a Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center , New York , NY , USA.
b Division of Environmental Health Sciences, University of California, Berkeley, School of Public Health , Berkeley , CA , USA.
Epigenetics. 2019 Oct;14(10):961-976. doi: 10.1080/15592294.2019.1626651. Epub 2019 Jun 12.
Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform . Here we culture primary human fibroblasts across the cellular lifespan (~6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated . The Skin & Blood clock shows the best linear correlation with chronological time (r = 0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to -47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high-temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan.
衰老与 DNA 甲基化（DNAm）的进行性和特定部位的变化有关。这些全局变化由 DNAm 时钟捕捉，这些时钟可以准确预测人类的实际年龄，但相对而言，人们对时钟的表现方式知之甚少。在这里，我们在细胞寿命（约 6 个月）范围内培养原代人成纤维细胞，并使用四种不同的 DNAm 时钟来显示与年龄相关的 DNAm 特征是保守和加速的。皮肤和血液时钟与时间的线性相关性最好（r=0.90），包括在复制性衰老期间。尽管性质相似，但在培养细胞中的表观遗传衰老速度大约是人体中的 62 倍。与数据一致，在高血糖条件下老化的细胞表现出大约三年的基线 DNAm 年龄升高。此外，基于候选基因的分析进一步证实了培养成纤维细胞中保守但加速的生物学衰老过程。成纤维细胞反映了人类血液中与年龄相关基因的既定 DNAm 拓扑结构，以及其启动子 cg16867657 的快速 hypermethylation，该启动子与 ELOVL2 mRNA 水平在整个寿命过程中的线性下降相关。使用十二个时间点的广义加性建模，我们还展示了单个 CpG 如何表现出特定位置、线性和非线性轨迹，其达到的速率高达每月 -47%（低甲基化）到 +23%（高甲基化）。总之，这些具有高时间分辨率的全局、基因特异性和单个 CpG 数据突出了培养成纤维细胞中表观遗传衰老的保守和加速性质，这可能构成了一个系统，可以在整个生命周期内评估年龄修饰干预措施。
