@article{e430fd9e274f4417a7c1c44f9ff7a84d,
title = "Lifetime stress accelerates epigenetic aging in an urban, African American cohort: Relevance of glucocorticoid signaling",
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.",
keywords = "Aging, Aging-related disease, DNA methylation, Epigenetics, Gene expression, Glucocorticoids, Psychological stres",
author = "Zannas, {Anthony S.} and Janinez Arloth and Tania Carrillo-Roa and Stella Iurato and Simone R{\"o}h and Ressler, {Kerry J.} and Nemeroff, {Charles B.} and Smith, {Alicia K.} and Bekh Bradley and Christine Heim and Andreas Menke and Lange, {Jennifer F.} and Tanja Br{\"u}ckl and Marcus Ising and Wray, {Naomi R.} and Angelika Erhardt and Binder, {Elisabeth B.} and Divya Mehta",
note = "Funding Information: 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 ERANET Neuron to AE. DM is supported by a grant from the National Health and Medical Research Council (1047956). 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). CBN is supported by the National Institute of Health, the American Psychiatric Publishing, Xhale, and Clintara; has been consulting for Xhale, Takeda, SK Pharma, Shire, Roche, Lilly, Allergan, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Lundbeck, Prismic Pharmaceuticals, Clintara LLC, Total Pain Solutions (TPS); is a stockholder of Xhale, Celgene, Seattle Genetics, Abbvie, Titan Pharmaceuticals; is in the scientific advisory board of American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF) (formerly named National Alliance for Research on Schizophrenia and Depression [NARSAD]), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Clintara LLC, RiverMend Health LLC; is in the board of directors of AFSP, Gratitude America, ADAA; and holds patents of Method and devices for transdermal delivery of lithium (US 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2)",
year = "2015",
month = dec,
day = "17",
doi = "10.1186/s13059-015-0828-5",
language = "English (US)",
volume = "16",
journal = "Genome Biology",
issn = "1465-6914",
publisher = "BioMed Central",
number = "1",
}