The Association of Accelerated Epigenetic Age with Time-to-death Mediated by Subclinical and Clinical Vascular Outcomes
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Epigenetic age is a biomarker of aging and has been correlated with cellular and organ system aging. Age acceleration (AA), the difference between epigenetic age and chronological age, is a strong predictor of lifespan and healthspan in the general population, but has not been evaluated in people with chronic conditions. Additionally, the underlying mechanisms of AA’s ability to predict mortality is unclear. Using 562 participants from the CATHGEN cohort and three AA measures (Horvath epigenetic age acceleration - HAA, phenotypic age acceleration - PhenoAA, and Grim age acceleration - GrimAA), we evaluated whether AA was associated with all-cause mortality and examined multiple pathways that may mediate AA-mortality associations. The total effect, direct effect, indirect effect and percentage mediated were estimated using a regression adjustment approach. Accelerated epigenetic aging was associated with greater hazard ratios for mortality (P ≤0.01), with PhenoAA and GrimAA more strongly associated than HAA. PhenoAA-mortality association was mediated by angiopoietin-2 (ANG2, a biomarker of peripheral vascular health, 19.8% mediated, P = 0.016) and diabetes (8.15%, P = 0.043). The GrimAA-mortality association was mediated by ANG2 (12.3%, P = 0.014), and potentially by left ventricular ejection fraction (5.3%, P = 0.065). These results indicate that epigenetic age acceleration is strongly predictive in individuals with underlying cardiovascular disease and associations in these populations may be mediated by metabolic and vascular factors. This abstract does not necessarily represent the views or policies of the US Environmental Protection Agency.