A multi-tissue full lifespan epigenetic clock for mice [I]. A multi-tissue full lifespan epigenetic clock for mice [I]

Human DNA-methylation data have been used to develop highly accurate biomarkers of aging ("epigenetic clocks"). Recent studies demonstrate that similar epigenetic clocks for mice (Mus Musculus) can be slowed by gold standard anti-aging interventions such as calorie restriction and growth hormone receptor knock-outs. Using DNA methylation data from previous publications with data collected in house for a total 1189 samples spanning 193,651 CpG sites, we developed 4 novel epigenetic clocks by choosing different regression models (elastic net- versus ridge regression) and by considering different sets of CpGs (all CpGs vs highly conserved CpGs). We demonstrate that accurate age estimators can be built on the basis of highly conserved CpGs. However, the most accurate clock results from applying elastic net regression to all CpGs. While the anti-aging effect of calorie restriction could be detected with all types of epigenetic clocks, only ridge regression based clocks replicated the finding of slow epigenetic aging effects in dwarf mice. Overall, this study demonstrates that there are trade-offs when it comes to epigenetic clocks in mice. Highly accurate clocks might not be optimal for detecting the beneficial effects of anti-aging interventions. Overall design: Reduced representation bisulfite-sequencing (RRBS) data from public and in-house sources were processed consistently and merged to form a set of over 1000 mouse samples from various tissues and chronological ages. These data were used to investigate the relationship between chronologic age and epigenetic age.

研究团队已基于人类DNA甲基化数据开发出高精度衰老生物标志物——表观遗传时钟（epigenetic clocks）。近期研究证实，针对小家鼠（Mus Musculus）的同类表观遗传时钟，可通过热量限制、生长激素受体敲除等金标准抗衰老干预手段实现衰老延缓。本研究整合既往公开文献中的DNA甲基化数据与实验室自研采集的样本数据，共计纳入1189个样本、193651个CpG位点；通过选用弹性网回归与岭回归两种不同回归模型，并分别针对全部CpG位点与高度保守CpG位点两类位点集合，开发了4种新型小鼠表观遗传时钟。研究结果显示，仅基于高度保守CpG位点即可构建精准的年龄预测模型；而将弹性网回归应用于全部CpG位点时，可得到精度最高的表观遗传时钟模型。尽管所有类型的表观遗传时钟均可检测到热量限制的抗衰老效应，但仅基于岭回归的时钟模型，可重复出侏儒小鼠表观遗传衰老延缓的研究结论。总体而言，本研究表明小鼠表观遗传时钟的开发存在权衡取舍：高精度时钟或许并非检测抗衰老干预有益效应的最优方案。实验整体设计：对来自公开数据源与实验室自研的简化代表性亚硫酸氢盐测序（Reduced representation bisulfite-sequencing, RRBS）数据进行统一处理与合并，最终构建得到覆盖多种组织、不同实足年龄的逾千份小鼠样本数据集；利用该数据集探究实足年龄与表观年龄之间的关联。