1. Loss of Epigenetic Information as a Cause of Mammalian Aging
- Author
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Brendan O'Connell, Xiaojing Yang, Jaime M. Ross, Yuancheng Lu, Jonathan G. Seidman, Mital Bhakta, Amy J. Wagers, João A. Amorim, Qiao Su, Bruce R. Ksander, Jae-Hyun Yang, Jill A. Kreiling, Elias L. Salfati, Stuart J. Shankland, Richard E. Green, Christine E. Seidman, Ana-Maria Balta, Andreas R. Pfenning, George F. Murphy, Michael Bonkowski, Benjamin A. Garcia, Luis A. Rajman, Patrick Griffin, Marco Blanchette, Yasuaki Mohri, Meghan A. Rego, Sarah J. Mitchell, Meredith S Gregory-Ksander, Kazuo Tsubota, Sachin Thakur, Raul Mostoslavsky, Caiyue Xu, Hiroko Wakimoto, John M. Sedivy, Norman S. Wolf, Philipp Oberdoerffer, Yap Ching Chew, John K. Apostolides, Alice E. Kane, Michael L. Creswell, Laura Schaevitz, Motoshi Hayano, Zhixun Dou, Margarita V. Meer, Giuseppe Coppotelli, Elizabeth M. Munding, Xiao Tian, Carlos M. Palmeira, Wei Guo, Shelley L. Berger, Tatjana C. Jakobs, Daniel L. Vera, Emi K. Nishimura, Lei Zhong, David A. Sinclair, Abhirup Das, Jeffrey W. Pippin, Vadim N. Gladyshev, Stephen J. Bonasera, and Neha Garg
- Subjects
Senescence ,History ,Polymers and Plastics ,DNA damage ,Epigenome ,Biology ,Industrial and Manufacturing Engineering ,Chromatin ,Cell biology ,KLF4 ,Ectopic expression ,sense organs ,Epigenetics ,Business and International Management ,Reprogramming - Abstract
All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. In yeast, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Using a transgenic mouse system called "ICE" (for Inducible Changes to the Epigenome), we show that the process of repairing non-mutagenic DNA breaks accelerates age-related physiological, cognitive, and molecular changes, including the erosion of the epigenetic landscape, a loss of cellular identity, cellular senescence and advancement of the epigenetic clock. Epigenetic reprogramming through ectopic expression of Oct4, Sox2 and Klf4 (OSK) restores patterns of youthful gene expression. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.
- Published
- 2021
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