Abstract
BACKGROUND: Epigenetic clocks, biomarkers of aging, show older biological ages among individuals with cardiometabolic disease. Epigenetic age acceleration, often calculated as the residuals from regressing epigenetic age on chronological age, reflects when an individual's biological age is older or younger than expected. Most clocks were developed and validated in Western populations. This study examined associations of epigenetic age acceleration with obesity, hypertension, diabetes, and metabolic syndrome among Guatemalan adults. METHODS: We conducted a cross-sectional analysis of data from participants in the Institute of Nutrition of Central America and Panama (INCAP) Nutritional Supplementation Trial Cohort. DNA methylation (DNAm) was assessed in buffy coat samples using the MethylationEPIC v2 array and standard quality control procedures. Epigenetic age was quantified using DunedinPACE, PhenoAge, and GrimAge. Linear regression models were used to assess associations of obesity, diabetes, hypertension, and metabolic syndrome with epigenetic age acceleration. Dependent variables were DunedinPACE values and PhenoAge and GrimAge residuals. Covariates included sex, birth year, and a clustering variable to account for sibships. RESULTS: We analyzed data from 1,095 adults (mean age 45 y; 60.3% female; 73.3% overweight or obese; 37.8% with hypertension; 15.4% with diabetes; 66.9% with metabolic syndrome). DunedinPACE (mean 1.2, SD 0.1), PhenoAge (mean 46.7, SD 6.7) and GrimAge (mean 56.3, SD 4.1) all indicate accelerated biological aging. Pearson correlations among the clocks were ≥ 0.5. DunedinPACE and PhenoAge indicated age acceleration among women (DunedinPACE β = 0.04; 95% CI: 0.03, 0.05; PhenoAge β = 0.94; 95% CI: 0.28, 1.60) whereas GrimAge suggested age acceleration among men (β= - 1.02; 95% CI: - 1.31, - 0.72). All three clocks showed accelerated aging among individuals with diabetes (DunedinPACE β = 0.09; 95% CI: 0.07, 0.10; PhenoAge β = 2.69; 95% CI: 1.63, 3.74; GrimAge β = 1.18; 95% CI: 0.71, 1.65). DunedinPACE indicated a faster rate of aging across all cardiometabolic conditions examined, whereas the strength and consistency of associations for PhenoAge and GrimAge varied by condition. CONCLUSIONS: We observed consistent associations of accelerated DunedinPACE with multiple cardiometabolic conditions. All epigenetic clocks showed associations of epigenetic age acceleration with diabetes. These findings emphasize the need for longitudinal analyses to determine the direction and causality of these relationships.