The use of epigenetic clocks to measure biological age faces a significant challenge in establishing a causal connection between the methylation status of specific CpG sites on the genome and age-related damage and dysfunction. This lack of connection renders the results obtained from epigenetic clock assays not actionable for guiding health practices or interventions. Various approaches, including Mendelian randomization, are being developed to address this challenge and connect DNA methylation to underlying mechanisms of aging. New epigenetic clocks, such as CausAge, DamAge, and AdaptAge, aim to distinguish between harmful and adaptive methylation changes and provide valuable insights for identifying biomarkers and evaluating interventions for promoting longevity and combating aging. These causality-enriched clocks offer a detailed landscape of CpG sites with putative causal links to lifespan and healthspan, enabling further studies on age-associated changes and potential reversibility.
