3747595620230722

2673-621742023Front AgingFrontiers in aging special issue: DNA repair and interventions in aging perspective on "loss of epigenetic information as a cause of mammalian aging".11995961199596119959610.3389/fragi.2023.1199596The recently published article in Cell by the Sinclair lab and collaborators entitled "Loss of Epigenetic Information as a Cause of Mammalian Aging" [1] implicates heritable changes in gene expression as the basis for aging, a postulate consistent with the emerging information theory of aging. Sinclair's group and colleagues induced epigenetic changes, i.e., DNA and histone modifications, via double-strand breaks (DSBs) catalyzed by the I-Pol endonuclease at specific genomic loci. The genomic DNA breaks, introduced without inducing insertion or deletion mutations (indels) in a mouse model, were targeted to 19 non-coding regions and one region in ribosomal DNA (rDNA), the latter shown to not have a significant effect on the function or transcription of rDNA [1]. With that experimental model in place, the authors present experimental evidence supporting a model that epigenetic changes drive aging via this inducible DNA break mechanism. After demonstrating the phenotypic alterations of this accelerated aging, they attempt to reverse selective phenotypes by resetting the altered epigenetic landscape. Establishing a causal relationship between epigenetic changes and aging, and how this connection might be manipulated to overturn cellular features of aging, is provocative and merits further study.Copyright © 2023 Schaffer, Beerman, de Cabo and Brosh.SchafferEthan DEDTranslational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.BeermanIsabelITranslational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.de CaboRafaelRTranslational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.BroshRobert MRMJrTranslational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.engJournal Article20230705

SwitzerlandFront Aging99182311997066762673-6217DNA damageagingdouble-strand breakepigeneticgene expressiongenetichealthspanmouseThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.2023432023623202372164320237216422023721358202375epublish37475956PMC1035425310.3389/fragi.2023.11995961199596Abate N. G., Hendzel M. J. (2022). Heterogeneity of organization of subcompartments in DSB repair foci. Front. Genet. 13, 887088. 10.3389/fgene.2022.88708810.3389/fgene.2022.887088PMC934049535923694Berkovich E., Monnat R. J., Jr., Kastan M. B. (2007). Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat. Cell Biol. 9, 683–690. 10.1038/ncb159910.1038/ncb159917486112Hughes A. L., Kelley J. R., Klose R. J. (2020). Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation. Biochimica biophysica acta. Gene Regul. Mech. 1863, 194567. 10.1016/j.bbagrm.2020.19456710.1016/j.bbagrm.2020.194567PMC729423132360393Kaeberlein M. (2018). How healthy is the healthspan concept? GeroScience 40, 361–364. 10.1007/s11357-018-0036-910.1007/s11357-018-0036-9PMC613629530084059Min S., Ji J. H., Heo Y., Cho H. (2022). Transcriptional regulation and chromatin dynamics at DNA double-strand breaks. Exp. Mol. Med. 54, 1705–1712. 10.1038/s12276-022-00862-510.1038/s12276-022-00862-5PMC963615236229590Shroff R., Arbel-Eden A., Pilch D., Ira G., Bonner W. M., Petrini J. H., et al. (2004). Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr. Biol. CB 14, 1703–1711. 10.1016/j.cub.2004.09.04710.1016/j.cub.2004.09.047PMC449376315458641Takahashi K., Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676. 10.1016/j.cell.2006.07.02410.1016/j.cell.2006.07.02416904174Waddington C. H. (1957). The strategy of the genes: A discussion of some aspects of theoretical Biology. London: Allen & Unwin.Yang J. H., Hayano M., Griffin P. T., Amorim J. A., Bonkowski M. S., Apostolides J. K., et al. (2023). Loss of epigenetic information as a cause of mammalian aging. Cell 186, 305–326.e27. 10.1016/j.cell.2022.12.02710.1016/j.cell.2022.12.027PMC1016613336638792Zhang Y., Sun Z., Jia J., Du T., Zhang N., Tang Y., et al. (2021). Overview of histone modification. Adv. Exp. Med. Biol. 1283, 1–16. 10.1007/978-981-15-8104-5_110.1007/978-981-15-8104-5_133155134374372482023073120240922

