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. VeraYuancheng 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

Research output: Contribution to journalArticlepeer-review

175 Scopus citations

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.

Original languageEnglish
Pages (from-to)305-326.e27
JournalCell
Volume186
Issue number2
DOIs
StatePublished - Jan 19 2023

Keywords

  • DNA damage
  • RCM
  • aging
  • chromatin
  • epigenetic clock
  • epigenetic reprogramming
  • relocalization of chromatin modifier
  • senescence

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