CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
TruDiagnostics, Lexington, KY, USA.
Nat Aging. 2024 Jun;4(6):886-901. doi: 10.1038/s43587-024-00600-8. Epub 2024 May 9.
DNA methylation clocks can accurately estimate chronological age and, to some extent, also biological age, yet the process by which age-associated DNA methylation (DNAm) changes are acquired appears to be quasi-stochastic, raising a fundamental question: how much of an epigenetic clock's predictive accuracy could be explained by a stochastic process of DNAm change? Here, using DNAm data from sorted immune cells, we build realistic simulation models, subsequently demonstrating in over 22,770 sorted and whole-blood samples from 25 independent cohorts that approximately 66-75% of the accuracy underpinning Horvath's clock could be driven by a stochastic process. This fraction increases to 90% for the more accurate Zhang's clock, but is lower (63%) for the PhenoAge clock, suggesting that biological aging is reflected by nonstochastic processes. Confirming this, we demonstrate that Horvath's age acceleration in males and PhenoAge's age acceleration in severe coronavirus disease 2019 cases and smokers are not driven by an increased rate of stochastic change but by nonstochastic processes. These results significantly deepen our understanding and interpretation of epigenetic clocks.
DNA 甲基化时钟可以准确估计年龄，在某种程度上还可以估计生物年龄，然而，与年龄相关的 DNA 甲基化（DNAm）变化的发生过程似乎是准随机的，这就提出了一个基本问题：表观遗传时钟的预测准确性有多少可以用 DNAm 变化的随机过程来解释？在这里，我们使用来自分选免疫细胞的 DNAm 数据构建了现实的模拟模型，随后在来自 25 个独立队列的 22770 多个分选和全血样本中证明，大约 66-75%的 Horvath 时钟的准确性可以由随机过程驱动。对于更准确的 Zhang 时钟，这一分值增加到 90%，但对于 PhenoAge 时钟则较低（63%），这表明生物衰老反映了非随机过程。证实了这一点，我们证明了 Horvath 时钟在男性中的年龄加速和 PhenoAge 时钟在严重的 2019 年冠状病毒病病例和吸烟者中的年龄加速不是由随机变化的增加速度驱动的，而是由非随机过程驱动的。这些结果大大加深了我们对表观遗传时钟的理解和解释。
