Yan Qi, Paul Kimberly C, Lu Ake T, Kusters Cynthia, Binder Alexandra M, Horvath Steve, Ritz Beate
Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Aging (Albany NY). 2020 Sep 29;12(18):17863-17894. doi: 10.18632/aging.103950.
DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.
DNA甲基化（DNAm）年龄估计器被广泛用于研究与衰老相关的状况。目前尚不清楚DNAm年龄是否与随机表观遗传突变（SEM）的积累有关，而随机表观遗传突变反映了表观遗传维持系统的功能障碍。在这里，我们将表观遗传突变负荷（EML）定义为每个个体的SEM总数。我们在四项基于人群的研究（总计n = 6388）中使用双权中相关评估了EML与DNAm年龄加速估计器之间的关联。EML不仅与实际年龄呈正相关（元r = 0.171），还与四种表观遗传年龄加速指标相关：霍瓦斯全组织时钟、内在表观遗传年龄加速、汉纳姆时钟和格里姆年龄时钟（荟萃分析相关性范围从r = 0.109至0.179）。我们进一步对每个参与者的SEM进行了通路富集分析。富集结果证明了表观遗传突变的随机性，同时涉及多个通路：信号传导、神经发生、神经递质、糖皮质激素和昼夜节律通路可能导致更快的DNAm年龄加速。最后，研究基因组区域特异性EML时，我们发现位于转录抑制区域（TSS1500、TSS200和第1外显子）内的EML与更快的年龄加速相关。总体而言，我们的研究结果表明表观遗传突变的积累在衰老过程中发挥作用。
