Epigenetic age and accelerated aging phenotypes: a tumor biomarker for predicting colorectal cancer.

Background: Epigenetic clocks, estimated via DNA methylation (DNAm), reflect individuals' biological aging in multiple tissues and are associated with age-related diseases, but their functional role in colorectal cancer (CRC), an age-associated disease, remains unconclusive. DNAm in tumor tissues exclusively exhibits cancerization with expansion of a stem cell pool, leading to the lowest DNAm age; this raises a question about its cancer predictability. Thus, the DNAm aging marker in pre-diagnostic peripheral blood leukocytes (PBLs) may provide key information on CRC etiology and prevention. We aim to examine pre-diagnostic epigenetic makers for aging in PBLs in association with CRC development and risk modification by lifestyles.

Methods: Using data from a large cohort study of white postmenopausal women, we examined biological aging status in PBLs via three well-established epigenetic clocks-Horvath's, Hannum's and Levine's-and prospectively evaluated CRC development in relation to the aging markers and risk modification by lifestyle factors.

Results: The epigenetic clocks strongly correlated with chronological age, and older DNAm age and age acceleration were significantly associated with increased risk for CRC. Women with bilateral oophorectomy before natural menopause had substantially higher risk for CRC development when they also had epigenetically accelerated aging phenotypes. Among women who maintained healthy dietary patterns, no apparently higher risk was found in those with accelerated aging compared with those with decelerated aging.

Conclusions: Our findings contribute to better understanding of the role of a pre-diagnostic epigenetic aging biomarker and its interplay with lifestyles in CRC carcinogenesis, informing risk stratification strategies for aged individuals.