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

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. VeraYuancheng 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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	305-326.e27
Journal	Cell
Volume	186
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2022.12.027
State	Published - Jan 19 2023

Keywords

DNA damage
RCM
aging
chromatin
epigenetic clock
epigenetic reprogramming
relocalization of chromatin modifier
senescence

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10.1016/j.cell.2022.12.027

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Yang, J. H., Hayano, M., Griffin, P. T., Amorim, J. A., Bonkowski, M. S., Apostolides, J. K., Salfati, E. L., Blanchette, M., Munding, E. M., Bhakta, M., Chew, Y. C., Guo, W., Yang, X., Maybury-Lewis, S., Tian, X., Ross, J. M., Coppotelli, G., Meer, M. V., Rogers-Hammond, R., ... Sinclair, D. A. (2023). Loss of epigenetic information as a cause of mammalian aging. Cell, 186(2), 305-326.e27. https://doi.org/10.1016/j.cell.2022.12.027

@article{8a64e9807a754f0cb6128cc32dfd41d4,

title = "Loss of epigenetic information as a cause of mammalian aging",

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",

author = "Yang, {Jae Hyun} and Motoshi Hayano and Griffin, {Patrick T.} and Amorim, {Jo{\~a}o A.} and Bonkowski, {Michael S.} and Apostolides, {John K.} and Salfati, {Elias L.} and Marco Blanchette and Munding, {Elizabeth M.} and Mital Bhakta and Chew, {Yap Ching} and Wei Guo and Xiaojing Yang and Sun Maybury-Lewis and Xiao Tian and Ross, {Jaime M.} and Giuseppe Coppotelli and Meer, {Margarita V.} and Ryan Rogers-Hammond and Vera, {Daniel L.} and Lu, {Yuancheng Ryan} and Pippin, {Jeffrey W.} and Creswell, {Michael L.} and Zhixun Dou and Caiyue Xu and Mitchell, {Sarah J.} and Abhirup Das and O'Connell, {Brendan L.} and Sachin Thakur and Kane, {Alice E.} and Qiao Su and Yasuaki Mohri and Nishimura, {Emi K.} and Laura Schaevitz and Neha Garg and Balta, {Ana Maria} and Rego, {Meghan A.} and Meredith Gregory-Ksander and Jakobs, {Tatjana C.} and Lei Zhong and Hiroko Wakimoto and {El Andari}, Jihad and Dirk Grimm and Raul Mostoslavsky and Wagers, {Amy J.} and Kazuo Tsubota and Bonasera, {Stephen J.} and Palmeira, {Carlos M.} and Seidman, {Jonathan G.} and Seidman, {Christine E.} 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 Philipp Oberdoerffer and Shankland, {Stuart J.} and Gladyshev, {Vadim N.} and Ksander, {Bruce R.} and Pfenning, {Andreas R.} and Rajman, {Luis A.} and Sinclair, {David A.}",

