Prospective Study of Epigenetic Age Acceleration and Incidence of Cardiovascular Disease Outcomes in the ARIC Study (Atherosclerosis Risk in Communities)

Background: DNA methylation-based patterns of biological aging, known as epigenetic age acceleration, are predictive of all-cause mortality, but little is known about their association with cardiovascular disease (CVD). Methods: We estimated 2 versions of epigenetic age acceleration (Horvath and Hannum) using whole-blood samples from 2543 blacks. Linear and Cox proportional hazards regression, respectively, were used to assess the association of age acceleration with carotid intima–media thickness (cross-sectionally) and incident cardiovascular events, including CVD mortality, myocardial infarction, fatal coronary heart disease, peripheral arterial disease, and heart failure, during a median 21-year follow-up. All models were adjusted for chronological age and traditional CVD risk factors. Results: In comparison to chronological age, the 2 measures of epigenetic age acceleration were weaker, but independent, potential risk markers for subclinical atherosclerosis and most incident cardiovascular outcomes, including fatal coronary heart disease, peripheral arterial disease, and heart failure. For example, each 5-year increment of epigenetic age acceleration was associated with an average of 0.01 mm greater carotid intima–media thickness (each P ≤0.01), and the hazard ratios (95% confidence intervals) of fatal coronary heart disease per 5-year increment in Horvath and Hannum age acceleration were 1.17 (1.02–1.33) and 1.22 (1.04–1.44), respectively. Conclusions: In this sample of blacks, increased epigenetic age acceleration in whole blood was a potential risk marker for incident fatal coronary heart disease, peripheral arterial disease, and heart failure independently of chronological age and traditional CVD risk factors. DNA methylation–based measures of biological aging may help to identify new pathophysiological mechanisms contributing to the development of CVD.