Cumulative lifetime stress may accelerate epigenetic aging

Cumulative lifetime stress may accelerate epigenetic aging

Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes.

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.

These findings contribute to our understanding of mechanisms linking
chronic stress with accelerated aging and heightened disease risk.

https://genomebiology.biomedcentral.com/track/pdf/10.1186/s13059-015-0828-5?site=http://genomebiology.biomedcentral.com

Membrane glucocorticoid receptors (mGRs) are a group of receptors which bind and are activated by glucocorticoids such as cortisol and corticosterone, as well as certain exogenous glucocorticoids such as dexamethasone.[1][2][3][4][5] Unlike the classical nuclear glucocorticoid receptor (GR), which mediates its effects via genomicmechanisms, mGRs are cell surface receptors which rapidly alter cell signaling via modulation of intracellular signaling cascades.[2][3] The identities of the mGRs have yet to be fully elucidated,[6] but are thought to include membrane-associated classical GRs[7][8] as well as yet-to-be-characterized G protein-coupled receptors(GPCRs).[1][4][9][10] Rapid effects of dexamethasone were found not be reversed by the GR antagonist mifepristone, indicating additional receptors besides just the classical GR.[11]

mGRs have been implicated in the rapid effects of glucocorticoids in the early central stress response[12][13] via modulating neuronal activity in the hypothalamushippocampusamygdala, and prefrontal cortex, among other areas.[7] In accordance, glucocorticoids are known to affect cognitionstress-adaptive behavior, and neuroendocrine output (e.g., suppression of oxytocin and vasopressin secretion)[4] within minutes.[7] mGRs appear to be partially involved in the anti-inflammatory and immunosuppressant effects of glucocorticoids.[3][5][14] mGRs are present in and appear to regulate many major bodily systems and organs, including the cardiovascularimmuneendocrine, and nervous systemssmooth and skeletal muscle, the liver, and fat tissue.[9] mGRs appear to cooperate with, complement, and synergize with classical nuclear GRs in various ways

 

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