Loss of epigenetic information as a cause of mammalian aging

Jae-Hyun Yang; Motoshi Hayano; Patrick T Griffin; João A Amorim; Michael S Bonkowski; John K Apostolides; Elias L Salfati; Marco Blanchette; Elizabeth M Munding; Mital Bhakta; Yap Ching Chew; Wei Guo; Xiaojing Yang; Sun Maybury-Lewis; Xiao Tian; Jaime M Ross; Giuseppe Coppotelli; Margarita V Meer; Ryan Rogers-Hammond; Daniel L Vera; Yuancheng Ryan Lu; Jeffrey W Pippin; Michael L Creswell; Zhixun Dou; Caiyue Xu; Sarah J Mitchell; Abhirup Das; Brendan L O'Connell; Sachin Thakur; Alice E Kane; Qiao Su; 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; Jihad El Andari; Dirk Grimm; 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; Richard E Green; Benjamin A Garcia; Shelley L Berger; Philipp Oberdoerffer; Stuart J Shankland; Vadim N Gladyshev; Bruce R Ksander; Andreas R Pfenning; Luis A Rajman; David A Sinclair

doi:10.1016/j.cell.2022.12.027

Loss of epigenetic information as a cause of mammalian aging

Cell. 2023 Jan 19;186(2):305-326.e27. doi: 10.1016/j.cell.2022.12.027. Epub 2023 Jan 12.

Authors

Jae-Hyun Yang¹, Motoshi Hayano², Patrick T Griffin³, João A Amorim⁴, Michael S Bonkowski³, John K Apostolides⁵, Elias L Salfati³, Marco Blanchette⁶, Elizabeth M Munding⁶, Mital Bhakta⁶, Yap Ching Chew⁷, Wei Guo⁷, Xiaojing Yang⁷, Sun Maybury-Lewis³, Xiao Tian³, Jaime M Ross³, Giuseppe Coppotelli³, Margarita V Meer⁸, Ryan Rogers-Hammond³, Daniel L Vera³, Yuancheng Ryan Lu³, Jeffrey W Pippin⁹, Michael L Creswell¹⁰, Zhixun Dou¹¹, Caiyue Xu¹¹, Sarah J Mitchell¹², Abhirup Das¹³, Brendan L O'Connell¹⁴, Sachin Thakur³, Alice E Kane³, Qiao Su⁵, Yasuaki Mohri¹⁵, Emi K Nishimura¹⁵, Laura Schaevitz¹⁶, Neha Garg³, Ana-Maria Balta³, Meghan A Rego³, Meredith Gregory-Ksander¹⁷, Tatjana C Jakobs¹⁷, Lei Zhong¹⁸, Hiroko Wakimoto¹⁹, Jihad El Andari²⁰, Dirk Grimm²⁰, Raul Mostoslavsky¹⁸, Amy J Wagers²¹, Kazuo Tsubota²², Stephen J Bonasera²³, Carlos M Palmeira²⁴, Jonathan G Seidman¹⁹, Christine E Seidman¹⁹, Norman S Wolf²⁵, Jill A Kreiling²⁶, John M Sedivy²⁶, George F Murphy²⁷, Richard E Green¹⁴, Benjamin A Garcia¹¹, Shelley L Berger¹¹, Philipp Oberdoerffer²⁸, Stuart J Shankland⁹, Vadim N Gladyshev⁸, Bruce R Ksander¹⁷, Andreas R Pfenning⁵, Luis A Rajman³, David A Sinclair²⁹

Affiliations

¹ Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA. Electronic address: jae-hyun_yang@hms.harvard.edu.
² Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA; Department of Ophthalmology, Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
³ Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.
⁴ Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA; IIIUC-Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
⁵ Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Cantata/Dovetail Genomics, Scotts Valley, CA, USA.
⁷ Zymo Research Corporation, Irvine, CA, USA.
⁸ Department of Medicine, Brigham and Women's Hospital, HMS, Boston, MA, USA.
⁹ Division of Nephrology, University of Washington, Seattle, WA, USA.
¹⁰ Division of Nephrology, University of Washington, Seattle, WA, USA; Georgetown University School of Medicine, Washington, DC, USA.
¹¹ Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
¹² Experimental Gerontology Section, NIA/NIH, Baltimore, MD, USA.
¹³ Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA; Department of Pharmacology, UNSW, Sydney, NSW, Australia.
¹⁴ Department of Biomolecular Engineering, UCSC, Santa Cruz, CA, USA.
¹⁵ Department of Stem Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.
¹⁶ Vium, San Mateo, CA, USA.
¹⁷ Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, HMS, Boston, MA, USA.
¹⁸ The Massachusetts General Hospital Cancer Center, HMS, Boston, MA, USA.
¹⁹ Department of Genetics, HMS, Boston, MA, USA.
²⁰ Department of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, University of Heidelberg, BioQuant, Heidelberg, Germany.
²¹ Paul F. Glenn Center for Biology of Aging Research, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Joslin Diabetes Center, Boston, MA, USA.
²² Department of Ophthalmology, Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
²³ Division of Geriatrics, University of Nebraska Medical Center, Durham Research Center II, Omaha, NE, USA.
²⁴ Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
²⁵ Department of Pathology, University of Washington, Seattle, WA, USA.
²⁶ Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
²⁷ Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁸ Laboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD, USA.
²⁹ Paul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA. Electronic address: david_sinclair@hms.harvard.edu.

Abstract

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Keywords: DNA damage; RCM; aging; chromatin; epigenetic clock; epigenetic reprogramming; relocalization of chromatin modifier; senescence.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging* / genetics
Animals
DNA Methylation
Epigenesis, Genetic*
Epigenome
Mammals / genetics
Nucleoproteins
Saccharomyces cerevisiae / genetics

Substances

Nucleoproteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding