When to Trust Epigenetic Clocks: Avoiding False Positives in Aging Interventions.

Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance. We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable PC-based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria. These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.