Epigenetic Aging and its association with cardiovascular and diseases: Systematic review and meta-analysis of cohort studies

Introduction Epigenetic clocks are models based on biomarkers developed to estimate an individual’s biological age, independently of chronological age. These tools could eventually be useful to assess cardiovascular (CV) risk, but the evidence for their clinical utility remains limited. Material &Methods We conducted a systematic review of cohort studies reporting epigenetic clocks as exposure (with firstgeneration clocks Horvath and Hannum, and second-generation clocks PhenoAge and GrimAge) and ASCVD (atherosclerotic cardiovascular disease), including CVD incidents, coronary heart disease, and stroke as outcomes. We searched MEDLINE, Embase, and Google Scholar up to 01.08.2024. Adjusted hazard ratios (HRs) for each clock were extracted and standardized in 5-year increments. Pooled effect estimates were then derived using a random-effects meta-analysis. Results Of the 928 screened records, 18 were eligible for inclusion, of which 9 were included in the meta-analysis; this corresponds to a total of 29,009 participants, with 16,075 women (55.4%) and 3,445 ASCVD events. First-generation clocks showed modest associations. Six studies reported Horvath (N = 19,916, HR = 1.05, 95% CI = 1.02–1.08, I² = 0.1%), and seven reported Hannum (N = 26,916, HR = 1.08, 95% CI = 1.02– 1.14, I² = 64.7%). Second-generation clocks demonstrated stronger associations. Five studies reported GrimAge (N = 22,402, HR = 1.31, 95% CI = 1.11–1.55, I² = 97.7%). Five studies reported DNAmPhenoAge (N = 22,402, HR = 1.14, 95% CI = 1.11–1.17, I² = 0.1%). Conclusion Epigenetic age acceleration measured using GrimAge is associated with an increased risk of CV disease. These findings support the potential utility of integrating epigenetic clocks into CV risk assessment or as potential surrogate markers in studies investigating interventions aimed at reducing CV risk.