Biological Aging in Combination with Lifestyle Factors in the Blood-Based Methylome: A Biomarker for Colorectal Cancer Susceptibility in African American Women

DNA methylation (DNAm)-based estimators of age are highly accurate for biological aging in multiple tissues, but their functional roles remain poorly understood in colorectal cancer (CRC), an age-related disease whose burden is higher in aged African Americans (AAs) than in whites. A greater rate of epigenetic age deviation from chronologic age was observed in AAs' colorectal tissues than in whites', emphasizing AA-specific investigation for epigenetic aging in CRC. Tumor tissue-based DNAm exclusively reflects cancerization, raising a question about its cancer predictability. A prediagnostic peripheral blood leukocyte (PBL)-based DNAm aging marker may thus provide keys to CRC etiology and prevention. From the largest study cohort, we examined 621 AA postmenopausal women 50-79 years old, including a subset of 14 who developed CRC, with their prediagnostic PBL-DNAm. Using three well-known pan-tissue- and blood-based epigenetic clocks, we evaluated correlations with CRC risk and to what degree the cancer risk is modified by lifestyle factors. Epigenetically older age and increased age acceleration were associated with reduced risk for CRC development. Of note, when women had accelerated aging phenotypes at screening, a substantial increased CRC risk was observed in short-term users of exogeneous estrogen, while a profound risk reduction was shown in women eating a healthy diet. Our study contributes to better understanding of the exertion of lifestyle factors in combination with methylome-based aging in colorectal carcinogenesis, detecting a prediagnostic PBL-based aging biomarker that promotes epigenetically targeted strategies tailored to aged AA women at high risk.