Psychological Stress and Epigenetic Aging in Older Men: The VA Normative Aging Study

Psychological stress remains an important risk factor for morbidity and mortality throughout the life course. However, there have been counterintuitive findings reported in previous studies of older persons that examine the relationships of perceived psychological stress with DNA methylation-based markers of aging, which also serve as predictors of morbidity and mortality (epigenetic age/clocks). We aimed to replicate and expand findings from existing work by examining relationships of self-reported stress with nine epigenetic clocks: Hannum, Horvath, Intrinsic, Extrinsic, SkinBloodClock, PhenoAge, GrimAge, DNAm Telomere Length, and Pace of Aging. We analyzed data from 607 male participants (mean age 73.2 years) of the VA Normative Aging Study with one to two study visits from 1999 to 2007 (observations = 956). Stress was assessed via the 14-item Perceived Stress Scale (PSS). Epigenetic age was calculated from DNA methylation measured in leukocytes with the HumanMethylation450 BeadChip. In linear mixed effects models adjusted for demographic/lifestyle/health factors, a standard deviation (sd) increase in PSS was associated with Horvath (β = -0.35-years, 95%CI: -0.61, -0.09, P=0.008) and Intrinsic (β = -0.40-years, 95%CI: -0.67, -0.13, P=0.004) epigenetic age deceleration. However, in models limited to participants with the highest levels of stress (≥ 75^th-percentile), Horvath (β = 2.29-years, 95%CI: 0.16, 4.41, P=0.04) and Intrinsic (β = 2.06-years, 95%CI: -0.17, 4.28, P=0.07) age acceleration associations were observed. Our results reinforce the complexity of psychological stress and epigenetic aging relationships and lay a foundation for future studies that explore longitudinal relationships with other adult stress metrics and factors that can influence stress such as resilience measures.