Associations of DNA Methylation Algorithms of Aging With Cardiovascular Disease and Mortality Risk Among US Older Adults

Background Several DNA methylation (DNAm) algorithms have recently emerged as robust predictors of aging and adverse health outcomes in older adults, offering valuable insights into cardiovascular disease (CVD) risk stratification. However, their predictive performance for CVD varies significantly. This study aimed to systematically investigate the associations of 12 widely used DNAm algorithms with CVD and mortality risk. Methods Data from the NHANES (National Health and Nutrition Examination Survey) 1999 to 2002 were used to assess 12 DNAm algorithms (eg, HannumAgeacc, PhenoAgeacc, GrimAgeMortacc, GrimAge2Mortacc) in relation to CVD risk and mortality. Two cohorts were analyzed: one for CVD risk (n=1230) and another for CVD mortality risk (n=1606). DNAm was measured using the Infinium Methylation EPIC BeadChip kit (Illumina). Odds ratios (ORs) and hazard ratios (HRs), along with 95% CIs per SD increase of these DNAm algorithms, were calculated. Results Significant associations were observed for GrimAgeMortacc and GrimAge2Mortacc with coronary heart disease and heart attack, with multivariable‐adjusted ORs per SD increase ranging from 2.15 to 2.76. However, several algorithms exhibited no significant association with self‐reported prevalent CVD. For mortality risk, HannumAgeacc, PhenoAgeacc, ZhangAgeacc, GrimAgeMortacc, and GrimAge2Mortacc were significantly associated with CVD mortality. The multivariable‐adjusted HRs per SD increase were 1.19 (95% CIs, 1.05–1.34), 1.13 (95% CIs, 1.01–1.26), 1.63 (95% CI, 1.08–2.47), 1.90 (95% CIs, 1.51–2.40), and 1.87 (95% CIs, 1.51–2.32), respectively. These associations were consistent across biological sex, age (≥50 and <65 versus ≥65 years), and race and ethnicity groups. Conclusions DNAm algorithms, particularly GrimAgeMortacc and GrimAge2Mortacc, may serve as valuable tools for CVD risk stratification and mortality risk assessment.