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.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. anthony_zannas@psych.mpg.de.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA. anthony_zannas@psych.mpg.de.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Zannas
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.|Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Arloth
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Stella
authors.initials: S
authors.lastname: Iurato
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Röh
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, GA, USA.|Howard Hughes Medical Institute, Chevy Chase, MD, USA.|Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
authors.affiliation: Department of Psychiatry and Behavioral Sciences and the Center on Aging, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, GA, USA.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, GA, USA.|Atlanta Veterans Affairs Medical Center, Decatur, GA, USA.
authors.forename: Bekh
authors.initials: B
authors.lastname: Bradley
authors.affiliation: Institute of Medical Psychology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Heim
authors.affiliation: Current Address: Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.|Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Menke
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Lange
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Brückl
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: The University of Queensland, Queensland Brain Institute, St Lucia, Qld 4072, Australia.
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Erhardt
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. binder@psych.mpg.de.|Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, GA, USA. binder@psych.mpg.de.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: The University of Queensland, Queensland Brain Institute, St Lucia, Qld 4072, Australia.
authors.forename: Divya
authors.initials: D
authors.lastname: Mehta
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000368:Aged; D000375:Aging / Q000235:genetics*; D016022:Case-Control Studies; D018899:CpG Islands; D003907:Dexamethasone / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011965:Receptors, Glucocorticoid / Q000819:agonists; D020218:Response Elements; D015398:Signal Transduction; D013315:Stress, Psychological / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014505:Urban Population
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone