Are depressive symptoms associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States

Authors: Herong Wang, MPH, Kelly M. Bakulski, PhD, Freida Blostein, PhD, Brittany R. Porath, MPH, John Dou, MPH, César Higgins Tejera, MD, PhD, Lindsay H. Ryan, PhD, Erin B. Ware, PhD

Major depressive disorder accelerates DNA methylation age, a biological aging marker. Subclinical depressive symptoms are common, but their link to DNA methylation aging in older adults remains unexplored. This study analyzed the crosssectional relationship between depressive symptoms and accelerated DNA methylation aging, considering gender and race/ethnicity in U.S. adults aged over 50. We used data from 3,882 diverse participants in the 2016 Health and Retirement Study wave, measuring blood DNA methylation age against chronologic age for acceleration. Depressive symptoms were assessed using the CES-D scale. Multiple linear regression evaluated the association between depressive symptoms and DNA methylation age acceleration, adjusting for sociodemographic factors, blood cell proportions, and health behaviors (physical activity, alcohol use, smoking, and chronic conditions). Gender and race/ethnicity modifications were also tested. Depressive symptoms, measured by continuous CES-D score, high depressive symptoms (CES-D ≥4), or any symptoms (CES-D ≥1), significantly correlated with increased GrimAge DNA methylation age acceleration (all p≤0.001) in unadjusted and sociodemographicadjusted models but were nonsignificant in fully adjusted models. No significant gender or race/ethnicity effect modifications were found in fully adjusted models. Nonetheless, a marginal interaction existed between any depressive symptoms and non-Hispanic Black or other race/ethnicity (B=0.57, SE=0.30, p=0.06) on GrimAge age acceleration in fully adjusted models, and a significant interaction between high depressive symptoms and female gender (B=-0.83, SE=0.41, p=0.04) in minimally adjusted models. Health behaviors significantly influence DNA methylation age acceleration and depressive phenotypes, underscoring the need to understand their roles in assessing psychological factors related to DNA methylation age acceleration.