Epigenetic Age Acceleration as a Modifiable Public Health Target: A Systematic Review and Meta-Analysis of...

Chronological age is a poor indicator of interindividual differences in biological aging. DNA methylation-based epigenetic clocks provide a reliable measure of biological age and epigenetic age acceleration (EAA). Although modifiable behavioral, environmental, and social factors appear to influence EAA, the magnitude, consistency, and potential preventability of these associations have never been systematically quantified. We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus were searched from inception to 7 April 2026 for English-language observational and interventional studies reporting quantitative associations between modifiable determinants and EAA measured using validated clocks (Horvath, PhenoAge, GrimAge, DunedinPACE). Effect sizes were harmonized into four analytical pools. Random-effects meta-analyses were performed using the DerSimonian-Laird estimator, with pre-specified subgroup analyses by exposure category. Heterogeneity, publication bias, and robustness were thoroughly assessed. A novel Modifiable Epigenetic Aging Burden Index (MEAB-Index) was developed to quantify the cumulative preventable burden. Only studies conducted in adult populations (≥18 years) were eligible. Eighty-three studies providing 118 distinct exposure-clock associations were included. In the primary analysis (Pool A, n = 60), adverse modifiable exposures were associated with accelerated EAA (pooled β = +0.310 years per unit exposure, 95% CI 0.255-0.366). The strongest associations were observed for metabolic and inflammatory markers (β = +0.913) and environmental exposures (β = +0.466). The MEAB-Index yielded a Cumulative Preventable Burden of +1.566 years (bootstrap 95% CI 1.011-2.123). Findings were robust across sensitivity analyses and remained directionally consistent in secondary pools (B-D). This study provides the most comprehensive quantitative synthesis to date on the modifiability of epigenetic aging. Our findings demonstrate that EAA is meaningfully shaped by behavioral, environmental, and social determinants. The MEAB-Index introduces a novel framework for estimating the preventable burden of biological aging and for prioritizing interventions. Reducing key modifiable risk factors, particularly metabolic/inflammatory and environmental exposures, could substantially slow biological aging at the population level and support the transition toward ageing-centered preventive strategies.