note = "Funding Information: This paper represents the work of many people over a dozen years, some of whom we lost. We dedicate this paper to coauthors Michael Bonkowski, Norman Wolf, and our supporters, Paul F. Glenn and Devon Dalio. Thanks to all members of the Sinclair laboratory, past and present, and to our financial supporters from the NIA/NIH, The Glenn Foundation for Medical Research, The Dalio Foundation, Susan and Duane Hoff, Edward Schulak, AFAR, Volo Foundation, Tony Robbins and Peter Diamandis, Vincent Giampapa, and The Aoki Foundation, with advice from Andrea Di Francesco, Phu Huynh, Kristal Kalafut, Erin Wade, Rafael de Cabo, Matthew LaPlante, Haeyoung Kim, Peter Adams, and Alex Banks. Thanks to Roberto Chiarle and Frederick Alt for the I-SceI mice. Supported by NIH/NIA (R01AG019719 and R37AG028730) and HMS Epigenetics Seed and Development Grants to D.A.S.; the Glenn Foundation for Medical Research to D.A.S. and A.J.W.; National Research Foundation of Korea (2012R1A6A3A03040476) to J.-H.Y.; HFSP (LT000680/2014-L) to M.H.; JSPS KAKENHI (17K13228, 19K16619, 19H05269) to M.H.; the Uehara Memorial Foundation to M.H.; NIH T32 (T32AG023480) to D.L.V. and E.L.S.; NIA K99/00 (K99AG055683) to J.M.R.; NIH/NIA (R01AG064223, R01AG065403) to V.N.G.; NEI (R01EY019703) to T.C.J.; NIH (5R01DK056799-10, 5R01DK056799-12, 1R01DK097598-01A1) to S.J.S.; a Glenn/AFAR Grant to Junior Faculty to A.R.P.; and St Vincent de Paul Foundation to B.R.K. D.A.S. conceived of the project, supervised its execution, analyzed data, and co-wrote the manuscript. D.A.S. and P.O. generated the ICE mouse. J.-H.Y. L.A.R. and D.A.S. initiated and designed most experiments. J.-H.Y. was the lead scientist, performed most experiments, analyzed data, and co-wrote the manuscript. M.H. analyzed ICE mice (2013–2017). A.R.P. J.-H.Y. P.T.G. S.M.-L. J.A.A. and Q.S. analyzed ChIP-seq and RNA-seq data. E.L.S. and J.-H.Y. analyzed WGS data. M. Blanchette, J.-H.Y. E.M.M. M. Bhakta, D.L.V. B.L.O'C. and R.E.G. performed/analyzed Hi-C and HiChIP data. J.-H.Y. J.A.A. G.C. J.M.R. M.S.B. Y.R.L. X.T. A.D. S.T. N.G. A.-M.B. S.J.B. S.J.M. L.S. Y.M. E.K.N. G.F.M. H.W. J.G.S. A.E.K. M.A.R. C.E.S. J.W.P. M.L.C. and S.J.S. analyzed mouse phenotypes. Z.D. C.X. B.A.G. J.-H.Y. and S.L.B. analyzed mass spec. data. P.T.G. M.V.M. V.N.G. Y.C.C. W.G. J.-H.Y. J.A.A. and X.Y. calculated epigenetic ages. N.S.W. M.G.-K. T.C.J. and B.R.K. analyzed eyes. J.A.K. and J.M.S. studied repetitive sequences. K.T. C.M.P. L.Z. R.M. R.R.-H. J.E.A. D.G. and A.J.W. provided advice and assistance. D.A.S. is a consultant, inventor, board member, and in some cases an investor in Life Biosciences (developing reprogramming medicines), InsideTracker, Zymo, EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, Caudalie, Galilei, Immetas, Animal Biosciences, Tally Health, and more. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. E.M.M. M. Blanchette, and M. Bhakta are employees of Catata Bio/Dovetail. Y.C.C. W.G. and X.Y. are employees of Zymo Research. A.J.W. advises Kate Therapeutics and Frequency Therapeutics and is a co-founder, adviser, and equity holder of Elevian, which sponsors Wagers Lab research. L.S. was an employee of Vium. Y.R.L. and L.A.R. are equity owners of Life Biosciences. M.S.B. and D.L.V. advise EdenRoc Sciences. A patent application was filed on the reprogramming methods. Funding Information: This paper represents the work of many people over a dozen years, some of whom we lost. We dedicate this paper to coauthors Michael Bonkowski, Norman Wolf, and our supporters, Paul F. Glenn and Devon Dalio. Thanks to all members of the Sinclair laboratory, past and present, and to our financial supporters from the NIA/NIH, The Glenn Foundation for Medical Research, The Dalio Foundation, Susan and Duane Hoff, Edward Schulak, AFAR, Volo Foundation, Tony Robbins and Peter Diamandis, Vincent Giampapa, and The Aoki Foundation, with advice from Andrea Di Francesco, Phu Huynh, Kristal Kalafut, Erin Wade, Rafael de Cabo, Matthew LaPlante, Haeyoung Kim, Peter Adams, and Alex Banks. Thanks to Roberto Chiarle and Frederick Alt for the I-SceI mice. Supported by NIH/NIA ( R01AG019719 and R37AG028730 ) and HMS Epigenetics Seed and Development Grants to D.A.S.; the Glenn Foundation for Medical Research to D.A.S. and A.J.W.; National Research Foundation of Korea ( 2012R1A6A3A03040476 ) to J.-H.Y.; HFSP ( LT000680/2014-L ) to M.H.; JSPS KAKENHI ( 17K13228 , 19K16619 , 19H05269 ) to M.H.; the Uehara Memorial Foundation to M.H.; NIH T32 ( T32AG023480 ) to D.L.V. and E.L.S.; NIA K99/00 ( K99AG055683 ) to J.M.R.; NIH/NIA (R01AG064223, R01AG065403) to V.N.G.; NEI ( R01EY019703 ) to T.C.J.; NIH ( 5R01DK056799-10 , 5R01DK056799-12 , 1R01DK097598-01A1 ) to S.J.S.; a Glenn/AFAR Grant to Junior Faculty to A.R.P.; and St Vincent de Paul Foundation to B.R.K. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2023",

