Two Separable Aging Domains in Blood DNA Methylation Scores Developed for Cancer Research: Mitotic Replication and Early-Life Systemic Dysregulation.

Background/Objectives: DNA methylation (DNAm)-based aging measures are increasingly being used in biological aging, disease vulnerability, and cancer-related risk. However, it remains unclear whether these measures capture a single generalized aging process or separable biological domains relevant to cancer-relevant biological vulnerability. Methods: Using data from the Family and Community Health Study (FACHS), we examine whether blood-based DNAm scores capture two distinct biological domains relevant to cancer susceptibility: a replication/mitotic domain, indexed by CellDRIFT, EpiTOC2, and MiAge, and an early-life systemic dysregulation domain, indexed by DunedinPACE, GrimAgeV2, and PhenoAge. Results: Regression results showed clear domain specificity. CRP, BMI, alcohol methylation, and AHRR/cg05575921 were positively associated with the early-life systemic dysregulation domain but showed weak or null associations with the replication/mitotic domain. Cross-domain tests confirmed significantly stronger associations for the early-life systemic dysregulation domain for CRP, BMI, and alcohol methylation, with a marginal difference for AHRR/cg05575921. In contrast, telomere-related methylation and immune-cell composition showed a different pattern. DNAmTL was inversely associated with both domains and did not differ significantly across domains. Conclusions: These findings suggest that blood-based DNAm aging measures do not reflect a single aging process. Instead, they distinguish at least two cancer-relevant methylation domains: one reflecting replication-driven mitotic aging and hematopoietic cell-turnover biology, and another reflecting early-life systemic dysregulation vulnerability linked to inflammation, metabolic risk, smoking methylation, and alcohol-related methylation. This two-domain framework may help clarify how blood DNAm profiles capture complementary biological processes relevant to cancer susceptibility and guide future studies of methylation-based cancer risk.