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DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

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
doi: https://doi.org/10.1101/808659
Motoshi Hayano
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
2Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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Jae-Hyun Yang
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Michael S. Bonkowski
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Joao A. Amorim
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
3IIIUC-Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
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Jaime M. Ross
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Giuseppe Coppotelli
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Patrick T. Griffin
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Yap Ching Chew
4Zymo Research Corporation, Irvine, CA 92614, USA
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Wei Guo
4Zymo Research Corporation, Irvine, CA 92614, USA
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Xiaojing Yang
4Zymo Research Corporation, Irvine, CA 92614, USA
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Daniel L. Vera
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Elias L. Salfati
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
19Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA
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Abhirup Das
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
5Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
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Sachin Thakur
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Alice E. Kane
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Sarah J. Mitchell
6Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
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Yasuaki Mohri
7Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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Emi K. Nishimura
7Department of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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Laura Schaevitz
8Vium Inc., San Mateo, CA 94402 USA
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Neha Garg
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Ana-Maria Balta
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Meghan A. Rego
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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Meredith Gregory-Ksander
9Schepens Eye Research Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114
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Tatjana C. Jakobs
9Schepens Eye Research Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114
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Lei Zhong
10The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
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Hiroko Wakimoto
11Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Raul Mostoslavsky
10The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
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Amy J. Wagers
12Paul F. Glenn Center for the Biology of Aging Research and Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA
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Kazuo Tsubota
2Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
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Stephen J. Bonasera
13Division of Geriatrics, Department of Internal Medicine, University of Nebraska Medical Center, 3028 Durham Research Center II, Omaha, NE, 68198-5039, USA
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Carlos M. Palmeira
14Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal
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Jonathan G. Seidman
11Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Christine E. Seidman
11Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Norman S. Wolf
15Department of Pathology, University of Washington, Seattle, WA 98195, USA
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Jill A. Kreiling
16Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
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John M. Sedivy
16Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
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George F. Murphy
17Program in Dermatopathology, Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Philipp Oberdoerffer
18Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA
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Bruce R. Ksander
9Schepens Eye Research Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114
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Luis A. Rajman
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
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David A. Sinclair
1Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
5Laboratory for Ageing Research, Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
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  • For correspondence: david_sinclair@hms.harvard.edu
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SUMMARY

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.

One Sentence Summary DNA breaks induce epigenomic changes that accelerate the aging clock in mammals

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Posted October 21, 2019.
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DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging
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
bioRxiv 808659; doi: https://doi.org/10.1101/808659
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DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging
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
bioRxiv 808659; doi: https://doi.org/10.1101/808659

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