Accelerated telomere shortening in response to life stress

Elissa Epel

Elizabeth Blackburn

Jue Lin

Firdaus Dhabhar

Nancy Adler

Jason Morrow

Richard Cawthon

^{Department of Psychiatry, University of California, 3333 California Street, Suite 465, San Francisco, CA 94143;}^{Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143;}^{Department of Oral Biology, College of Dentistry, and Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, Ohio State University, Columbus, OH 43210;}^{Department of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232; and}^{Department of Human Genetics, University of Utah, 15 North 2030 E Street, Room 2100, Salt Lake City, UT 84112}

^{To whom correspondence should be addressed. E-mail:}ude.fscu.asti@assile.

Contributed by Elizabeth H. Blackburn, September 28, 2004

Freely available online through the PNAS open access option.

Abstract

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets “under the skin” remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress— both perceived stress and chronicity of stress—is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.

Keywords: psychological stress, telomere length, telomerase, oxidative stress

Abstract

People who are stressed over long periods tend to look haggard, and it is commonly thought that psychological stress leads to premature aging and the earlier onset of diseases of aging. Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function (1, 2). Nevertheless, the exact mechanisms of how such stress exerts these effects are not well known, including whether stress accelerates aging at a cellular level and how cellular aging translates to organismal aging. Recent research points to the crucial roles of telomeres and telomerase in cellular aging and potentially in disease. Telomeres are DNA–protein complexes that cap chromosomal ends, promoting chromosomal stability. When cells divide, the telomere is not fully replicated because of limitations of the DNA polymerases in completing the replication of the ends of the linear molecules, leading to telomere shortening with every replication (3). In vitro, when telomeres shorten sufficiently, the cell is arrested into senescence. In people, telomeres shorten with age in all replicating somatic cells that have been examined, including fibroblasts and leukocytes (4). Thus, telomere length can serve as a biomarker of a cell's biological (versus chronological) “age” or potential for further cell division.

Telomerase, a cellular enzyme, adds the necessary telomeric DNA (T₂AG₃ repeats) onto the 3′ ends of the telomere (5). Telomerase also has direct telomere-protective functions (6). In human T cells, telomerase activity increases with acute antigen exposure but decreases with repeated antigen stimulation and as the cells approach senescence (7). People with dyskeratosis congenita, a rare genetic disease that diminishes the ability to synthesize sufficient telomerase, have shortened telomeres and die prematurely from progressive bone marrow failure and vulnerability to infections (8).

Cellular environment also plays an important role in regulating telomere length and telomerase activity. Most notably, in vitro, oxidative stress can shorten telomeres and antioxidants can decelerate shortening (9, 10). Perceived stress has been linked to one measure of oxidative DNA damage in leukocytes in women (11, 12). Given these observed links, we hypothesized that chronic psychological stress may lead to telomere shortening and lowered telomerase function in peripheral blood mononuclear cells (PBMCs) and to oxidative stress.

Values are correlations adjusted for age only, with correlations adjusted for age, BMI, smoking, and vitamin use in parentheses. When people are stressed, some tend to eat and smoke more, and they may not engage in self-care behaviors, such as taking antioxidant multivitamin supplements. Therefore, potential mediators (BMI, smoking, and vitamin use) were controlled for along with age. Even when these factors are controlled for, stress was still significantly associated with shorter telomeres and lower telomerase activity, although the relationship with oxidative stress index was no longer significant and thus partially mediated by health behaviors. Perceived stress was not directly related to isoprostanes (r = 0.18, P value not significant) or vitamin E (r = -0.09, P value not significant) but was related to the oxidative stress index (the ratio of isoprostanes divided by vitamin E levels). †, P < 0.01; ‡, P < 0.05 (one-tailed). n values vary because of missing data, because years of caregiving was measured in the caregivers only, or because oxidative stress was measured on a subset of the sample (n = 44).

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Acknowledgments

We thank Drs. Teresa Seeman, Margaret Kemeny, and Bruce McEwen for intellectual support; Jean M. Tillie for expert help with flow cytometry; Michael Acree for statistical expertise; Drs. Melvin Heyman, Bryna Siegel, and Paul Harmatz for help recruiting clinic participants; Sheryln Jimenez, Denise Kruszewski, and Drs. Judith Moskowitz, Susan Folkman, and Judith Stewart for crucial help; and the busy mothers for volunteering their time. E.S.E. was supported by the John D. and Catherine T. MacArthur Foundation Network on Socioeconomic Status and Health; the Hellman Family Fund; and the University of California, San Francisco, Pediatric Clinical Research Center (under the auspices of National Institute of Mental Health Grant M01-RR01271), National Institute of Mental Health Award K08 MH64110-01A1, and a National Alliance for Research on Schizophrenia and Depression Young Investigator's Award. E.H.B. was supported by the Steven and Michele Kirsch Foundation and National Institutes of Health Grant GM26259. J.D.M. was supported by the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and National Institutes of Health Grants GM15431, CA77839, DK48851, and RR00095. F.S.D. was supported by the Dana Foundation and National Institutes of Health Grant AI48995.

Acknowledgments

Notes

Abbreviations: PBMC, peripheral blood mononuclear cell; BMI, body-mass index; T/S, telomere repeat copy number/single-copy gene copy number.

Notes

Abbreviations: PBMC, peripheral blood mononuclear cell; BMI, body-mass index; T/S, telomere repeat copy number/single-copy gene copy number.

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