There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic "age" clocks, but what drives these changes is not known. Using a transgenic mouse system called "ICE" (for inducible changes to the epigenome), we show that a tissue's response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.
Keywords: DNA damage, chromatin, aging, epigenetic clock, histone modification, RCM(Relocalization of Chromatin Modifiers)
Hayano, Motoshi and Yang, Jae-Hyun and Bonkowski, Michael S. and Amorim, Joao A. and Ross, Jaime M. and Coppotelli, Giuseppe and Griffin, Patrick and Chew, Yap Ching and Guo, Wei and Yang, Xiaojing and Vera, Daniel L. and Salfati, Elias L. and Das, Abhirup and Thakur, Sachin and Kane, Alice E. and Mitchell, Sarah J. 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 Oberdoerffer, Philipp and Ksander, Bruce R. and Rajman, Luis A. and Sinclair, David A., DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging (October 8, 2019). Available at SSRN: https://ssrn.com/abstract=3466338 or http://dx.doi.org/10.2139/ssrn.3466338
This version of the paper has not been formally peer reviewed.
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