Blood methylation clocks capture two distinct biological domains of aging

In human participants from the Family and Community Health Study, researchers evaluated whether blood-based DNA methylation aging scores reflect a single process or distinct biological domains. They evaluated a replication and mitotic domain, indexed by CellDRIFT, EpiTOC2, and MiAge, against an early-life systemic dysregulation domain, indexed by DunedinPACE, GrimAgeV2, and PhenoAge. Regression analyses demonstrated clear domain specificity. C-reactive protein, body mass index, alcohol-related methylation, and AHRR/cg05575921 were positively associated with systemic dysregulation but showed weak or null associations with mitotic replication. Cross-domain tests confirmed significantly stronger associations for the systemic dysregulation domain across these markers. In contrast, telomere-related methylation, measured by DNAmTL, was inversely associated with both domains and did not differ significantly between them. The findings confirm that blood methylation scores separate replication-driven mitotic aging from systemic vulnerability.