Motoshi Hayano , Jae-Hyun Yang , Michael S. Bonkowski , Joao A. Amorim , Jaime M. Ross , Giuseppe Coppotelli , Patrick T. Griffin , Yap Ching Chew , Wei Guo , Xiaojing Yang , Daniel L. Vera , Elias L. Salfati , Abhirup Das , Sachin Thakur , Alice E. Kane , Sarah J. Mitchell , 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 , 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 , Philipp Oberdoerffer , Bruce R. Ksander , Luis A. Rajman , David A. Sinclair
October 21 2019
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.