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Loss of Epigenetic Information as a Cause of Mammalian Aging

102 Pages Posted: 27 Oct 2021 Publication Status: Under Review

See all articles by Jae-Hyun Yang

Jae-Hyun Yang

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

Motoshi Hayano

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

Joao A. Amorim

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

Michael S. Bonkowski

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

John K. Apostolides

Carnegie Mellon University - Computational Biology Department

Marco Blanchette

Dovetail Genomics

Elizabeth M. Munding

Dovetail Genomics

Mital Bhakta

Dovetail Genomics

Elias L. Salfati

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

Yuancheng Lu

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

Daniel L. Vera

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

Jaime M. Ross

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

Giuseppe Coppotelli

Harvard University - 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

Margarita V. Meer

Harvard Medical School - Genetics Division

Xiao Tian

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

Zhixun Dou

University of Pennsylvania - Department of Cell and Developmental Biology

Caiyue Xu

University of Pennsylvania - Department of Cell and Developmental Biology

Jeffrey W. Pippin

University of Washington - Division of Nephrology

Michael Creswell

University of Washington - Division of Nephrology

Sarah J. Mitchell

National Institutes of Health - Experimental Gerontology Section

Abhirup Das

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

Brendan L. O’Connell

University of California, Santa Cruz - Department of Biomolecular Engineering (BME)

Sachin Thakur

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

Alice E. Kane

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

Qiao Su

Carnegie Mellon University - Computational Biology Department

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 University - 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 - The Massachusetts General Hospital Cancer Center

Hiroko Wakimoto

Harvard Medical School - Department of Genetics

Raul Mostoslavsky

Harvard Medical School - Cancer Center

Amy J. Wagers

Harvard University - Department of Stem Cell and Regenerative Biology

Kazuo Tsubota

Tsubota Laboratory, Inc.

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 Medical School - Department of Genetics

Christine Seidman

Harvard Medical School - Department of Genetics

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 University - Program in Dermatopathology

Richard E. Green

University of California, Santa Cruz - Department of Biomolecular Engineering (BME)

Benjamin A. Garcia

University of Pennsylvania - Department of Cell and Developmental Biology; University of Pennsylvania - Department of Biochemistry and Biophysics

Shelley L. Berger

University of Pennsylvania - Department of Cell and Developmental Biology

Philipp Oberdoerffer

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

Stuart J. Shankland

University of Washington - Division of Nephrology

Vadim N. Gladyshev

Harvard Medical School - Genetics Division

Bruce R. Ksander

Harvard Medical School - Schepens Eye Research Institute

Andreas R. Pfenning

Carnegie Mellon University - Department of Computational Biology

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

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)

Suggested Citation

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.

Jae-Hyun Yang

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

25 Shattuck St
Boston, MA 02115
United States

Motoshi Hayano

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

Joao A. Amorim

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

United States

Michael S. Bonkowski

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

25 Shattuck St
Boston, MA 02115
United States

John K. Apostolides

Carnegie Mellon University - Computational Biology Department ( email )

Pittsburgh, PA 15213-3890
United States

Marco Blanchette

Dovetail Genomics ( email )

Santa Cruz, CA
United States

Elizabeth M. Munding

Dovetail Genomics ( email )

Santa Cruz, CA
United States

Mital Bhakta

Dovetail Genomics

Santa Cruz, CA
United States

Elias L. Salfati

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

United States

Yuancheng Lu

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

25 Shattuck St
Boston, MA 02115
United States

Daniel L. Vera

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

25 Shattuck St
Boston, MA 02115
United States

Jaime M. Ross

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

25 Shattuck St
Boston, MA 02115
United States

Giuseppe Coppotelli

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

25 Shattuck St
Boston, MA 02115
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

Margarita V. Meer

Harvard Medical School - Genetics Division ( email )

Boston, MA 02115
United States

Xiao Tian

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

25 Shattuck St
Boston, MA 02115
United States

Zhixun Dou

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Caiyue Xu

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Jeffrey W. Pippin

University of Washington - Division of Nephrology ( email )

United States

Michael Creswell

University of Washington - Division of Nephrology ( email )

Seattle, WA 98195
United States

Sarah J. Mitchell

National Institutes of Health - Experimental Gerontology Section

United States

Abhirup Das

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

United States

Brendan L. O’Connell

University of California, Santa Cruz - Department of Biomolecular Engineering (BME) ( email )

1156 High Street
335 Baskin Engineering Building
Santa Cruz, CA 95064
United States

Sachin Thakur

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

25 Shattuck St
Boston, MA 02115
United States

Alice E. Kane

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

United States

Qiao Su

Carnegie Mellon University - Computational Biology Department ( email )

Pittsburgh, PA 15213
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 University - Paul F. Glenn Center for Biology of Aging Research ( email )

25 Shattuck St
Boston, MA 02115
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 - The Massachusetts General Hospital Cancer Center ( email )

Boston, MA 02114
United States

Hiroko Wakimoto

Harvard Medical School - Department of Genetics ( email )

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

Tsubota Laboratory, Inc. ( email )

34 Shinanomachi
304 Toshin Shinanomachi Eki mae
Shinjuku-ku, Tokyo 1600016
Japan

HOME PAGE: http://https://tsubota-lab.com

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 Medical School - Department of Genetics ( email )

25 Shattuck St
Boston, MA 02115
United States

Christine Seidman

Harvard Medical School - Department of Genetics ( email )

25 Shattuck St
Boston, MA 02115
United States

Norman S. Wolf

University of Washington - Department of Pathology

Seattle, WA 98195
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 ( email )

Box 1860
Providence, RI 02912
United States

George F. Murphy

Harvard University - Program in Dermatopathology ( email )

United States

Richard E. Green

University of California, Santa Cruz - Department of Biomolecular Engineering (BME) ( email )

1156 High Street
335 Baskin Engineering Building
Santa Cruz, CA 95064
United States

Benjamin A. Garcia

University of Pennsylvania - Department of Cell and Developmental Biology

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

University of Pennsylvania - Department of Biochemistry and Biophysics ( email )

Philadelphia, PA 19104
United States

Shelley L. Berger

University of Pennsylvania - Department of Cell and Developmental Biology ( email )

3400 Civic Center Blvd
Philadelphia, PA 19104
United States

Philipp Oberdoerffer

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

Bethesda, MD
United States

Stuart J. Shankland

University of Washington - Division of Nephrology ( email )

United States

Vadim N. Gladyshev

Harvard Medical School - Genetics Division ( email )

Boston, MA 02115
United States

Bruce R. Ksander

Harvard Medical School - Schepens Eye Research Institute ( email )

United States

Andreas R. Pfenning

Carnegie Mellon University - Department of Computational Biology ( email )

Pittsburgh, PA 15213
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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