DNA methylation-based epigenetic clocks highlight immune-driven aging acceleration in COVID-19 across diverse...

The SARS-CoV-2 pandemic has affected millions worldwide, with aging being a key risk factor for severe disease outcomes. This study examines the rate of epigenetic aging, as measured by DNA methylation-based aging markers, in COVID-19 patients versus healthy individuals. We found that PCGrimAge, a next-generation epigenetic clock associated with immune dysregulation and inflammation, showed the strongest correlation with the chronological age of the European COVID-19 patients. Several other next-generation epigenetic clocks, including PCGrimAge, DunedinPACE, and ZhangY2017, also exhibited accelerated aging in both older and female COVID-19 patients. Interestingly, first-generation clocks, such as Hannum2013, indicated a significant reduction in epigenetic aging, likely reflecting limitations in their sensitivity to infection-related biological changes rather than an actual deceleration of the aging process. Our results also showed that immune dysregulation, rather than intrinsic cellular aging, may be the primary driver of accelerated epigenetic aging in COVID-19. This is supported by stronger associations observed in Age Acceleration (AA) and Extrinsic Epigenetic Age Acceleration (EEAA) compared to Intrinsic Epigenetic Age Acceleration (IEAA). Furthermore, immune dysregulation may be linked to CpG site demethylation, which in turn influences epigenetic clock dynamics. We also identified disparities between European and non-European populations, characterized by significantly higher IEAA for PCPhenoAge and DunedinPACE among non-European patients with COVID-19. In summary, our results underscore the differential sensitivity of epigenetic clocks to COVID-19-related biological changes.