DNA甲基化与人类健康衰老

DNA methylation and healthy human aging

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|核心内容：

人体衰老过程伴随着细胞和分子水平的一系列变化，包括细胞衰老、端粒缩短和基因表达的变化。表观遗传模式也会随着寿命的延长而变化，这表明表观遗传变化可能构成衰老过程的重要组成部分。研究最多的表观遗传标记是DNA甲基化，即CpG二核苷酸上存在甲基。这些二核苷酸通常位于基因启动子附近，并与基因表达水平相关。早期研究表明，全基因组DNA甲基化水平在生命的最初几年逐年上升，然后在成年后期开始下降。最近，随着微阵列和下一代测序技术的出现，人们观察到DNA甲基化的变异性随年龄的增加而增加，并发现了一些位点特异性的模式。研究还表明，某些CpG位点与年龄高度相关，以至于使用少量这些位点的预测模型可以准确地预测测试者的实际年龄。总而言之，这些观察指出了两种现象的存在：表观遗传漂移和表观遗传时钟。这两种现象都与年龄相关的DNA甲基化变化有关，甚至存在因果关系。在这篇文章中，我们关注人类一生中的健康衰老，并讨论DNA甲基化的动态变化以及基因组、环境和表观基因组之间的相互作用如何影响衰老速率。我们还讨论了确定“表观遗传年龄”对人类健康的影响，并概述了对现有和未来的相关研究的一些重要警告。

图1：表观遗传漂移与表观遗传时钟的示意图

如果一个特定的CpG位点与个体内的年龄(顶部)相关，它可能正在经历表观遗传漂移(左)或表观遗传时钟位点(右）。这两种现象都有不同的特点，当审查跨越一个群体或在一个孪生集合。

原文摘要：

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next-generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site-specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age-related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining 'epigenetic age’ for human health and outline some important caveats to existing and future studies. 

Key words: aging; DNA methylation; epigenetics; human; review.

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参考文献：https://sci-hub.se/10.1111/acel.12349