Concordance between changes in epigenetic clocks and changes in clinical outcomes in geroscience intervention trials: A systematic review

OBJECTIVE: To evaluate whether intervention-induced changes in epigenetic clocks correspond to changes in clinical outcomes in human geroscience intervention studies. METHODS: We systematically reviewed studies reporting pre-post changes in at least one DNA-methylation clock and one clinical outcome. Study-level concordance was classified from paired clock and clinical effects. Individual-level change associations, mediation analyses, risk of bias, and certainty of evidence were also assessed. RESULTS: Twenty-six independent studies were included: 13 comparative and 13 single-arm pre-post studies. Fifteen were mixed, six indeterminate, four jointly inconclusive, and one uncontrolled study uniformly concordant for intermediate outcomes; no comparative study or study of patient-important outcomes was uniformly concordant. Eleven studies assessed individual-level associations, responder differences, or mediation, but clear findings were isolated and not replicated across independent studies. No intervention-clock-clinical outcome combination met the criteria for meta-analysis, and no trial-level surrogate-endpoint validation was identified. Certainty was very low across all assessed evidence bodies. CONCLUSION: Concordance between epigenetic-clock and clinical-outcome changes was inconsistent, with favorable signals concentrated mainly in selected intermediate outcomes. Epigenetic clocks should currently be considered exploratory or adjunctive biomarkers of intervention response rather than validated clinical surrogate endpoints.