Abstract Body: Introduction: Epigenetic (DNA methylation) clocks have been derived as hallmarks of biological age based on their ability to predict chronological age or aging-related phenotypes. However, studies comprehensively examining the associations between epigenetic age acceleration and premature mortality in nationally representative U.S. populations are lacking.
Hypothesis: Epigenetic age acceleration will be associated with higher risks of premature mortality in the general US population.
Methods: We included 2,191 participants aged 50-79 years from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) who underwent DNA methylation measurement. We included five epigenetic clocks (Horvath’s, Hannum’s, PhenoAge, GrimAge, and DunedinPoAm), and calculated epigenetic age acceleration as the residual from regressing epigenetic age on chronological age (except for DunedinPoAm, which reflects aging rates). Premature mortality was defined as death before age 80, with a sensitivity analysis using a cutoff of 75 years. Cox proportional hazards models were used to assess the association between epigenetic age acceleration and premature mortality.
Results: We found that faster epigenetic age acceleration was significantly associated with a 19% to 61% higher risk of premature mortality across the 5 clocks, adjusting for demographic, socioeconomic, and behavioral factors (Table). GrimAge age acceleration was the strongest predictor, while Horvath age acceleration was the weakest. The associations were consistent when premature mortality was defined as death before age 75.
Conclusions: Our examination of epigenetic age acceleration measures in a representative U.S. population lends innovative evidence to support the potential application of epigenetic clocks as hallmarks for monitoring biological aging and a promising target for prevention of premature mortality and aging-related disorders in the broader US populations.