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      Stress, Telomeres, and Psychopathology: Toward a Deeper Understanding of a Triad of Early Aging

      , 1
      Annual Review of Clinical Psychology
      Annual Reviews

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          Abstract

          Telomeres play an important part in aging and show relationships to lifetime adversity, particularly childhood adversity. Meta-analyses demonstrate reliable associations between psychopathology (primarily depression) and shorter telomere length, but the nature of this relationship has not been fully understood. Here, we review and evaluate the evidence for impaired telomere biology as a consequence of psychopathology or as a contributing factor, and the important mediating roles of chronic psychological stress and impaired allostasis. There is evidence for a triadic relationship among stress, telomere shortening, and psychiatric disorders that is positively reinforcing and unfolds across the life course and, possibly, across generations. We review the role of genetics and biobehavioral responses that may contribute to shorter telomere length, as well as the neurobiological impact of impaired levels of telomerase. These complex interrelationships are important to elucidate because they have implications for mental and physical comorbidity and, potentially, for the prevention and treatment of depression.

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          Most cited references120

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          Telomere dysfunction induces metabolic and mitochondrial compromise.

          Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
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            Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies.

            With negative treatment trials, the role of depression as an aetiological or prognostic factor in coronary heart disease (CHD) remains controversial. We quantified the effect of depression on CHD, assessing the extent of confounding by coronary risk factors and disease severity. Meta-analysis of cohort studies measuring depression with follow-up for fatal CHD/incident myocardial infarction (aetiological) or all-cause mortality/fatal CHD (prognostic). We searched MEDLINE and Science Citation Index until December 2003. In 21 aetiological studies, the pooled relative risk of future CHD associated with depression was 1.81 (95% CI 1.53-2.15). Adjusted results were included for 11 studies, with adjustment reducing the crude effect marginally from 2.08 (1.69-2.55) to 1.90 (1.49-2.42). In 34 prognostic studies, the pooled relative risk was 1.80 (1.50-2.15). Results adjusted for left ventricular function result were available in only eight studies; and this attenuated the relative risk from 2.18 to 1.53 (1.11-2.10), a 48% reduction. Both aetiological and prognostic studies without adjusted results had lower unadjusted effect sizes than studies from which adjusted results were included (P<0.01). Depression has yet to be established as an independent risk factor for CHD because of incomplete and biased availability of adjustment for conventional risk factors and severity of coronary disease.
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              Life stress, the "kindling" hypothesis, and the recurrence of depression: considerations from a life stress perspective.

              Major depression is frequently characterized by recurrent episodes over the life course. First lifetime episodes of depression, however, are typically more strongly associated with major life stress than are successive recurrences. A key theoretical issue involves how the role of major life stress changes from an initial episode over subsequent recurrences. The primary conceptual framework for research on life stress and recurrence of depression is the "kindling" hypothesis (R. M. Post, 1992). Despite the strengths of the kindling hypothesis, a review of the research literature reveals inconsistencies and confusion about life stress and its implications for the recurrence of depression. Adopting a life stress perspective, the authors introduce 3 major themes that resolve the inconsistencies in the current literature. They integrate these themes and extrapolate the ideas with available data to develop a preliminary framework for evaluating competing explanatory models and to guide research on life stress and the recurrence of depression.
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                Author and article information

                Journal
                Annual Review of Clinical Psychology
                Annu. Rev. Clin. Psychol.
                Annual Reviews
                1548-5943
                1548-5951
                May 07 2018
                May 07 2018
                : 14
                : 1
                : 371-397
                Affiliations
                [1 ]Department of Psychiatry; Center for Health and Community; Aging, Metabolism, and Emotions Center; University of California, San Francisco, California 94118, USA;,
                Article
                10.1146/annurev-clinpsy-032816-045054
                572b0a73-25d8-4aaf-83cd-9ac146e79d75
                © 2018
                History

                Sociology,Psychology,Anthropology,Social & Behavioral Sciences,General social science,General behavioral science

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