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 hypothesized, shorter telomere length was related to greater cortisol secretion to the acute stressor, to greater overnight cortisol secretion, and to flatter cortisol slopes throughout the day. These findings are in accord with the in vitro
] showing that high doses of hydrocortisone exposure decrease activity of telomerase in PBMCs. We did not find associations between telomere length and total daytime salivary cortisol secretion or the cortisol awakening response in this sample.
Greater cortisol reactivity to an acute lab stressor was associated with shorter telomere length, which is important for several reasons. It indirectly provides support for laboratory-based cortisol reactivity to serve as a test of the “repeated hits” pattern of allostatic load, in that greater reactivity to stressful stimuli in the lab might indicate latent tendency to overreact to other mild stressors naturalistically. This finding also demonstrates that telomere length is associated with stress reactivity specifically, not just basal output of cortisol. So far, telomere length has been related to higher overnight cortisol and catecholamines [34
]. We note that Parks and colleagues did not observe a relation between telomere length and nocturnal cortisol [35
], which may have been due to the different cell types studied (all leukocytes versus PBMCs).
We also found that nocturnal and diurnal patterning of cortisol was related to telomere length, supporting the idea from the allostatic load model that dysregulated diurnal rhythms of cortisol contribute to poor health, or are at least associated with poor health. Specifically, we found a flatter diurnal cortisol slope and greater overnight output of cortisol were related to shorter telomere length. Flattened slopes have previously been linked to chronic and acute psychological stress [36
], cardiovascular disease outcomes [37
], mortality from breast cancer [38
], and both all-cause and cardiovascular mortality [39
]. Our study suggests that the flattened diurnal cortisol rhythm may also be related to accelerated cellular aging.
Urinary cortisol provides an integrated measure of cortisol during sleeping hours—usually difficult to measure using other techniques [40
]. Overnight cortisol, in contrast to diurnal cortisol, tends to be a measure of how well one’s system is able to regulate and recover from demands of the day and consolidate immune cell memory function [41
]. In normal function, limbic-hippocampal and other neural networks inhibit adrenocorticotropin and adrenocortical release of cortisol nocturnally, particularly during early sleep [41
]. After acute stress and chronic stress [41
], as well as in Cushing’s disease and in older humans [42
], a lack of inhibition of cortisol during sleep is observed. Our findings suggest that in a healthy sample, high nocturnal adrenocortical activity is associated with and perhaps may contribute to an accelerated rate of immune cell aging.
Telomere length was not related to all measures of cortisol secretion. Although telomere length was related to overnight cortisol secretion, it was not significantly related to total secretion throughout waking hours. This may be due to the relatively few samples that were collected during the day, generating greater variability in the diurnal cortisol AUC and missing most of daytime arousal. Unlike our urinary cortisol measure, which directly measured the total free cortisol secretion during the entire nocturnal period, diurnal cortisol was derived from only three time points using the AUC formula. Likewise, telomere length was not significantly related to the CAR. This again may have also been due to the relatively few samples collected to measure the awakening response (two samples when three or more are preferable). The different parameters of cortisol secretion were generally unrelated to one another in this study, and are thought to interrogate different aspects of HPA function [43
]. For example, the CAR specifically is considered to be a discrete component of the circadian rhythm of cortisol, regulated by its own psychological processes and neural networks [40
Here we focused on PBMCs in order to extend Choi et al.’s finding [25
] on cortisol exposure and PBMCs in vitro. However, we also examined relations with whole blood telomere length (data not shown), which is comprised mostly of the short-lived granulocytes. We did not see relations across any HPA axis measures with whole blood, and it is possible this is because the cells are not exposed to blood cortisol as much as the more long-lived circulating PBMCs, which play a very active role in the early acute stress response. Choi et al. found the strongest cortisol effects on telomerase with CD8+ cells. Future studies should separate out cell types to examine if the relationships observed here are specific to subpopulations of PBMCs.
This study only captures a snapshot in time of interrelations among HPA axis parameters and telomere length. The data are consistent with the hypothesis that these cortisol measures affect telomere length, as it is unlikely that telomere length, which changes over months or years, changes HPA axis function. However, this is at best preliminary evidence that cortisol may be related to telomere length, and the true mechanism linking dysregulated allostasis to cellular aging is likely much more complex. This study was also limited by the small sample size, as well as by being confined to postmenopausal women. Researchers should generalize these findings to other populations with caution. Future studies would benefit from more intensive measurement of daytime cortisol dynamics and examining these relations longitudinally to understand temporal and potential causal dynamics of cortisol on cellular aging.
Finally, future studies should test other patterns of the allostatic load model. One pattern is mounting an inadequate cortisol response (hypocortisolism), thereby allowing inflammatory processes to ensue. Several studies link inflammatory markers such as IL-6 to shorter telomere length [18
]. Thus, hypocortisolism might be associated with short telomere length to the extent it permits excessive inflammation. Examining both inflammation and HPA axis function simultaneously will aid our understanding of allostatic load, hyper- versus hypocortisolism, and telomere length.
In summary, we have provided initial evidence supporting the allostatic load model by demonstrating that strained allostasis is associated with a long-term marker of cellular aging. Specifically, greater cortisol reactivity to acute stressors, less inhibition of cortisol during sleep, and a flattened diurnal cortisol slope all predicted shorter telomere length. Future studies are needed to further test and validate whether telomere length can indeed serve as a molecular marker of allostatic load. While the exact mechanisms through which stress might erode telomeres need to be elucidated the long-term consequences of excessive cortisol exposure during reactivity and quiescent basal states may include accelerated telomere shortening.