1945-458915132023Jul12Aging (Albany NY)Chemically induced reprogramming to reverse cellular aging.596659895966-598910.18632/aging.204896A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.YangJae-HyunJHPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.PettyChristopher ACAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.Dixon-McDougallThomasTPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.LopezMaria VinaMVMolecular and Biomedical Sciences, University of Maine, Orono, ME 04467, USA.TyshkovskiyAlexanderADivision of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119234, Russia.Maybury-LewisSunSPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.TianXiaoXPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.IbrahimNabilahNPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.ChenZhiliZPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.GriffinPatrick TPTPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.ArnoldMatthewMPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.LiJienJPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.MartinezOswaldo AOAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.Department of Biology and Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.BehnAlexanderAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.Rogers-HammondRyanRPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.AngeliSuzanneSMolecular and Biomedical Sciences, University of Maine, Orono, ME 04467, USA.GladyshevVadim NVNDivision of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.SinclairDavid ADAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA 02115, USA.engK99 AG068303AGNIA NIH HHSUnited StatesR01 AG019719AGNIA NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, N.I.H., Extramural20230712

United StatesAging (Albany NY)1015086171945-4589IMAnimalsHumansCellular ReprogramminggeneticsCellular SenescencegeneticsAginggeneticsDNA MethylationInduced Pluripotent Stem CellsMammalsepigeneticsinformation theory of agingrejuvenation medicinereprogrammingsmall moleculesCONFLICTS OF INTEREST: Declaration of interests: D.A.S. is a consultant, inventor, board member, and in some cases a founder and investor in Life Biosciences (a reprogramming company), EdenRoc Sciences/Cantata/Dovetail/Metrobiotech, InsideTracker, Fully Aligned, Zymo, Athletic Greens, Levels Health, Galilei, Immetas, Animal Biosciences, Tally Health, and others. See https://sinclair.hms.harvard.edu/david-sinclairs-affiliations. J-H.Y., T.D., C.A.P. and D.A.S. are inventors on a provisional patent application.202363020237420237316432023712197202371216332023715ppublish37437248PMC1037396610.18632/aging.204896204896López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194–217. 10.1016/j.cell.2013.05.03910.1016/j.cell.2013.05.039PMC383617423746838López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023; 186:243–78. 10.1016/j.cell.2022.11.00110.1016/j.cell.2022.11.00136599349Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science. 1997; 277:1313–6. 10.1126/science.277.5330.131310.1126/science.277.5330.13139271578Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell. 1999; 97:609–20. 10.1016/s0092-8674(00)80772-210.1016/s0092-8674(00)80772-210367890Oberdoerffer P, Sinclair DA. The role of nuclear architecture in genomic instability and ageing. Nat Rev Mol Cell Biol. 2007; 8:692–702. 10.1038/nrm223810.1038/nrm223817700626Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, Bhimavarapu A, Luikenhuis S, de Cabo R, Fuchs C, Hahn WC, Guarente LP, Sinclair DA. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 2008; 3:e2020. 10.1371/journal.pone.000202010.1371/journal.pone.0002020PMC228987918414679Yang 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, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023; 186:305–26.e27. 10.1016/j.cell.2022.12.02710.1016/j.cell.2022.12.027PMC1016613336638792Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature. 2020; 588:124–9. 10.1038/s41586-020-2975-410.1038/s41586-020-2975-4PMC775213433268865Sinclair DA, LaPlante MD. Lifespan: why we age—and why we don’t have to. Atria books, Simon and Schuster. 2019.Yousefzadeh M, Henpita C, Vyas R, Soto-Palma C, Robbins P, Niedernhofer L. DNA damage-how and why we age? Elife. 