Traumatic Stress, Epigenetic Aging, and Cardiovascular Risk in the Million Veteran Program

Background & Innovation: This project will make use of Million Veteran Program (MVP) data to address questions concerning the relationships between traumatic stress, epigenetic aging in DNA methylation data, and cardiovascular disease (CVD, including ischemic stroke, myocardial infarction, coronary artery disease- related death, and coronary and peripheral artery disease) in a nationally representative sample of Veterans (n = 45,600). Under Aim 1, part A, we will examine how traumatic stress is associated with several prominent epigenetic metrics of cellular age (e.g., Horvath, GrimAge). In Aim 1, part B, we will use temporally-separated mediation models to see if the effects of prior traumatic stress on new-onset (future) CVD are mediated by advanced epigenetic age. In Aim 1, part C, we will test potential modifiable (nutrition, exercise, medication use) and non-modifiable (genotypes, demographic characteristics) factors as moderators of the strength of the associations between traumatic stress and epigenetic age and between epigenetic age and CVD outcomes. In Aim 2, we will develop a translational algorithm that uses epigenetic age estimates to predict risk for CVD and quantifies how much advanced epigenetic age (beyond chronological age) is associated with increased risk, even among individuals without prominent CVD risk factors such as diabetes and cigarette use. In Aim 3, we will use genome-wide association, biological pathway enrichment, and Mendelian randomization studies to address questions concerning how epigenetic age relates to the broader biological mechanisms of aging and if traumatic stress is causally implicated in the development of advanced epigenetic age and CVD. The proposed work is innovative in the following ways: (1) its use of MVP for testing temporal hypotheses in the largest cohort to date; (2) its evaluation of whether health disparities associated with minoritized groups are reflected at the cellular level; (3) its efforts to identify sub-populations at greatest risk for accelerated aging and associated disease; and (4) its goal of identifying biological and behavioral processes underlying accelerated aging so as to point towards future treatment discoveries to slow the pace of aging and reduce disease burden. Significance & Impact to Veterans Healthcare: Veterans are an aging population with greater disease incidence and health burden than comparative civilian populations. Their risk for premature morbidity and mortality is related to numerous Veteran-centric risk factors, such as exposure to traumatic stress. Our work will build on an existing clinical CVD risk stratification tool to identify Veterans at risk for future CVD as a function of an epigenome-wide indicator referred to as advanced epigenetic age. We will do this in a way that leads to a population-specific (race, ethnicity, sex) understanding of risk. We also seek to identify Veterans at risk for CVD who do not show obvious chronic risk factors. Understanding the biology and genetics of epigenetic aging will point towards new therapeutics to improve Veteran healthspan. Path to Translation/Implementation: If this application is successful, the next steps would be to: (1) measure epigenetic age among Veterans (clinically) and integrate this information with Veteran CVD risk models to provide personalized risk assessments and intervene on CVD risk early; and (2) conduct intervention trials to see if epigenetic age changes in response to modifiable lifestyle factors (exercise, nutrition), PTSD treatment (therapy & psychopharmacology), and pharmacological agents targeting the underlying biology of epigenetic aging. Ultimately, these efforts will help identify Veterans at greatest risk for premature morbidity and mortality and allow for interventions that promote healthy aging. Project Number: 1I01BX006510-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: ERIKA WOLF | Institution: VA BOSTON HEALTH CARE SYSTEM, BOSTON, MA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 CARA-P (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11043948