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

97 Pages Posted: 8 Oct 2019 Publication Status: Review Complete

See all articles by Motoshi Hayano

Motoshi Hayano

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Jae-Hyun Yang

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Michael S. Bonkowski

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Joao A. Amorim

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Jaime M. Ross

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Giuseppe Coppotelli

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Patrick Griffin

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Yap Ching Chew

Zymo Research Corporation

Wei Guo

Zymo Research Corporation

Xiaojing Yang

Zymo Research Corporation

Daniel L. Vera

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Elias L. Salfati

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Abhirup Das

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Sachin Thakur

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Alice E. Kane

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Sarah J. Mitchell

National Institutes of Health - Experimental Gerontology Section

Yasuaki Mohri

Tokyo Medical and Dental University - Department of Stem Cell Biology

Emi K. Nishimura

Tokyo Medical and Dental University - Department of Stem Cell Biology

Laura Schaevitz

Vium Inc.

Neha Garg

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Ana-Maria Balta

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Meghan A. Rego

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

Meredith Gregory-Ksander

Harvard Medical School - Schepens Eye Research Institute

Tatjana C. Jakobs

Harvard Medical School - Schepens Eye Research Institute

Lei Zhong

Harvard Medical School - Cancer Center

Hiroko Wakimoto

Harvard University - Harvard Medical School

Raul Mostoslavsky

Harvard Medical School - Cancer Center

Amy J. Wagers

Harvard University - Department of Stem Cell and Regenerative Biology

Kazuo Tsubota

Keio University - Department of Ophthalmology

Stephen J. Bonasera

University of Nebraska Medical Center - Division of Geriatrics, Gerontology, and Palliative Medicine

Carlos M. Palmeira

Universidade de Coimbra - Department of Life Sciences

Jonathan G. Seidman

Harvard University - Harvard Medical School

Christine Seidman

Harvard University - Harvard Medical School

Norman S. Wolf

University of Washington - Department of Pathology

Jill A. Kreiling

Brown University - Department of Molecular Biology, Cell Biology and Biochemistry

John M. Sedivy

Brown University - Department of Molecular Biology, Cell Biology and Biochemistry

George F. Murphy

Harvard Medical School - Program in Dermatopathology

Philipp Oberdoerffer

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression

Bruce R. Ksander

Harvard Medical School - Schepens Eye Research Institute

Luis A. Rajman

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

David A. Sinclair

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

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Abstract

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)

Suggested Citation

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 is a paper under consideration at Cell Press and has not been peer-reviewed.

Motoshi Hayano

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Jae-Hyun Yang

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

Michael S. Bonkowski

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Joao A. Amorim

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Jaime M. Ross

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Giuseppe Coppotelli

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Patrick Griffin

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Yap Ching Chew

Zymo Research Corporation ( email )

United States

Wei Guo

Zymo Research Corporation

United States

Xiaojing Yang

Zymo Research Corporation

United States

Daniel L. Vera

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

Elias L. Salfati

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Abhirup Das

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Sachin Thakur

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Alice E. Kane

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Sarah J. Mitchell

National Institutes of Health - Experimental Gerontology Section

United States

Yasuaki Mohri

Tokyo Medical and Dental University - Department of Stem Cell Biology ( email )

Japan

Emi K. Nishimura

Tokyo Medical and Dental University - Department of Stem Cell Biology ( email )

Japan

Laura Schaevitz

Vium Inc. ( email )

United States

Neha Garg

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research

United States

Ana-Maria Balta

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Meghan A. Rego

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

Meredith Gregory-Ksander

Harvard Medical School - Schepens Eye Research Institute ( email )

United States

Tatjana C. Jakobs

Harvard Medical School - Schepens Eye Research Institute ( email )

United States

Lei Zhong

Harvard Medical School - Cancer Center

Boston, MA 02114
United States

Hiroko Wakimoto

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Raul Mostoslavsky

Harvard Medical School - Cancer Center ( email )

Boston, MA 02114
United States

Amy J. Wagers

Harvard University - Department of Stem Cell and Regenerative Biology ( email )

7 Divinity Avenue
Cambridge, MA 02138
United States

Kazuo Tsubota

Keio University - Department of Ophthalmology ( email )

35 Shinanomachii
Tokyo, 160-8582
Japan

Stephen J. Bonasera

University of Nebraska Medical Center - Division of Geriatrics, Gerontology, and Palliative Medicine ( email )

United States

Carlos M. Palmeira

Universidade de Coimbra - Department of Life Sciences ( email )

Portugal

Jonathan G. Seidman

Harvard University - Harvard Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Christine Seidman

Harvard University - Harvard Medical School ( email )

25 Shattuck St
Boston, MA 02115
United States

Norman S. Wolf

University of Washington - Department of Pathology

Seattle, WA 98115
United States

Jill A. Kreiling

Brown University - Department of Molecular Biology, Cell Biology and Biochemistry ( email )

Box 1860
Providence, RI 02912
United States

John M. Sedivy

Brown University - Department of Molecular Biology, Cell Biology and Biochemistry

Box 1860
Providence, RI 02912
United States

George F. Murphy

Harvard Medical School - Program in Dermatopathology

United States

Philipp Oberdoerffer

National Institutes of Health - Laboratory of Receptor Biology and Gene Expression ( email )

Bethesda, MD
United States

Bruce R. Ksander

Harvard Medical School - Schepens Eye Research Institute ( email )

United States

Luis A. Rajman

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

David A. Sinclair (Contact Author)

Harvard Medical School - Paul F. Glenn Center for Biology of Aging Research ( email )

United States

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