Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.
Tick tock, tick tock: Mouse culture and tissue aging captured by an epigenetic clock.
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DOI：
10.1111/acel.13553
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发表时间：
2022-03
期刊：
影响因子：
7.8
通讯作者：
Levine ME
中科院分区：
文献类型：
--
作者：
Minteer C;Morselli M;Meer M;Cao J;Higgins-Chen A;Lang SM;Pellegrini M;Yan Q;Levine ME
衰老与DNA甲基化（DNAm）的巨大变化有关，尽管这种变化的原因和后果尚不清楚。我们通过实验发现表观遗传衰老机制的能力将大大增强我们使用体外模型研究和操纵这些变化的能力。然而，目前还不清楚培养中的细胞引起的变化是否可以作为体内衰老组织中观察到的变化的模型。为了测试这一点，我们连续传代小鼠胚胎成纤维细胞（MEF），并通过减少代表性亚硫酸氢盐测序评估在每个时间点的DNAm的变化。通过开发一种在体外跟踪细胞衰老的方法，我们测试了它是否跟踪了各种小鼠组织的生理衰老，以及抗衰老干预措施是否调节了这种方法。我们的测量，称为CultureAGE，在多个组织（肝，肺，肾，血液和脂肪）中检查时，显示出随着年龄的增长而强烈增加。作为对照，我们证实该测量不是细胞衰老的标志物，这表明它反映了可以在体外诱导的独特但进行性的细胞衰老现象。此外，我们证明了在经历热量限制的动物中的表观遗传衰老较慢，并且当重新编程为iPSC时，我们在肺和肾成纤维细胞中的测量重新设定。富集和聚类分析牵连EED和Polycomb组（PcG）的因素作为潜在的重要染色质调节剂在翻译文化老化表型。总的来说，这项研究支持的概念，生理相关的衰老变化可以在体外诱导，并用于揭示机制的见解表观遗传衰老。我们提出了一种培养衰老模型来训练一种新的表观遗传年龄预测因子CultureAGE，并验证了多个衰老小鼠体内队列中多组织生理相关性的测量。然后，我们研究了时钟的内部运作，发现文化表观遗传衰老可以通过热量限制和重编程来调节，并由富含Polycomb组因子的CpG驱动。
Aging is associated with dramatic changes to DNA methylation (DNAm), although the causes and consequences of such alterations are unknown. Our ability to experimentally uncover mechanisms of epigenetic aging will be greatly enhanced by our ability to study and manipulate these changes using in vitro models. However, it remains unclear whether the changes elicited by cells in culture can serve as a model of what is observed in aging tissues in vivo. To test this, we serially passaged mouse embryonic fibroblasts (MEFs) and assessed changes in DNAm at each time point via reduced representation bisulfite sequencing. By developing a measure that tracked cellular aging in vitro, we tested whether it tracked physiological aging in various mouse tissues and whether anti‐aging interventions modulate this measure. Our measure, termed CultureAGE, was shown to strongly increase with age when examined in multiple tissues (liver, lung, kidney, blood, and adipose). As a control, we confirmed that the measure was not a marker of cellular senescence, suggesting that it reflects a distinct yet progressive cellular aging phenomena that can be induced in vitro. Furthermore, we demonstrated slower epigenetic aging in animals undergoing caloric restriction and a resetting of our measure in lung and kidney fibroblasts when re‐programmed to iPSCs. Enrichment and clustering analysis implicated EED and Polycomb group (PcG) factors as potentially important chromatin regulators in translational culture aging phenotypes. Overall, this study supports the concept that physiologically relevant aging changes can be induced in vitro and used to uncover mechanistic insights into epigenetic aging. We proposed a culture aging model to train a novel epigenetic age predictor, CultureAGE, and validated the measure for multi‐tissue physiological relevance in multiple aged mouse in vivo cohorts. We then investigated the inner workings of the clock and found culture epigenetic aging can be modulated via caloric restriction and reprogramming and is driven by CpGs enriched in Polycomb group factors.
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影响因子：
3
作者：
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通讯作者：
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全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
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影响因子：
16
作者：
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DOI：
10.1073/pnas.1511377112
发表时间：
2015-11-17
影响因子：
11.1
作者：
Basenko, Evelina Y.;Sasaki, Takahiko;Lewis, Zachary A.
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Lewis, Zachary A.
影响因子：
1.5
作者：
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通讯作者：
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