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BACKGROUND: Biological aging is thought to be associated with colorectal cancer (CRC), however, the mechanisms underlying are not fully understood. This study aimed to elucidate how biological aging contributes to the onset of CRC.METHODS: We first performed a longitudinal cohort study (5448 incident CRC and 317,192 controls) to evaluate the relationships between biological aging (i.e., leukocyte telomere length, PhenoAge, Klemera-Doubal, homeostatic dysregulation [HD] score, frailty) and CRC, and assessed how it contributes to the association of modifiable risk factors with CRC using Cox regression models. Then, we performed Mendelian randomization (MR) studies to evaluate the relationship of biological aging with CRC risk from the epigenetic perspective (epigenetic aging clocks). Finally, a three-step MR analysis between aging-related DNA methylation (DNAm), gene expression, and CRC followed by colocalization analysis was performed to elucidate the CpGs/genes and possible pathways underlying aging and CRC.FINDINGS: In the longitudinal cohort study, we found PhenoAge acceleration and HD score associated with increased CRC risk, and these associations were stronger for early-onset CRC (HR [95% CI]: 1.29 [1.07-1.55] for PhenoAge acceleration and 1.35 [1.08-1.69] for HD score) than late-onset CRC (HR [95% CI]: 1.06 [1.03-1.09] for PhenoAge acceleration and 1.05 [1.02-1.08] for HD score) (P<0.05). Accelerated biological aging partly mediated the adverse effect of unhealthy lifestyle and its components on CRC, with proportions of mediation ranging from 0.18% to 27.00%. In the epigenetic MR, genetically determined DNAm GrimAge was positively associated with CRC risk. Altered methylation at 15 aging-related CpGs was associated with CRC and was prioritized with high colocalization evidence. Four mapped genes (TNF, BICC1, NCF2, DIP2B) were significantly associated with CRC. The lower expression of TNF, NCF2, and DIP2B mediated the adverse effect of the methylation at cg04425624 and cg03037030 (TNF), cg09076123 (NCF2), and cg05512157 (DIP2B) on CRC, respectively, and higher expression of BICC1 mediated the adverse effect of the methylation at 4 CpGs (cg08353444, cg23963517, cg06424110, cg09578524) on CRC.INTERPRETATION: This study found that accelerated biological aging was associated with a higher risk of CRC and implied potential intervention opportunities by adherence to healthy lifestyles. Aging-related DNAm and altered gene expression might contribute to this biological association, which yielded insights into the etiology and potential therapeutic targets of CRC.FUNDING: The National Nature Science Foundation of China, Zhejiang Provincial Clinical Research Center for CANCER, and the National Institutes of Health.