Telomere Attrition: A Window Into Common Mental Disorders and Cellular Aging

In this issue of the Journal, Verhoeven and colleagues (1) further document the association between depressive and anxiety disorders and shorter leukocyte telomere length (LTL), an indicator of cellular aging. The researchers, reporting data from 2,936 participants in the Netherlands Study of Depression and Anxiety (NESDA) (2), observed that participants with remitted and with current depressive and anxiety disorders show shorter LTL than never-affected controls across baseline and 6-year follow-up. The researchers controlled for lifestyle and somatic health variables known also to affect telomere length. As illustrated in Figure 2 of their report, the longitudinal course of illness over 6 years (e.g., new onset, persistent remission, relapse, chronic) was not associated with differences in LTL attrition rates. The investigators conclude that short LTL could be either a long-term consequence (“imprint”) of depression and anxiety or a biomarker of an underlying vulnerability factor for these common mental disorders. The study was not designed to address this conundrum conclusively.

What is new about this study is its focus on the longitudinal course of illness and LTL attrition. In a previous cross-sectional report published in Molecular Psychiatry and addressing depression and accelerated cellular aging (3), the investigators observed significantly shorter LTL in both currently depressed (5,461 base pairs) and remitted (5,459 base pairs) patients compared with controls (5,541 base pairs). These differences in length were estimated to be the equivalent of 4–6 years of accelerated physiologic—not chronologic—aging. As in the current study, the large sample size of NESDA participants permitted control for potential confounders such as smoking, body mass index, alcohol use, and physical activity. In the Molecular Psychiatry report, the investigators reported evidence of a dose-response gradient: both depression severity and duration of depressive symptoms in the previous 4 years were associated with shorter telomeres. That relationship appears not to have been confirmed in the current longitudinal study, which offered a much finer-grained analysis of illness course. The researchers have posited that prior depression leaves a telomere scar even after the episode is over—that is, an “imprint” of past exposure to depression. They raise further questions of profound public health and clinical moment, for example, does telomere shortening contribute to medical comorbidities commonly seen in depressed patients, such as heart disease, diabetes, obesity, and cancer? Finally, they point out that how telomere length relates to treatment response is still unclear, although in the current report LTL was not found to be associated with cumulative antidepressant exposure.

In order to place these observations in further context, this commentary will first summarize contemporary understanding of what telomeres are, their function, and their relationship to cellular aging. Secondly, the commentary will offer several observations emerging in the literature of geroscience that account for mechanisms of telomere shortening and the relevance of these mechanisms to common mental disorders like depression. Finally, to recapture a clinical perspective, recent observations relating depression treatment to reductions in mortality secondary to cancer will be summarized.