month = jan,

day = "19",

doi = "10.1016/j.cell.2022.12.027",

language = "English",

volume = "186",

pages = "305--326.e27",

journal = "Cell",

issn = "0092-8674",

number = "2",

}

Yang, JH, Hayano, M, Griffin, PT, Amorim, JA, Bonkowski, MS, Apostolides, JK, Salfati, EL, Blanchette, M, Munding, EM, Bhakta, M, Chew, YC, Guo, W, Yang, X, Maybury-Lewis, S, Tian, X, Ross, JM, Coppotelli, G, Meer, MV, Rogers-Hammond, R, Vera, DL, Lu, YR, Pippin, JW, Creswell, ML, Dou, Z, Xu, C, Mitchell, SJ, Das, A, O'Connell, BL, Thakur, S, Kane, AE, Su, Q, Mohri, Y, Nishimura, EK, Schaevitz, L, Garg, N, Balta, AM, Rego, MA, Gregory-Ksander, M, Jakobs, TC, Zhong, L, Wakimoto, H, El Andari, J, Grimm, D, Mostoslavsky, R, Wagers, AJ, Tsubota, K, Bonasera, SJ, Palmeira, CM, Seidman, JG, Seidman, CE, Wolf, NS, Kreiling, JA, Sedivy, JM, Murphy, GF, Green, RE, Garcia, BA, Berger, SL, Oberdoerffer, P, Shankland, SJ, Gladyshev, VN, Ksander, BR, Pfenning, AR, Rajman, LA & Sinclair, DA 2023, 'Loss of epigenetic information as a cause of mammalian aging', Cell, vol. 186, no. 2, pp. 305-326.e27. https://doi.org/10.1016/j.cell.2022.12.027

TY - JOUR

T1 - Loss of epigenetic information as a cause of mammalian aging

AU - Yang, Jae Hyun

AU - Hayano, Motoshi

AU - Griffin, Patrick T.

AU - Amorim, João A.

AU - Bonkowski, Michael S.

AU - Apostolides, John K.

AU - Salfati, Elias L.

AU - Blanchette, Marco

AU - Munding, Elizabeth M.

AU - Bhakta, Mital

AU - Chew, Yap Ching

AU - Guo, Wei

AU - Yang, Xiaojing

AU - Maybury-Lewis, Sun

AU - Tian, Xiao

AU - Ross, Jaime M.

AU - Coppotelli, Giuseppe

AU - Meer, Margarita V.

AU - Rogers-Hammond, Ryan

AU - Vera, Daniel L.

AU - Lu, Yuancheng Ryan

AU - Pippin, Jeffrey W.

AU - Creswell, Michael L.

AU - Dou, Zhixun

AU - Xu, Caiyue

AU - Mitchell, Sarah J.

AU - Das, Abhirup

AU - O'Connell, Brendan L.

AU - Thakur, Sachin

AU - Kane, Alice E.

AU - Su, Qiao

AU - Mohri, Yasuaki

AU - Nishimura, Emi K.

