Our findings suggest a modest overall relationship between current perceived stress and shorter telomere length in the study sample. Stratified analyses suggested significant associations of perceived stress and shorter telomeres in some subgroups, namely women with higher urinary catecholamines, those experiencing recent major stressors, and women age 55 years and older. History of major life losses and degree of familial breast cancer risk were not associated with telomere length overall, and did not seem to clearly modify the association of perceived stress and telomere length.
Based on the observations by Epel et al. (1
), we expected to see a stronger association and dose-response relationship between perceived stress and telomere length. Differences in the present study include a larger sample size, an older and broader age distribution, and lower perceived stress scores. Because of the wide distribution of telomere length in the population, cross-sectional studies require a large sample size to detect differences (22
); compared with Epel et al. (1
), our sample size should have been sufficient to detect a difference of similar magnitude. Despite a lack of additional specific stress scales, we identified groups of objective stressors based on existing data (e.g., recent death of a first-degree relatives or spouse, divorce, or separation), which modified the association between telomere length and perceived stress.
There are few published studies on psychosocial stress and telomere length. A recent study reported shorter telomere length in caregivers of Alzheimer patients compared with age and sex-matched controls (23
). Caregivers in this study tended to be older (average age 65 years) and were more likely than controls to report depressive symptoms. Another study reported shorter telomeres in patients with major depression (24
); in our data, history of depression was associated with higher perceived stress but not significantly related to shorter telomeres. Confidence in the present findings is increased by the replication of expected covariate associations with telomere length, such as age, obesity, smoking, and cardiovascular disease (25
). The observed association of shorter telomeres and lower education supports an effect of socioeconomic status described by others (26
), although this association was attenuated in the fully adjusted model, suggesting socioeconomic factors and other covariates may operate along a shared causal pathway.
Urinary catecholamines and cortisol are often considered markers of current physiologic stress response. Although overnight or first morning urines can be considered an “integrative” measure of general stress levels (13
), neuroendocrine hormones may vary with circadian and seasonal rhythms and are influenced by acute and chronic stressors. We saw no clear associations of urinary stress hormones with telomere length, in contrast to Epel’s previous findings showing a significant association between elevated cortisol, epinephrine, and norepineprine and telomere length in the caregiver study (12
). The relatively high coefficient of variation in our assays could have led to nondifferential misclassification, reducing the likelihood of observing associations. Nevertheless, expected correlations between urinary hormones were observed and adjustment for plate variation did not seem to alter the overall lack of main effects (data not shown). Significant interactions between perceived stress and neuroendocrine hormones were observed, however, supporting our premise that telomere length may be affected by elevated perceived stress primarily in the context of an elevated physiologic stress response, and consistent with a hypothesis that telomere length may represent an intermediate on the pathway linking the biological stress response with disease outcomes.
Interpreting urinary cortisol data is complicated by the typical daily rhythm and rapid increase in cortisol during and after awakening. First morning values may reflect basal hypothalamic-pituitary-adrenal activity and responsiveness, minimizing the influence of daytime activities. The U-shaped pattern showing shorter telomeres at lower and higher cortisol levels is suggestive given evidence that chronic, traumatic, or early life stress may be associated with increased or blunted hypothalamic-pituitary-adrenal activity (27
). Dopamine has not been previously studied in relation to telomere length. Although not traditionally considered a stress hormone, dopamine is a precursor of norepinephrine and is released in response to stress (14
). Dopamine may also influence the immune system via paracrine or autocrine pathways, along with the other catecholamines (30
). In our data, epinephrine and norepinephrine levels were generally higher in women with higher dopamine levels. However, these hormones did not explain the association of perceived stress and shorter telomeres seen in women with elevated dopamine.
We observed no overall dose-response for telomere length and higher perceived stress, except in analyses stratified by urinary catecholamines and recent major stressors. The perceived stress scale reflects the influence of contemporary or recent stressors, general stress responsiveness, and coping resources, so women with high scores likely included some experiencing atypical or transient stressors, as well as those with a more typical high stress response to chronic or daily stressors. We had limited data on external stressors or psychosocial determinants of perceived stress. Although we saw no apparent main effects or confounding by recent major stressors, higher perceived stress was significantly associated with shorter telomeres in women with a history of a recent major stressor. This does not necessarily imply that brief, intense stressors effect telomere length, however, as these events may have been preceded by years of chronic stress. This finding may simply represent our ability to observe an effect in women with more homogeneous levels of external stressors.
