Accelerated Epigenetic Aging Is Associated With Multiple Cardiometabolic, Hematologic, and Renal Abnormalities: A Project Baseline Health Substudy

Background: Epigenetic clocks estimate chronologic age using methylation levels at specific loci. We tested the hypothesis that accelerated epigenetic aging is associated with abnormal values in a range of clinical, imaging, and laboratory characteristics. Methods: The Project Baseline Health Study recruited 2502 participants, including 1661 with epigenetic age estimates from the Horvath pan-tissue clock. We classified individuals with extreme values as having epigenetic age acceleration (EAA) or epigenetic age deceleration. A subset of participants with longitudinal methylation profiling was categorized as accelerated versus nonaccelerated. Using principal components analysis, we created phenoclusters using 122 phenotypic variables and compared individuals with EAA versus epigenetic age deceleration, and at one year of follow-up, using logistic regression models adjusted for sex (false discovery rate [Q] <0.10); in secondary exploratory analyses, we tested individual clinical variables. Results: The EAA (n=188) and epigenetic age deceleration (n=195) groups were identified as having EAA estimates ≥5 years or ≤−5 years, respectively. In primary analyses, individuals with EAA had higher values for phenoclusters summarizing lung function and lipids, and lower values for a phenocluster representing physical function. In secondary analyses of individual variables, neutrophils, body mass index, and waist circumference were significantly higher in individuals with EAA (Q<0.10). No phenoclusters were significantly different between participants with accelerated (n=148) versus nonaccelerated (n=112) longitudinal aging. Conclusions: We report multiple cardiometabolic, hematologic, and physical function features characterizing individuals with EAA. These highlight factors that may mediate the adverse effects of aging and identify potential targets for study of mitigation of these effects. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03154346.