Accelerated biological aging and its hallmarks in DNA methylation drive the association between unhealthy lifestyles and the onset of colorectal cancer

作者：Jing Sun, Min Liu, Xiaoqian Zhang, Xinxuan Li, Xinxuan Li, Jingyu Ye, Jianhui Zhao, Siyun Zhou, Haosen Ji, Yuqian Tan, Zilong Bian, Dongfeng Zhang, Malcolm G. Dunlop, Mingyang Song, Stephanie A. Smith‐Warner, Hao Wu, Evropi Τheodoratou, Qian Cao, Xue Li, Xue Li · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.106005 · 被引用次数：6 · 研究领域：Epigenetics and DNA Methylation、Telomeres, Telomerase, and Senescence、Dietary Effects on Health

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: <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 significant...