Cross-sectional data on perceived stress is a crude proxy for the lifetime burden of acute and chronic stress. The low perceived stress scores in this cohort are likely due to the age-distribution and psychosocial characteristics of these volunteer participants. Although older women on average reported lower perceived stress, the stronger association with shorter telomeres in older women may reflect the cumulative burden of stress over time. Alternatively, aging may be related to differences in the physiologic stress response. Hormonal changes with aging might remove a buffer against stress-related effects on telomere length, for example, as suggested by experimental research showing altered negative feedback of the hypothalamic-pituitary-adrenal-axis to acute stress in older women, and potentially modulating effects of estrogen replacement therapy on feedback sensitivity (32
). In our data, hormone replacement therapy was not independently associated with telomere length and did not modify the association of perceived stress and telomere length (data not shown). Our ability to examine these effects was limited by sample size and the close relationship between age, menopausal status, and hormone replacement therapy.
The high-throughput PCR-based assay of relative telomere length has attained popularity in epidemiologic studies, and is thought to provide a reasonable estimate of average telomere length in whatever tissue was used for DNA. Our study determined telomere length in total leukocytes compared with peripheral blood mononuclear cells in the caregiver studies (1
). These studies did not show an influence of lymphocyte phenotypes that explained the associations with telomere length (1
). Differences in our findings might reflect differential effects of stress on granulocytes (the predominant population of total leukocytes) compared with lymphocytes (the majority of peripheral blood mononuclear cell). Effects in shorter lived leukocytes may reflect to a greater extent the effects of stress on hematopoetic stem cells rather than effects on the replication and expansion of longer lived lymphocytes. Stress has been linked to systemic inflammation, i.e., induction of the acute phase response or inflammatory cytokines (33
) but may have either stimulatory or suppressive effects on lymphocytes depending on whether stress is acute or chronic (35
) and the specific mechanisms examined (36
). Further studies examining immune phenotype and inflammatory biomarkers might help elucidate pathways relating stress to leukocyte and lymphocyte telomere length.
Our data showed that age-related differences in telomere length surpassed the differences associated with perceived stress and modifiable factors such as obesity and smoking. The biological impact of effect sizes observed (e.g., older women with higher perceived stress had 5% shorter telomeres than low stress women) is also unclear given the broad range of variation of telomere length in the population, and is part of the larger question relating telomere length to aging and disease outcomes.
Although our cohort consists of volunteers with a sister with breast cancer, participants reported a diverse range of health risk factors and conditions (data not shown), and most had only one affected sister. The proportion with known breast cancer genes is expected to be low, and most of the excess risk associated with family history is likely due to shared environment and multiple gene polymorphisms that individually confer low risk. The fact that we saw expected associations of telomere length with age, obesity, and smoking provides further reassurance about the generality of our findings. We hypothesized that breast cancer family history would comprise a potential stressor, but reported stress levels were low, so the sample was enriched for higher perceived stress. The sample was also enriched for non-White race and smoking, neither of which confounded the association of perceived stress and telomere length. Smoking has inflammatory and immunosuppressive effects and may also be associated with psychosocial factors and neuroendocrine stress responsiveness (37
). However, post hoc
analyses of the telomere/stress association did not show effect modification by current smoking status.
In sum, although we did not observe a dramatic overall association of telomere length with current stress measures, our findings suggest perceived stress effects on telomere length may vary depending on neuroendocrine responsiveness and exposure to environmental stressors, and may be stronger in older women. The observed subgroup findings may be notable. In older women, for example, the difference in telomere length associated with a relatively small elevation in perceived stress score was comparable with differences associated with being obese, current smoking, or diagnosis of cardiovascular disease. Thus, even moderately elevated stress levels in a low-stress population could have substantial effect on telomere length.