Stress and telomere biology: A lifespan perspective
Introduction
Telomeres are the DNA-based caps and protein structures at the chromosome tips. Telomeres shorten with each cell replication until a certain (Hayflick) limit, at which point the cell arrests and enters a state of senescence. Telomerase is the intracellular ribonucleoprotein that can help maintain and elongate telomeres. The telomere/telomerase maintenance system was originally studied in model systems, and now has been studied extensively in people. Telomeres are longest in germ cells, where they play an important role in cell cycle throughout the lifespan, but are also important in any dividing tissue that must be replenished throughout life, from parts of the hippocampus, to blood, and bone. This complex cell aging system regulates the longevity of cells as well as senescence. In the last ten years, there has been a rapidly increasing epidemiological research body suggesting that telomere length (TL) serves as an early predictor of onset of disease and earlier mortality. It is interesting to note that although the word ‘aging’ is usually associated with old age, aging in the sense of telomeres is a life-time phenomenon that begins even before birth. Age-related diseases manifest mostly in old age, but the aging process, at the cellular level, can be viewed as a lifelong progression. Indeed, abnormalities in telomere maintenance, resulting from mutations in telomere maintenance genes, are associated with premature aging in rare genetic diseases, collectively called ‘telomere syndromes’ (Armanios and Blackburn, 2012). Many clinical features of telomere syndromes are characteristic of geriatrics, and children with this disorder have a phenotype that resembles premature aging, signifying a causal link between telomere biology and aging.
Given the apparent centrality of this aging system in human health it is important to identify the multitude of factors that shape TL early on in life and regulate TL maintenance throughout adulthood. While genetics play a role in regulating TL and telomerase activity, a wide range of environmental and behavioral factors also appear to affect TL and telomerase. Stress has emerged as a major influence on telomere erosion. This brief review focuses on how life stress may impact telomere maintenance, starting from in utero (Fig. 1). Stress shapes the biochemical milieu, in ways that may promote telomere damage, inflammation, and greater rate of leukocyte division in part through impairing telomerase mediated elongation, but also through other pathways, as explored elsewhere (Epel, 2012, Shalev, 2012). The shaping of stem cell health and turnover is influenced during development and early childhood. Novel research by Entringer and colleagues suggests that maternal stress during pregnancy may model offspring TL. Childhood adversity has been studied most, and appears to impact TL during the periods of exposure, as well as later in adulthood, although longitudinal studies are needed to establish how early adversity leads to longer-term effects. Depression, as well as other major mental disorders and physical disorders, have been linked to TL shortness in several studies, and it is likely that they are both influenced by cellular aging and contribute further to accelerate cell aging. Lastly, there are suggestions that healthy lifestyle factors may promote telomere maintenance or even lengthening; this may matter particularly in the face of adversity. Conversely, unhealthy lifestyle factors may significantly shorten telomeres. Together, a picture emerges that TL is an informative ‘clock’ that can be accelerated during critical periods or exposures, likely through different mechanisms. A better understanding of the mechanisms that mediate the effects of stress on telomere maintenance is an active avenue of investigation. Regardless of mechanism, shortened TL appears to index rate of biological aging and thus may provide insights into group and individual differences in early aging.
Section snippets
Fetal programming of telomere biology
Growing evidence from epidemiological, clinical, and molecular studies suggests that conditions during early development (i.e., embryonic, fetal and early postnatal periods of life) interact with the genome of an individual to exert a major impact on structural and functional integrity of the developing brain and other peripheral systems. This interaction, in turn, influences an individual's subsequent state of health and her or his propensity, or susceptibility, for developing one or more of
Early life stress and telomere length
Childhood stress, a major public-health and social-welfare problem, is known to have a powerful direct effect on poor health in later life. But how can stress during early life lead to health problems that only emerge decades later? This direct effect requires one or more underlying mechanisms that can maintain it across the life-course. Now, new evidence suggests telomere erosion is a potential mechanism for the long-term cellular embedding of stress.
In the past few years, several studies of
Mental health disorders and telomere maintenance
Common mental disorders like depression and anxiety may also be associated with changes in telomere maintenance. Major depressive disorder (MDD) and other serious mental illnesses are associated with high rates of comorbid medical illnesses, many of which are more common in the elderly, such as cardiovascular disease, stroke and dementia. One possible explanation for this comorbidity is that these mental illnesses are associated with accelerated rates of cellular/biological aging. As reviewed
Health behaviors and telomere biology
Early chronic disease onset and early mortality are accounted for in large part by chronic poor health behaviors, including physical inactivity, poor diet, poor sleep, smoking and other tobacco use, and excessive alcohol consumption (Murray et al., 2013). The importance of healthy behaviors to the prevention and treatment of disease cannot be understated (Fisher et al., 2011). Work over the past decade directs attention to the many protective cellular effects of healthy behaviors that are
Discussion
The German-French philosopher Albert Schweitzer once said that “the tragedy of life is what dies inside a man while he lives”. Although he was not referring to telomeres, it echoes well with new evidence from the field of telomere science. What dies inside us, or at least becomes senescent, are our cells, and it seems that telomeres are key elements in the causal chain of normal and premature senescence from very early in life. Moreover, recent empirical studies suggest that the telomere
Role of the funding source
The funding agencies had no role in the writing of this mini-review.
Conflict of interest
Elissa S. Epel and Jue Lin are co-founders of Telome Health, Inc., a telomere measurement company. Owen M. Wolkowitz is on the Scientific Advisory Board of Telome Health, Inc. All other authors declare no conflict of interest.
Acknowledgments
This article was based on the 2012 Annual ISPNE symposium entitled- Cellular aging: From physical to mental syndromes. Funding for the preparation of this manuscript was provided, in part, by NICHD grant HD061298 and by the Jacobs Foundation to I.S., US PHS (NIH) grants HD-065825 to S.E. and HD-060628 to P.D.W., NIA BSR R01 AG030424 to E.S.E, K99 HL109247 to E.P., and NIMH R01 MH083784 to O.M.W., E.S.E. and Synthia H. Mellon.
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