2023,
Cell.
DOI:
10.1016/j.cell.2022.12.027
Loss of epigenetic information as a cause of mammalian aging
Jae-Hyun Yang
, Motoshi Hayano
, Patrick T. Griffin
, João A. Amorim
, Michael S. Bonkowski
, John K. Apostolides
, Elias L. Salfati
, Marco Blanchette
, Elizabeth M. Munding
, Mital Bhakta
, Yap Ching Chew
, Wei Guo
, Xiaojing Yang
, Sun Maybury-Lewis
, Xiao Tian
, Jaime M. Ross
, Giuseppe Coppotelli
, Margarita V. Meer
, Ryan Rogers-Hammond
, Daniel L. Vera
, Yuancheng Ryan Lu
, Jeffrey W. Pippin
, Michael L. Creswell
, Zhixun Dou
, Caiyue Xu
, Sarah J. Mitchell
, Abhirup Das
, Brendan L. O’Connell
, Sachin Thakur
, Alice E. Kane
, Qiao Su
, Yasuaki Mohri
, Emi K. Nishimura
, Laura Schaevitz
, Neha Garg
, Ana-Maria Balta
, Meghan A. Rego
, Meredith Gregory-Ksander
, Tatjana C. Jakobs
, Lei Zhong
, Hiroko Wakimoto
, Jihad El Andari
, Dirk Grimm
, Raul Mostoslavsky
, Amy J. Wagers
, Kazuo Tsubota
, Stephen J. Bonasera
, Carlos M. Palmeira
, Jonathan G. Seidman
, Christine E. Seidman
, Norman S. Wolf
, Jill A. Kreiling
, John M. Sedivy
, George F. Murphy
, Richard E. Green
, Benjamin A. Garcia
, Shelley L. Berger
, Philipp Oberdoerffer
, Stuart J. Shankland
, Vadim N. Gladyshev
, Bruce R. Ksander
, Andreas R. Pfenning
, Luis A. Rajman
, David A. Sinclair
Abstract:
All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.
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2023-02-28 20:31:00
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#paper doi：https://doi.org/10.1016/j.cell.2022.12.027
Loss of epigenetic information as a cause of mammalian aging 本文主要论述细胞对DNA断裂（DSB）修复过程中染色质修饰剂的重新定位(RCM)的变化，侵蚀了表观遗传图谱，这种表观遗传信息的丢失加速了细胞衰老和老化。本文使用I-PpoI内切酶建立 DSB 的细胞和小鼠（ICE）老化模型，通过比较十个月后肝脏、皮肤、脑、肌肉、活力等方面在代谢、基因组、表观遗传和组蛋白水平的衰老标志物，ICE 小鼠较对照小鼠 表现更高的老化速度。提出以下观点：1.哺乳动物的衰老与DSB修复效率相关，但与其他类型的修复无关，可能是因为只有对细胞生存的严重威胁才足以破坏表观基因组，从而导致衰老。2.RCM反应会发育破坏基因、DNA甲基转移酶(DNMTs)的表达模式，并释放被沉默的逆转录转座子。3.通过OSK（Yamanaka因子Oct4、Sox2、Klf4）处理，衰老细胞的衰老标记物的水平恢复到与阴性对照相似的水平，（哺乳动物衰老细胞可能保留了恢复年轻的表观遗传信息）。4.表观遗传信息的丢失是衰老的原因。