Interpreting Epigenetic Clocks Through Causal Interventions

Epigenetic clocks are widely used to quantify biological aging, yet their interpretation is often implicitly predictive rather than causal. In particular, reductions in clock‑estimated age are frequently equated with aging reversal, despite most clocks capturing DNA methylation patterns that lie downstream of aging biology and remain sensitive to confounding, disease status, and direct epigenetic manipulation. Here, we propose a causal framework for interpreting epigenetic clocks by situating them relative to interventions that act at distinct levels of the aging system. Using caloric restriction as an upstream causal benchmark, CR mimetics as partial pathway perturbations, and partial reprogramming as a direct epigenetic stress test, we show how clock responses can be decoupled from true modification of aging biology. This framework clarifies what epigenetic clocks can legitimately claim and provides guidance for their interpretation and future development as causally interpretable tools in aging research.