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.
Keywords: DNA damage, Chromatin, aging, epigenetic clock, epigenetic reprogramming, senescence, RCM (Relocalization of Chromatin Modifiers)
Yang, Jae-Hyun and Hayano, Motoshi and Griffin, Patrick and Amorim, Joao A. and Bonkowski, Michael S. and Apostolides, John K. and Blanchette, Marco and Munding, Elizabeth M. and Bhakta, Mital and Salfati, Elias L. and Lu, Yuancheng and Vera, Daniel L. and Ross, Jaime M. and Coppotelli, Giuseppe and Chew, Yap Ching and Guo, Wei and Yang, Xiaojing and Meer, Margarita V. and Tian, Xiao and Dou, Zhixun and Xu, Caiyue and Pippin, Jeffrey W. and Creswell, Michael and Mitchell, Sarah J. and Das, Abhirup and O’Connell, Brendan L. and Thakur, Sachin and Kane, Alice E. and Su, Qiao and Mohri, Yasuaki and Nishimura, Emi K. and Schaevitz, Laura and Garg, Neha and Balta, Ana-Maria and Rego, Meghan A. and Gregory-Ksander, Meredith and Jakobs, Tatjana C. and Zhong, Lei and Wakimoto, Hiroko and Mostoslavsky, Raul and Wagers, Amy J. and Tsubota, Kazuo and Bonasera, Stephen J. and Palmeira, Carlos M. and Seidman, Jonathan G. and Seidman, Christine and Wolf, Norman S. and Kreiling, Jill A. and Sedivy, John M. and Murphy, George F. and Green, Richard E. and Garcia, Benjamin A. and Berger, Shelley L. and Oberdoerffer, Philipp and Shankland, Stuart J. and Gladyshev, Vadim N. and Ksander, Bruce R. and Pfenning, Andreas R. and Rajman, Luis A. and Sinclair, David A., Loss of Epigenetic Information as a Cause of Mammalian Aging. Available at SSRN: https://ssrn.com/abstract=3951490 or http://dx.doi.org/10.2139/ssrn.3951490
This version of the paper has not been formally peer reviewed.