2021; 10:e62852. 10.7554/eLife.6285210.7554/eLife.62852PMC784627433512317Song S, Tchkonia T, Jiang J, Kirkland JL, Sun Y. Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities. Adv Sci (Weinh). 2020; 7:2002611. 10.1002/advs.20200261110.1002/advs.202002611PMC770998033304768Miller KN, Dasgupta N, Liu T, Adams PD, Vizioli MG. Cytoplasmic chromatin fragments-from mechanisms to therapeutic potential. Elife. 2021; 10:e63728. 10.7554/eLife.6372810.7554/eLife.63728PMC784627233512316McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018; 217:65–77. 10.1083/jcb.20170809210.1083/jcb.201708092PMC574899029114066Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol. 1962; 10:622–40.13951335Wakayama T, Perry AC, Zuccotti M, Johnson KR, Yanagimachi R. Full-term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature. 1998; 394:369–74. 10.1038/2861510.1038/286159690471Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH. Viable offspring derived from fetal and adult mammalian cells. Cloning Stem Cells. 2007; 9:3–7. 10.1089/clo.2006.000210.1089/clo.2006.000217386005Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126:663–76. 10.1016/j.cell.2006.07.02410.1016/j.cell.2006.07.02416904174Shi Y, Inoue H, Wu JC, Yamanaka S. Induced pluripotent stem cell technology: a decade of progress. Nat Rev Drug Discov. 2017; 16:115–30. 10.1038/nrd.2016.24510.1038/nrd.2016.245PMC641614327980341Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007; 318:1917–20. 10.1126/science.115152610.1126/science.115152618029452Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ, Yu J, Hebrok M, Hochedlinger K, et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat Cell Biol. 2011; 13:541–9. 10.1038/ncb223910.1038/ncb2239PMC398791321499256Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011; 9:17–23. 10.1016/j.stem.2011.06.00710.1016/j.stem.2011.06.00721726830Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, et al. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. 2016; 167:1719–33.e12. 10.1016/j.cell.2016.11.05210.1016/j.cell.2016.11.052PMC567927927984723Browder KC, Reddy P, Yamamoto M, Haghani A, Guillen IG, Sahu S, Wang C, Luque Y, Prieto J, Shi L, Shojima K, Hishida T, Lai Z, et al. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Nat Aging. 2022; 2:243–53. 10.1038/s43587-022-00183-210.1038/s43587-022-00183-237118377Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, Tran CM, Chu CR, Horvath S, Qi LS, Bhutani N, Rando TA, Sebastiano V. Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nat Commun. 2020; 11:1545. 10.1038/s41467-020-15174-310.1038/s41467-020-15174-3PMC709339032210226Rodríguez-Matellán A, Alcazar N, Hernández F, Serrano M, Ávila J. In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice. Stem Cell Reports. 2020; 15:1056–66. 10.1016/j.stemcr.2020.09.01010.1016/j.stemcr.2020.09.010PMC766378233096049Macip CC, Hasan R, Hoznek V, Kim J, Metzger LE IV, Sethna S, Davidsohn N. Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice. bioRxiv. 2023. 10.1101/2023.01.04.52250710.1101/2023.01.04.522507PMC1090973238381405Sung YK, Kim SW. Recent advances in the development of gene delivery systems. Biomater Res. 2019; 23:8. 10.1186/s40824-019-0156-z10.1186/s40824-019-0156-zPMC641726130915230Liuyang S, Wang G, Wang Y, He H, Lyu Y, Cheng L, Yang Z, Guan J, Fu Y, Zhu J, Zhong X, Sun S, Li C, et al. Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming. Cell Stem Cell. 2023; 30:450–9.e9. 10.1016/j.stem.2023.02.00810.1016/j.stem.2023.02.00836944335Hu Y, Yang Y, Tan P, Zhang Y, Han M, Yu J, Zhang X, Jia Z, Wang D, Yao K, Pang H, Hu Z, Li Y, et al. Induction of mouse totipotent stem cells by a defined chemical cocktail. Nature. 2023; 617:792–7. 10.1038/s41586-022-04967-910.1038/s41586-022-04967-935728625Guan J, Wang G, Wang J, Zhang Z, Fu Y, Cheng L, Meng G, Lyu Y, Zhu J, Li Y, Wang Y, Liuyang S, Liu B, et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature. 2022; 605:325–31. 10.1038/s41586-022-04593-510.1038/s41586-022-04593-535418683Hou P, Li Y, Zhang X, Liu C, Guan J, Li H, Zhao T, Ye J, Yang W, Liu K, Ge J, Xu J, Zhang Q, et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science. 2013; 341:651–4. 