AU - Schaevitz, Laura

AU - Garg, Neha

AU - Balta, Ana Maria

AU - Rego, Meghan A.

AU - Gregory-Ksander, Meredith

AU - Jakobs, Tatjana C.

AU - Zhong, Lei

AU - Wakimoto, Hiroko

AU - El Andari, Jihad

AU - Grimm, Dirk

AU - Mostoslavsky, Raul

AU - Wagers, Amy J.

AU - Tsubota, Kazuo

AU - Bonasera, Stephen J.

AU - Palmeira, Carlos M.

AU - Seidman, Jonathan G.

AU - Seidman, Christine E.

AU - Wolf, Norman S.

AU - Kreiling, Jill A.

AU - Sedivy, John M.

AU - Murphy, George F.

AU - Green, Richard E.

AU - Garcia, Benjamin A.

AU - Berger, Shelley L.

AU - Oberdoerffer, Philipp

AU - Shankland, Stuart J.

AU - Gladyshev, Vadim N.

AU - Ksander, Bruce R.

AU - Pfenning, Andreas R.

AU - Rajman, Luis A.

AU - Sinclair, David A.

N1 - Funding Information: This paper represents the work of many people over a dozen years, some of whom we lost. We dedicate this paper to coauthors Michael Bonkowski, Norman Wolf, and our supporters, Paul F. Glenn and Devon Dalio. Thanks to all members of the Sinclair laboratory, past and present, and to our financial supporters from the NIA/NIH, The Glenn Foundation for Medical Research, The Dalio Foundation, Susan and Duane Hoff, Edward Schulak, AFAR, Volo Foundation, Tony Robbins and Peter Diamandis, Vincent Giampapa, and The Aoki Foundation, with advice from Andrea Di Francesco, Phu Huynh, Kristal Kalafut, Erin Wade, Rafael de Cabo, Matthew LaPlante, Haeyoung Kim, Peter Adams, and Alex Banks. Thanks to Roberto Chiarle and Frederick Alt for the I-SceI mice. Supported by NIH/NIA (R01AG019719 and R37AG028730) and HMS Epigenetics Seed and Development Grants to D.A.S.; the Glenn Foundation for Medical Research to D.A.S. and A.J.W.; National Research Foundation of Korea (2012R1A6A3A03040476) to J.-H.Y.; HFSP (LT000680/2014-L) to M.H.; JSPS KAKENHI (17K13228, 19K16619, 19H05269) to M.H.; the Uehara Memorial Foundation to M.H.; NIH T32 (T32AG023480) to D.L.V. and E.L.S.; NIA K99/00 (K99AG055683) to J.M.R.; NIH/NIA (R01AG064223, R01AG065403) to V.N.G.; NEI (R01EY019703) to T.C.J.; NIH (5R01DK056799-10, 5R01DK056799-12, 1R01DK097598-01A1) to S.J.S.; a Glenn/AFAR Grant to Junior Faculty to A.R.P.; and St Vincent de Paul Foundation to B.R.K. D.A.S. conceived of the project, supervised its execution, analyzed data, and co-wrote the manuscript. D.A.S. and P.O. generated the ICE mouse. J.-H.Y. L.A.R. and D.A.S. initiated and designed most experiments. J.-H.Y. was the lead scientist, performed most experiments, analyzed data, and co-wrote the manuscript. M.H. analyzed ICE mice (2013–2017). A.R.P. J.-H.Y. P.T.G. S.M.-L. J.A.A. and Q.S. analyzed ChIP-seq and RNA-seq data. E.L.S. and J.-H.Y. analyzed WGS data. M. Blanchette, J.-H.Y. E.M.M. M. Bhakta, D.L.V. B.L.O'C. and R.E.G. performed/analyzed Hi-C and HiChIP data. J.-H.Y. J.A.A. G.C. J.M.R. M.S.B. Y.R.L. X.T. A.D. S.T. N.G. A.-M.B. S.J.B. S.J.M. L.S. Y.M. E.K.N. G.F.M. H.W. J.G.S. A.E.K. M.A.R. C.E.S. J.W.P. M.L.C. and S.J.S. analyzed mouse phenotypes. Z.D. C.X. B.A.G. J.-H.Y. and S.L.B. analyzed mass spec. data. P.T.G. M.V.M. V.N.G. Y.C.C. W.G. J.-H.Y. J.A.A. and X.Y. calculated epigenetic ages. N.S.W. M.G.