic load theory provides a framework for how psychological stress gets under the skin to affect health. ► Telomere length is a marker and mediator of cellular aging. ► We found that HPA axis parameters indicative of allostatic load were related to shorter telomere length.
Introduction
How does psychological stress “get under the skin” to cause deleterious health outcomes? McEwen and colleagues have put forth a helpful model describing how the wear-and-tear of repeated physiological responses to psychological stress that are part of allostasis, over time, lead to allostatic load (damage due to these fluctuations) and eventually poor health outcomes. Much population and experimental data support this model [1], [2], and it is relatively well established that chronic psychological stress is harmful to health. Stress has been linked longitudinally to disease states such as metabolic syndrome, cardiovascular disease, diabetes, and other diseases of aging [[3], [4], [5]]. These general and pervasive effects of stress may be linked to changes proximal to the stress response, such as changes in regulation of the HPA axis, but also may have common cellular mechanisms. Telomeres may be one of the common cellular mechanisms linking chronic stress to diseases of aging. Telomeres are DNA–protein complexes that protect chromosomal DNA from damage. As mitotic cells divide, telomeres get shorter, leaving the cell vulnerable to genomic instability, end-to-end chromosome fusion, less efficient mitosis, and loss of ability for cell replenishment and thus tissue replenishment [6], [7]. Even non-mitotic cells may develop shortened telomeres when chronically exposed to oxidative stress [8]. When telomeres shorten to a certain point, cells undergo senescence. Telomere shortening, therefore, represents both a marker and mechanism of biological aging [9], as the progression toward senescence can be monitored by telomere shortness and telomere dysfunction activates p53-mediated cellular damage [10].
Chronic caregiving stress has been related to shorter telomere length in both young women [11] and in older men and women [12]. Similar findings have emerged in experimental models of stress in mice [13]. Thus, telomere shortening may be one important pathway by which stress gets under the skin to promote early aging. Shorter telomere length has been related to conditions of chronic adversity, such as longer working hours [14], being single [15], lower socioeconomic status [16], major depression [17] and duration of depression [18], and childhood trauma [19], [20].
Given that telomere length is associated with a variety of stressor exposures, here we conceptualize telomere length as a potential molecular-level measure of allostatic load. Allostatic load incorporates dysregulation across multiple systems and telomere length may provide an index of cumulative inputs from multiple regulatory systems. Shorter telomere length is associated with worse function across multiple regulatory systems, including greater inflammation, oxidative stress, and insulin resistance [[21], [22], [23]]. Moreover, the cumulative inflammatory load of being high on both interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was related to shorter telomere length than being high on just one individually [21]. For these reasons we conceptualize telomere length as a potential summary measure of total cumulative biochemical stressor exposures [24]—in a sense a molecular measure of allostatic load.
Psychological stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, and the end product, cortisol, can be used as one index of stress reactivity. In vitro studies have demonstrated that the application of high doses of hydrocortisone to lymphocytes lowers telomerase [25], the enzyme primarily responsible for telomere maintenance. Telomerase elongates telomeric DNA to counteract shortening of telomeres and thus protects them [26]. The allostatic load model predicts that multiple patterns of altered responses to stress (strained allostasis) can contribute to allostatic load. Given the consistent associations of stress with telomere shortness, it follows that certain stress-related patterns of allostasis may also lead to telomere shortening. Relevant here, an individual might: (1) experience exaggerated responses to repeated “hits” of acute stress and therefore have excessive exposure to physiological stress mediators; or (2) have a dysregulated diurnal rhythm of stress mediators, in particular flat slope or high evening levels of cortisol.
In the current study, we tested whether patterns of HPA axis dysregulation that are hypothesized to contribute significantly to development of allostatic load are associated with immune cell aging as measured by telomere shortness. We assessed the magnitude of diurnal cortisol slope as well as several other patterns that may indicate altered allostasis in the form of exaggerated reactivity or slow recovery from daily stress arousal. We exposed participants to an acute psychological stressor in the laboratory and measured their salivary cortisol response. Exaggerated response may indicate greater stress responding to the minor hassles of daily life. We also measured nocturnal cortisol output to assess basal activity during the quiescent period of the diurnal rhythm. We predicted that greater reactivity to acute psychological stress and signs of diurnal dysregulation such as a flatter rhythm or greater nocturnal output of cortisol would be associated with shorter telomere length.
Section snippets
Participants
To draw from a population experiencing a wide range of chronic psychological stress, the study sample was drawn from a community sample and comprised 14 women caring for a partner with dementia and 9 non-caregiving women of similar age and BMI. Caregivers were recruited via flyers and ads in the community, from the University of California, San Francisco (UCSF) Memory and Aging Clinic, and from community organizations for dementia. Their matched non-caregivers were recruited through flyers and
Discussion
The cost of repeated stress exposure on physiology takes many forms of allostatic load, and telomere length has recently been proposed as a measure regulated in part by cumulative exposure to stress, and thus a potential marker of allostatic load [33]. Here, we tested whether PBMC telomere length was related first to aspects of HPA axis regulation, including greater cortisol reactivity to a novel standardized acute stressor, and second to a number of measures indicative of HPA axis function. As
Conflict of interest
Dr. E Epel, J. Lin, and E. Blackburn are co-founders in Telome Health, Inc, a telomere measurement company.
Acknowledgements
This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131, NIMH K08 MH64110-01A1 to E. Epel. A. J. Tomiyama was supported by the Robert Wood Johnson Foundation Health and Society Scholars Program.
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