BACKGROUND The role of DNA methylation in aging has been widely studied. However, epigenetic mutations, here defined as aberrant methylation levels compared to the distribution in a population, are less understood. Hence, we investigated longitudinal accumulation of epigenetic mutations, using 994 blood samples collected at up to five time points from 375 individuals in old ages. RESULTS We verified earlier cross-sectional evidence on the increase of epigenetic mutations with age, and identified important contributing factors including sex, CD19+ B cells, genetic background, cancer diagnosis, and technical artifacts. We further classified epigenetic mutations into High/Low Methylation Outliers (HMO/LMO) according to their changes in methylation, and specifically studied methylation sites (CpGs) that were prone to mutate (frequently mutated CpGs). We validated four epigenetically mutated CpGs using pyrosequencing in 93 samples. Furthermore, by using twins, we concluded that the age-related accumulation of epigenetic mutations was not related to genetic factors, hence driven by stochastic or environmental effects. CONCLUSIONS Here we conducted a comprehensive study of epigenetic mutation and highlighted its important role in aging process and cancer development.

中文翻译：

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对衰老中表观遗传突变的综合纵向研究。

背景技术已经广泛研究了DNA甲基化在衰老中的作用。然而，对表观遗传突变（这里定义为与人群中分布相比异常的甲基化水平）的了解较少。因此，我们使用多达375个老年人的五个时间点收集的994个血液样本，调查了表观遗传突变的纵向积累。结果我们验证了表观遗传突变随年龄增加的早期横断面证据，并确定了重要的促成因素，包括性别，CD19 + B细胞，遗传背景，癌症诊断和技术伪像。我们根据甲基化的变化将表观遗传突变进一步分为高/低甲基化离群值（HMO / LMO），并专门研究了易于突变的CpGs（经常发生突变的CpGs）。我们在93个样品中使用焦磷酸测序验证了四个表观遗传突变的CpG。此外，通过使用双胞胎，我们得出结论，表观遗传突变的年龄相关积累与遗传因素无关，因此是由随机或环境影响驱动的。结论在这里，我们对表观遗传突变进行了全面的研究，并强调了其在衰老过程和癌症发展中的重要作用。