-K. T.C.J. and B.R.K. analyzed eyes. J.A.K. and J.M.S. studied repetitive sequences. K.T. C.M.P. L.Z. R.M. R.R.-H. J.E.A. D.G. and A.J.W. provided advice and assistance. D.A.S. is a consultant, inventor, board member, and in some cases an investor in Life Biosciences (developing reprogramming medicines), InsideTracker, Zymo, EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, Caudalie, Galilei, Immetas, Animal Biosciences, Tally Health, and more. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. E.M.M. M. Blanchette, and M. Bhakta are employees of Catata Bio/Dovetail. Y.C.C. W.G. and X.Y. are employees of Zymo Research. A.J.W. advises Kate Therapeutics and Frequency Therapeutics and is a co-founder, adviser, and equity holder of Elevian, which sponsors Wagers Lab research. L.S. was an employee of Vium. Y.R.L. and L.A.R. are equity owners of Life Biosciences. M.S.B. and D.L.V. advise EdenRoc Sciences. A patent application was filed on the reprogramming methods. Funding Information: This paper represents the work of many people over a dozen years, some of whom we lost. We dedicate this paper to coauthors Michael Bonkowski, Norman Wolf, and our supporters, Paul F. Glenn and Devon Dalio. Thanks to all members of the Sinclair laboratory, past and present, and to our financial supporters from the NIA/NIH, The Glenn Foundation for Medical Research, The Dalio Foundation, Susan and Duane Hoff, Edward Schulak, AFAR, Volo Foundation, Tony Robbins and Peter Diamandis, Vincent Giampapa, and The Aoki Foundation, with advice from Andrea Di Francesco, Phu Huynh, Kristal Kalafut, Erin Wade, Rafael de Cabo, Matthew LaPlante, Haeyoung Kim, Peter Adams, and Alex Banks. Thanks to Roberto Chiarle and Frederick Alt for the I-SceI mice. Supported by NIH/NIA ( R01AG019719 and R37AG028730 ) and HMS Epigenetics Seed and Development Grants to D.A.S.; the Glenn Foundation for Medical Research to D.A.S. and A.J.W.; National Research Foundation of Korea ( 2012R1A6A3A03040476 ) to J.-H.Y.; HFSP ( LT000680/2014-L ) to M.H.; JSPS KAKENHI ( 17K13228 , 19K16619 , 19H05269 ) to M.H.; the Uehara Memorial Foundation to M.H.; NIH T32 ( T32AG023480 ) to D.L.V. and E.L.S.; NIA K99/00 ( K99AG055683 ) to J.M.R.; NIH/NIA (R01AG064223, R01AG065403) to V.N.G.; NEI ( R01EY019703 ) to T.C.J.; NIH ( 5R01DK056799-10 , 5R01DK056799-12 , 1R01DK097598-01A1 ) to S.J.S.; a Glenn/AFAR Grant to Junior Faculty to A.R.P.; and St Vincent de Paul Foundation to B.R.K. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2023/1/19

Y1 - 2023/1/19

N2 - 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.

AB - 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.

KW - DNA damage

KW - RCM

KW - aging

KW - chromatin

KW - epigenetic clock

KW - epigenetic reprogramming

KW - relocalization of chromatin modifier

KW - senescence

UR - http://www.scopus.com/inward/record.url?scp=85146287252&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2022.12.027

DO - 10.1016/j.cell.2022.12.027

M3 - Article

C2 - 36638792

AN - SCOPUS:85146287252

SN - 0092-8674

VL - 186

SP - 305-326.e27

JO - Cell

JF - Cell

IS - 2

ER -

Loss of epigenetic information as a cause of mammalian aging

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