BACKGROUND Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual's susceptibility to age-related diseases such as CRC. METHODS We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual's chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. RESULTS Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10-30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. CONCLUSIONS Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.

中文翻译：

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正常结肠癌和结直肠癌风险的功能失调表观遗传老化。

背景实际年龄是包括结直肠癌(CRC)在内的多种癌症的显着风险因素。然而，即使在同一年龄组内，个体之间的 CRC 风险也存在很大差异，这可能反映了人与人之间生物组织老化的异质性。基于 DNA 甲基化的表观遗传时钟是生物衰老过程的有用度量，有可能作为个体对年龄相关疾病（如 CRC）易感性的生物标志物。方法 我们对正常结肠黏膜样本（N = 334）进行了全基因组 DNA 甲基化研究。根据他们的个人腺瘤或癌症病史，将受试者分配到三个癌症风险组（低、中和高）。使用先前建立的表观遗传时钟（Hannum、Horvath、PhenoAge 和 EpiTOC），我们估计了每个样本的生物学年龄，并通过将估计的生物学年龄回归到个体的实际年龄来评估样本中的表观遗传年龄加速。我们使用多元线性回归模型比较了不同风险组之间的表观遗传年龄加速，并调整了每个表观遗传时钟的性别和细胞类型分数。进行了全表观基因组关联研究 (EWAS) 以确定与 CRC 风险相关的差异甲基化变化。结果 每个表观遗传时钟与受试者的实际年龄显着相关，Horvath 时钟在所有风险组中表现出最强的相关性（r > 0.8，p < 1 × 10-30）。PhenoAge 时钟 (p = 0.0012) 显示与低风险组相比，高风险组的表观遗传年龄减慢。结论 在四种基于 DNA 甲基化的生物年龄测量中，Horvath 时钟是估计个体实足年龄最准确的。具有高 CRC 风险的个体在通过 PhenoAge 时钟测量的正常结肠中具有表观遗传年龄减速，这可能反映了功能失调的表观遗传衰老过程。