Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling

• Type of Material: Article
• Authors: Anthony S. Zannas, Max Planck Institute of Psychiatry; Janine Arloth, Max Planck Institute of Psychiatry; Tania Carrillo-Roa, Max Planck Institute of Psychiatry; Stella Iurato, Max Planck Institute of Psychiatry; Simone Röh, Max Planck Institute of Psychiatry; Kerry Ressler, Emory University; Charles B. Nemeroff, University of Miami; Alicia Smith, Emory University; Bekh Bradley-Davino, Emory University; Christine Heim, Charité Universitätsmedizin Berlin; Andreas Menke, Max Planck Institute of Psychiatry; Jennifer F. Lange, Max Planck Institute of Psychiatry; Tanja Brückl, Max Planck Institute of Psychiatry; Marcus Ising, Max Planck Institute of Psychiatry; Naomi R. Wray, University of Queensland; Angelika Erhardt, Max Planck Institute of Psychiatry; Elisabeth Binder, Emory University; Divya Mehta, University of Queensland
• Language: English
• Date: 2015-12-17
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Zannas et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13059-015-0828-5
• Title of Journal or Parent Work: Genome Biology
• ISSN: 1465-6906
• Volume: 16
• Issue: 1
• Start Page: 266
• End Page: 266
• Grant/Funding Information: CH is supported in part by Public Health Service Grant UL1 RR025008 from the Clinical and Translational Science Award program, the US National Institutes of Health, the National Center for Research Resources, and by a K Award (K01 MH073698–01, Neural Substrates of Depression Risk after Child Abuse).; This work was supported by a European Research Council starting grant (grant# 281338, GxE molmech) within the FP7 framework to E.B.B., a Marie-Sklodowska Curie fellowship (H2020 grant# 653240) to ASZ, a grant from the National Alliance for Research in Schizophrenia and Affective Disorders and a grant from the Behrens Weise Stiftung to EBB, a grant from the National Institute of Mental Health (MH071538) to KJR, a grant from the National Institute of Mental Health (MH58922) to CBN, a grant by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant # 01ZX1314J to EB), and a grant from ERA-NET Neuron to AE. DM is supported by a grant from the National Health and Medical Research Council (1047956).
• Keywords: Gene expression; HUMAN BRAIN; Psychological stress; Glucocorticoids; DEMETHYLATION; CARDIOVASCULAR-DISEASE; DNA METHYLATION CHANGES; Genetics & Heredity; Life Sciences & Biomedicine; DNA methylation; Epigenetics; PSYCHOMETRIC PROPERTIES; Science & Technology; AGE; Aging; ADVERSE CHILDHOOD EXPERIENCES; Aging-related disease; Biotechnology & Applied Microbiology; RECEPTOR FUNCTION; DISORDER; DEPRESSION
• Research Categories: Health Sciences, Mental Health; Health Sciences, Epidemiology; Biology, Genetics

Abstract

Background: Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. Results: We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Conclusions: Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.