10.1126/science.123927810.1126/science.123927823868920An S, Cho SY, Kang J, Lee S, Kim HS, Min DJ, Son E, Cho KH. Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts. Proc Natl Acad Sci U S A. 2020; 117:31535–46. 10.1073/pnas.192033811710.1073/pnas.1920338117PMC773385833229519Du J, Zheng L, Gao P, Yang H, Yang WJ, Guo F, Liang R, Feng M, Wang Z, Zhang Z, Bai L, Bu Y, Xing S, et al. A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell. 2022; 29:545–58.e13. 10.1016/j.stem.2022.03.00910.1016/j.stem.2022.03.00935395187Mertens J, Paquola ACM, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, et al. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015; 17:705–18. 10.1016/j.stem.2015.09.00110.1016/j.stem.2015.09.001PMC592913026456686D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009; 136:284–95. 10.1016/j.cell.2008.11.03710.1016/j.cell.2008.11.037PMC280515119167330Gatto N, Dos Santos Souza C, Shaw AC, Bell SM, Myszczynska MA, Powers S, Meyer K, Castelli LM, Karyka E, Mortiboys H, Azzouz M, Hautbergue GM, Márkus NM, et al. Directly converted astrocytes retain the ageing features of the donor fibroblasts and elucidate the astrocytic contribution to human CNS health and disease. Aging Cell. 2021; 20:e13281. 10.1111/acel.1328110.1111/acel.13281PMC781184933314575Zhang JH, Chung TD, Oldenburg KR. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen. 1999; 4:67–73. 10.1177/10870571990040020610.1177/10870571990040020610838414Park JH, Ryu SJ, Kim BJ, Cho HJ, Park CH, Choi HJC, Jang EJ, Yang EJ, Hwang JA, Woo SH, Lee JH, Park JH, Choi KM, et al. Disruption of nucleocytoplasmic trafficking as a cellular senescence driver. Exp Mol Med. 2021; 53:1092–108. 10.1038/s12276-021-00643-610.1038/s12276-021-00643-6PMC825758734188179Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z, Capell BC, Xu C, Xu M, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017; 550:402–6. 10.1038/nature2405010.1038/nature24050PMC585093828976970Dou Z, Xu C, Donahue G, Shimi T, Pan JA, Zhu J, Ivanov A, Capell BC, Drake AM, Shah PP, Catanzaro JM, Ricketts MD, Lamark T, et al. Autophagy mediates degradation of nuclear lamina. Nature. 2015; 527:105–9. 10.1038/nature1554810.1038/nature15548PMC482441426524528Freund A, Laberge RM, Demaria M, Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. 2012; 23:2066–75. 10.1091/mbc.E11-10-088410.1091/mbc.E11-10-0884PMC336417222496421Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF, Wu H, Berger SL, Adams PD. Lysosome-mediated processing of chromatin in senescence. J Cell Biol. 2013; 202:129–43. 10.1083/jcb.20121211010.1083/jcb.201212110PMC370498523816621Lenain C, de Graaf CA, Pagie L, Visser NL, de Haas M, de Vries SS, Peric-Hupkes D, van Steensel B, Peeper DS. Massive reshaping of genome-nuclear lamina interactions during oncogene-induced senescence. Genome Res. 2017; 27:1634–44. 10.1101/gr.225763.11710.1101/gr.225763.117PMC563002728916540Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Rai TS, McBryan T, Gregory BD, Adams PD, Berger SL. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 2013; 27:1787–99. 10.1101/gad.223834.11310.1101/gad.223834.113PMC375969523934658Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 2011; 25:2579–93. 10.1101/gad.179515.11110.1101/gad.179515.111PMC324868022155925Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016; 7:8524–31. 10.18632/oncotarget.738310.18632/oncotarget.7383PMC489098426885756Kabacik S, Lowe D, Fransen L, Leonard M, Ang SL, Whiteman C, Corsi S, Cohen H, Felton S, Bali R, Horvath S, Raj K. The relationship between epigenetic age and the hallmarks of aging in human cells. Nat Aging. 2022; 2:484–93. 10.1038/s43587-022-00220-010.1038/s43587-022-00220-0PMC1007797137034474Campisi J, Morreo G, Pardee AB. Kinetics of G1 transit following brief starvation for serum factors. Exp Cell Res. 1984; 152:459–66. 10.1016/0014-4827(84)90647-510.1016/0014-4827(84)90647-56373328López-Domínguez JA, Rodríguez-López S, Ahumada-Castro U, Desprez PY, Konovalenko M, Laberge RM, Cárdenas C, Villalba JM, Campisi J. Cdkn1a transcript variant 2 is a marker of aging and cellular senescence. Aging (Albany NY). 2021; 13:13380–92. 10.18632/aging.20311010.18632/aging.203110PMC820286334035185Gill D, Parry A, Santos F, Okkenhaug H, Todd CD, Hernando-Herraez I, Stubbs TM, Milagre I, Reik W. