Do epigenetic aging biomarkers mediate the association between exposure and health outcomes? A scoping review of mediation analysis

Epigenetic aging biomarkers are promising novel biological age indicators derived from algorithms based on DNA methylation patterns. Since epigenetic age was first described over a decade ago, it has been used as an exposure or an outcome in biomedical research to address the fundamental question of “aging”. Yet, a critical question remains unresolved: how epigenetic age mediates the effects of exposures on health outcomes. Mediation analysis provides a rigorous statistical framework for decomposing total effects into direct and indirect pathways, thereby testing the extent to which epigenetic age deviation explains exposure-outcome relationships. Meanwhile, the reporting quality using mediation analysis varied across studies. This scoping review provides a methodological primer on causal mediation analysis and a literature review using epigenetic age as a mediator with quality assessment. We conducted an initial literature search through four online databases (PubMed, Embase, MEDLINE, and CINAHL) at the beginning of September 2025. We identified 22 studies (published since 2022) examining epigenetic aging as a mediator between environmental/lifestyle exposures and health outcomes. Most studies used blood-based DNA methylation and applied causal mediation frameworks. GrimAge, PhenoAge, and DunedinPACE were more frequently used. Outcomes primarily included mortality and cardiovascular disease, while exposures covered smoking, diet, socioeconomic factors, clinical biomarkers, and environmental pollutants. Although causal mediation analysis suggested that epigenetic aging could be a possible mechanistic mediator linking exposures to disease risk, many studies lacked methodological rigor. To enhance epigenetic evaluation in broad settings, further work should apply causal mediation analysis to epigenetic aging markers with a rigorous methodology.