Abstract
BackgroundChronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.ResultsWe 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.ConclusionsCumulative 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0828-5) contains supplementary material, which is available to authorized users.
Highlights
Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear
Examining glucocorticoid receptor (GR) signaling as a potential mechanism underlying this effect, we identify that a high number of epigenetic clock Cytosine-phosphate-Guanosine sites (CpGs) are located within functional glucocorticoid response elements (GREs) and show dynamic methylation changes following GR activation by exposure to the GR agonist dexamethasone (DEX)
Prediction of chronological age using the epigenetic clock DNAM-age was calculated from peripheral blood from two independent samples, derived from the Grady Trauma Project (GTP) and the Max Planck Institute of Psychiatry (MPIP) cohorts using genome-wide Illumina HumanMethylation450 BeadChips (450 K), as previously described [27]
Summary
Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. The number of older adults is predicted to more than double over the two decades [1, 2] While this increase in life expectancy is undoubtedly one of the biggest achievements of modern medicine, population aging brings forth. Stress-related psychiatric disorders, including major depression and post-traumatic stress disorder (PTSD), are themselves risk factors for such diseases [15, 16]. Despite these observations, the molecular mechanisms linking psychological stress with accelerated aging and agingrelated diseases remain largely unknown
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