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. Elife. 2022; 11:e71624. 10.7554/eLife.7162410.7554/eLife.71624PMC902305835390271Olova N, Simpson DJ, Marioni RE, Chandra T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell. 2019; 18:e12877. 10.1111/acel.1287710.1111/acel.12877PMC635182630450724Kriukov D, Khrameeva EE, Gladyshev VN, Dmitriev SE, Tyshkovskiy A. Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity. bioRxiv. 2022. 10.1101/2022.12.12.52005810.1101/2022.12.12.520058Li Y, Zhang Q, Yin X, Yang W, Du Y, Hou P, Ge J, Liu C, Zhang W, Zhang X, Wu Y, Li H, Liu K, et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res. 2011; 21:196–204. 10.1038/cr.2010.14210.1038/cr.2010.142PMC319340520956998Zhang Z, Xiang D, Wu WS. Sodium butyrate facilitates reprogramming by derepressing OCT4 transactivity at the promoter of embryonic stem cell-specific miR-302/367 cluster. Cell Reprogram. 2014; 16:130–9. 10.1089/cell.2013.007010.1089/cell.2013.0070PMC396737624568633Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, et al. Oct4-induced pluripotency in adult neural stem cells. Cell. 2009; 136:411–9. 10.1016/j.cell.2009.01.02310.1016/j.cell.2009.01.02319203577Velychko S, Adachi K, Kim KP, Hou Y, MacCarthy CM, Wu G, Schöler HR. Excluding Oct4 from Yamanaka Cocktail Unleashes the Developmental Potential of iPSCs. Cell Stem Cell. 2019; 25:737–53.e4. 10.1016/j.stem.2019.10.00210.1016/j.stem.2019.10.002PMC690074931708402Schoenfeldt L, Paine PT, Kamaludeen M NH, Phelps GB, Mrabti C, Perez K, Ocampo A. Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan. bioRxiv. 2022. 10.1101/2022.08.29.50522210.1101/2022.08.29.505222Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet. 2005; 14:R47–58. 10.1093/hmg/ddi11410.1093/hmg/ddi11415809273Liu Z, Leung D, Thrush K, Zhao W, Ratliff S, Tanaka T, Schmitz LL, Smith JA, Ferrucci L, Levine ME. Underlying features of epigenetic aging clocks in vivo and in vitro. Aging Cell. 2020; 19:e13229. 10.1111/acel.1322910.1111/acel.13229PMC757625932930491Fahy GM, Brooke RT, Watson JP, Good Z, Vasanawala SS, Maecker H, Leipold MD, Lin DTS, Kobor MS, Horvath S. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell. 2019; 18:e13028. 10.1111/acel.1302810.1111/acel.13028PMC682613831496122Tyshkovskiy A, Ma S, Shindyapina AV, Tikhonov S, Lee SG, Bozaykut P, Castro JP, Seluanov A, Schork NJ, Gorbunova V, Dmitriev SE, Miller RA, Gladyshev VN. Distinct longevity mechanisms across and within species and their association with aging. Cell. 2023; 186:2929–49.e20. 10.1016/j.cell.2023.05.00210.1016/j.cell.2023.05.002PMC1119217237269831Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015; 525:56–61. 10.1038/nature1497310.1038/nature14973PMC480074226308891Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014; 15:384–96. 10.1038/nrm381010.1038/nrm381024854788Huang J, Zhang H, Yao J, Qin G, Wang F, Wang X, Luo A, Zheng Q, Cao C, Zhao J. BIX-01294 increases pig cloning efficiency by improving epigenetic reprogramming of somatic cell nuclei. Reproduction. 2016; 151:39–49. 10.1530/REP-15-046010.1530/REP-15-046026604326Papait R, Serio S, Pagiatakis C, Rusconi F, Carullo P, Mazzola M, Salvarani N, Miragoli M, Condorelli G. Histone Methyltransferase G9a Is Required for Cardiomyocyte Homeostasis and Hypertrophy. Circulation. 2017; 136:1233–46. 10.1161/CIRCULATIONAHA.117.02856110.1161/CIRCULATIONAHA.117.02856128778944Singh VK, Kumar N, Kalsan M, Saini A, Chandra R. Mechanism of Induction: Induced Pluripotent Stem Cells (iPSCs). J Stem Cells. 2015; 10:43–62.26665937Takeda Y, Harada Y, Yoshikawa T, Dai P. Chemical compound-based direct reprogramming for future clinical applications. Biosci Rep. 2018; 38:BSR20171650. 10.1042/BSR2017165010.1042/BSR20171650PMC593843029739872Ichida JK, Blanchard J, Lam K, Son EY, Chung JE, Egli D, Loh KM, Carter AC, Di Giorgio FP, Koszka K, Huangfu D, Akutsu H, Liu DR, et al. A small-molecule inhibitor of tgf-Beta signaling replaces sox2 in reprogramming by inducing nanog. Cell Stem Cell. 2009; 5:491–503. 10.1016/j.stem.2009.09.01210.1016/j.stem.2009.09.012PMC333519519818703Maherali N, Hochedlinger K. Tgfbeta signal inhibition cooperates in the induction of iPSCs and replaces Sox2 and cMyc. Curr Biol. 2009; 19:1718–23. 