Investigation of psychosocial stress and DNA methylation in genes related to immune response, metabolism, and calcium signaling among African American and White middle-aged adults

Identification of genes and pathways associated with chronic restraint stress-induced anxiodepressive-like behaviors in female mice by transcriptomic and genome-wide DNA methylation combinational-analysis.

Women are at a higher risk for depression and anxiety than men, yet research into the biological mechanisms and pharmacological treatments for female-specific mental disorders, such as perinatal and perimenopausal depression, remains insufficient. DNA methylation, a key epigenetic modification, has been implicated in the pathogenesis of depression. In this study, we exposed female mice to chronic restraint stress (CRS) for 2 weeks, which induced both depression-like and anxiety-like behaviors. We then collected genomic DNA and total RNA from the medial prefrontal cortex (mPFC), a brain region critically involved in depression pathophysiology, and performed RNA sequencing (RNA-Seq) and whole-genome enzymatic methylation sequencing (EM-seq) to investigate stress-related transcriptional and epigenetic changes. Transcriptomic analysis identified 105 upregulated and 71 downregulated genes in the mPFC of CRS-exposed mice. Notably, CRS increased the expression of genes associated with the complement and coagulation cascades, while downregulating the expression of genes encoding neurotransmitter receptors, their downstream signaling regulators, and markers of neuronal activity. Epigenetic profiling revealed 6,848 hypermethylated and 4,530 hypomethylated regions, with CRS altering both CG- and CHH-type DNA methylation. Integrative analysis uncovered 13 downregulated genes with significant hypermethylation, most of which were implicated in neuronal activity regulation, and 8 upregulated genes with hypomethylation. Our findings suggest that CRS-induced DNA hypermethylation at CG and CHH sites in the female mPFC may contribute to stress-induced transcriptional dysregulation, potentially driving anxiodepressive-like behaviors. These results provide new insights into the epigenetic mechanisms underlying sex-specific stress responses.

Psychosocial Stress and Allostatic Load Among Underrepresented Minority Women with Familial Cancer Risk

Social experiences and mortality risk: mediating roles of epigenetic aging, allostatic load, and health status

Social environments affect health and longevity, yet biological pathways remain incompletely understood. Data from Midlife in the United States (MIDUS) study were used to examine whether social experiences predicted mortality and whether effects were mediated by epigenetic aging, allostatic load, and health status. Outcomes included epigenetic clocks (e.g., GrimAgeV2), allostatic load (e.g., immune/inflammatory biomarkers), health status, and all-cause mortality. Among 1309 participants, positive social experiences (e.g., attending meetings) were associated with reduced mortality risk, epigenetic age deceleration, and better health; negative social experiences (e.g., childhood adversities) were associated with shortened survival, epigenetic age acceleration, and poorer health. Epigenetic aging partially mediated the mortality risk of positive and negative social exposures; inflammation attenuated the associations of positive social experiences and childhood adversity with mortality. Epigenetic aging appears to be an influential pathway linking social experiences to survival. Social conditions that slow biological aging and reduce inflammation offer promise as approaches to enhance longevity.

Social Adversity, Systemic Inflammation, and the Ticking of the Biological Aging Clocks in Men and Women

It is found that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes, including metabolomic aging, and that socioeconomic adversity influences not only inflammatory pathways but also distinct biological aging processes.

Glucocorticoid receptor gene (NR3C1) DNA methylation, early-life trauma, and resilience in obsessive-compulsive disorder

It is suggested that epigenetic alterations of NR3C1 may contribute to stress-related vulnerability in OCD, with resilience representing a key psychological pathway linking stress-related biological processes, including HPA-axis regulation, to clinical outcomes.

PTSD is Associated with Advanced Epigenetic Age in 45,091 US Military Veterans

Background: Posttraumatic stress disorder (PTSD) has been associated with advanced biological age in DNA methylation data, but results have been inconsistent. This study evaluated PTSD in association with epigenetic age in the largest cohort to date (by about 20 fold). Methods: Participants were 45,091 US Veterans (92.76% male) enrolled in the VA Million Veteran Program, with VA electronic health record (EHR), self-report PTSD severity (n = 22,835), and DNA methylation and genotype data. PTSD diagnoses predated the blood draw for obtaining DNA by > = one year. Results: PTSD diagnosis, severity, and duration were associated with age-adjusted metrics of epigenetic age (age residuals) per the Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE epigenetic age algorithms after multiple testing adjustment. The strongest and most robust effect (to additional covariates) was evident for PTSD severity in association with GrimAge residuals (B = .029, adjusted-p = 2.48e-53, up to 2 years advanced age). The relationships between PTSD severity and GrimAge and PhenoAge residuals were stronger among younger vs. older Veterans. In stratified analyses, all PTSD variables were associated with all epigenetic age residuals in the European ancestry subgroup (n = 27,578), but significant associations only emerged for GrimAge and DunedinPACE in the African ancestry participants (n = 11,690). Conclusions: PTSD was associated with advanced epigenetic aging in the largest study to date to evaluate this question. Effects were generally small in magnitude, though meaningful when considering the personal and healthcare system impact of advanced aging in the large population of VA users with PTSD.