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

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.

Risk Factors contributing to Methylation Shifts in BRCA1 and associated genes in African Americans with Triple Negative Breast Cancer

“…But this does not take into account risk factors and ethnic backgrounds that increase the occurrence of these diagnostic markers. These studies show that through lifestyle choice and socioeconomic status, AA are predisposed to diabetes, hypertension and other conditions that lead to detrimental changes in methylation profiles [8,9,14]. This confirms the nature of increased epigenetic changes for the AA community versus other ethnicities.…”

“…This mechanism of action looks at the response of stress to glucocorticoids that then alter lasting changes in DNA methylation patterns. What is also hypothesized is that cumulative stress throughout life increased the probability of this type of methylation [8,46]. When taking environmental factors out of the equation the amount of global methylation hits its lowest point with the non-Hispanic blacks compared to non-Hispanic Whites.…”

“…These variables can include various environmental, genetic, and socioeconomic factors [8,9]. Such disparities are evident because there is a prognostic difference between African American women and Non-Hispanic White Women, and this holds true for TNBC [41,20].…”

“…There is also a correlation between stress levels and epigenetic aging, where more long-term stress can aid in the acceleration of epigenetic changes [8,46]. This mechanism of action looks at the response of stress to glucocorticoids that then alter lasting changes in DNA methylation patterns.…”

“…The definitive nature of this outcome continues to be the subject of debate. But what is well understood are the effects of genetics, environmental, and socioeconomic factors on changes in DNA methylation profiles [8,9] that can be considered risk factors. These changes cause hyper methylation leading to BRCA1 becoming silenced, which result in increased mortality rate [10].…”