Accelerated biological aging based on DNA methylation clocks is a predictor of stroke occurrence: a systematic review and meta-analysis

Background: Although traditional vascular risk factors, such as hypertension and diabetes, are incorporated into stroke risk prediction models, a significant proportion of stroke events remain unexplained by these models. Increasing evidence suggests that accelerated biological aging, as measured by DNA methylation clocks, may reflect reduced organ function and heightened susceptibility to disease. However, the relationship between epigenetic age acceleration (EAA) and stroke risk remains poorly understood, with limited comprehensive synthesis of the available evidence. Methods: We conducted a systematic search of PubMed, Embase, Web of Science, and Cochrane Library databases (up to January 10, 2025) for observational studies examining the relationship between DNA methylation-derived EAA and stroke risk. The study protocol was registered with PROSPERO (CRD420251010621). Results: Thirteen studies met the inclusion criteria. Random-effects meta-analysis revealed a significant positive association between accelerated biological aging and stroke risk (OR = 1.16, 95% CI 1.13–1.19, I² = 98.9%, p < 0.001). Stratified analysis by stroke event demonstrated a stronger association with incident stroke (OR = 1.28, 95% CI 1.25–1.35, I² = 92.6%, p = 0.001) compared to stroke recurrence (OR = 1.11, 95% CI 1.06–1.16, I² = 63.6%, p = 0.041). Sensitivity analyses confirmed the robustness of these findings. Conclusion: DNA methylation-derived measures of accelerated biological aging are robust predictors of stroke. These findings provide new insights into stroke risk assessment and emphasize potential biomarkers for early detection and prevention. Further large-scale prospective studies are needed to validate these associations and examine the role of additional modifying factors.