10.1016/j.cub.2009.08.02510.1016/j.cub.2009.08.025PMC353837219765992Fu Y, Huang C, Xu X, Gu H, Ye Y, Jiang C, Qiu Z, Xie X. Direct reprogramming of mouse fibroblasts into cardiomyocytes with chemical cocktails. Cell Res. 2015; 25:1013–24. 10.1038/cr.2015.9910.1038/cr.2015.99PMC455981926292833Tu WZ, Fu YB, Xie X. RepSox, a small molecule inhibitor of the TGFβ receptor, induces brown adipogenesis and browning of white adipocytes. Acta Pharmacol Sin. 2019; 40:1523–31. 10.1038/s41401-019-0264-210.1038/s41401-019-0264-2PMC747145731235818Mali P, Chou BK, Yen J, Ye Z, Zou J, Dowey S, Brodsky RA, Ohm JE, Yu W, Baylin SB, Yusa K, Bradley A, Meyers DJ, et al. Butyrate greatly enhances derivation of human induced pluripotent stem cells by promoting epigenetic remodeling and the expression of pluripotency-associated genes. Stem Cells. 2010; 28:713–20. 10.1002/stem.40210.1002/stem.402PMC301521720201064Ladewig J, Mertens J, Kesavan J, Doerr J, Poppe D, Glaue F, Herms S, Wernet P, Kögler G, Müller FJ, Koch P, Brüstle O. Small molecules enable highly efficient neuronal conversion of human fibroblasts. Nat Methods. 2012; 9:575–8. 10.1038/nmeth.197210.1038/nmeth.197222484851Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, et al. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell Stem Cell. 2015; 17:195–203. 10.1016/j.stem.2015.06.00310.1016/j.stem.2015.06.00326253201Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, et al. Direct Conversion of Normal and Alzheimer’s Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell. 2015; 17:204–12. 10.1016/j.stem.2015.07.00610.1016/j.stem.2015.07.00626253202Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015; 12:357–60. 10.1038/nmeth.331710.1038/nmeth.3317PMC465581725751142Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015; 33:290–5. 10.1038/nbt.312210.1038/nbt.3122PMC464383525690850Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15:550. 10.1186/s13059-014-0550-810.1186/s13059-014-0550-8PMC430204925516281Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102:15545–50. 10.1073/pnas.050658010210.1073/pnas.0506580102PMC123989616199517Weber C, Hirst MB, Ernest B, Schaub NJ, Wilson KM, Wang K, Baskir HM, Chu PH, Tristan CA, Singeç I. SEQUIN is an R/Shiny framework for rapid and reproducible analysis of RNA-seq data. Cell Rep Methods. 2023; 3:100420. 10.1016/j.crmeth.2023.10042010.1016/j.crmeth.2023.100420PMC1008809137056373366387922023012520241102

1097-417218622023Jan19CellLoss of epigenetic information as a cause of mammalian aging.305326.e27305-326.e2710.1016/j.cell.2022.12.027S0092-8674(22)01570-7All 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.Copyright © 2022 Elsevier Inc. All rights reserved.YangJae-HyunJHPaul 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.HayanoMotoshiMPaul 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.GriffinPatrick TPTPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.AmorimJoão AJAPaul 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.BonkowskiMichael SMSPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.ApostolidesJohn KJKComputational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.SalfatiElias LELPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.BlanchetteMarcoMCantata/Dovetail Genomics, Scotts Valley, CA, USA.MundingElizabeth MEMCantata/Dovetail Genomics, Scotts Valley, CA, USA.BhaktaMitalMCantata/Dovetail Genomics, Scotts Valley, CA, USA.ChewYap ChingYCZymo Research Corporation, Irvine, CA, USA.GuoWeiWZymo Research Corporation, Irvine, CA, USA.YangXiaojingXZymo Research Corporation, Irvine, CA, USA.Maybury-LewisSunSPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.TianXiaoXPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.RossJaime MJMPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.CoppotelliGiuseppeGPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.MeerMargarita VMVDepartment of Medicine, Brigham and Women's Hospital, HMS, Boston, MA, USA.Rogers-HammondRyanRPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.VeraDaniel LDLPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.LuYuancheng RyanYRPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.PippinJeffrey WJWDivision of Nephrology, University of Washington, Seattle, WA, USA.CreswellMichael LMLDivision of Nephrology, University of Washington, Seattle, WA, USA; Georgetown University School of Medicine, Washington, DC, USA.DouZhixunZDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.XuCaiyueCDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.MitchellSarah JSJExperimental Gerontology Section, NIA/NIH, Baltimore, MD, USA.DasAbhirupAPaul 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.O'ConnellBrendan LBLDepartment of Biomolecular Engineering, UCSC, Santa Cruz, CA, USA.ThakurSachinSPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.KaneAlice EAEPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.SuQiaoQComputational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.MohriYasuakiYDepartment of Stem Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.NishimuraEmi KEKDepartment of Stem Cell Biology, Tokyo Medical and Dental University, Tokyo, Japan.SchaevitzLauraLVium, San Mateo, CA, USA.GargNehaNPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.BaltaAna-MariaAMPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.RegoMeghan AMAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.Gregory-KsanderMeredithMSchepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, HMS, Boston, MA, USA.JakobsTatjana CTCSchepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, HMS, Boston, MA, USA.ZhongLeiLThe Massachusetts General Hospital Cancer Center, HMS, Boston, MA, USA.WakimotoHirokoHDepartment of Genetics, HMS, Boston, MA, USA.El AndariJihadJDepartment of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, University of Heidelberg, BioQuant, Heidelberg, Germany.GrimmDirkDDepartment of Infectious Diseases/Virology, Section Viral Vector Technologies, Medical Faculty, University of Heidelberg, BioQuant, Heidelberg, Germany.MostoslavskyRaulRThe Massachusetts General Hospital Cancer Center, HMS, Boston, MA, USA.WagersAmy JAJPaul 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.TsubotaKazuoKDepartment of Ophthalmology, Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.BonaseraStephen JSJDivision of Geriatrics, University of Nebraska Medical Center, Durham Research Center II, Omaha, NE, USA.PalmeiraCarlos MCMDepartment of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.SeidmanJonathan GJGDepartment of Genetics, HMS, Boston, MA, USA.SeidmanChristine ECEDepartment of Genetics, HMS, Boston, MA, USA.WolfNorman SNSDepartment of Pathology, University of Washington, Seattle, WA, USA.KreilingJill AJADepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.SedivyJohn MJMDepartment of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.MurphyGeorge FGFDepartment of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.GreenRichard EREDepartment of Biomolecular Engineering, UCSC, Santa Cruz, CA, USA.GarciaBenjamin ABADepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.BergerShelley LSLDepartment of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.OberdoerfferPhilippPLaboratory of Receptor Biology and Gene Expression, NCI, NIH, Bethesda, MD, USA.ShanklandStuart JSJDivision of Nephrology, University of Washington, Seattle, WA, USA.GladyshevVadim NVNDepartment of Medicine, Brigham and Women's Hospital, HMS, Boston, MA, USA.KsanderBruce RBRSchepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, HMS, Boston, MA, USA.PfenningAndreas RARComputational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.RajmanLuis ALAPaul F. Glenn Center for Biology of Aging Research, Department of Genetics, Blavatnik Institute, Harvard Medical School (HMS), Boston, MA, USA.SinclairDavid ADAPaul 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.engR01 EY019703EYNEI NIH HHSUnited StatesF99 AG073499AGNIA NIH HHSUnited StatesK99 AG068303AGNIA NIH HHSUnited StatesK99 AG055683AGNIA NIH HHSUnited StatesR37 AG028730AGNIA NIH HHSUnited StatesP01 AG051449AGNIA NIH HHSUnited StatesR00 AG070102AGNIA NIH HHSUnited StatesP30 EY003790EYNEI NIH HHSUnited StatesR01 AG019719AGNIA NIH HHSUnited StatesR01 DK056799DKNIDDK NIH HHSUnited StatesR01 AG065403AGNIA NIH HHSUnited StatesR01 DK097598DKNIDDK NIH HHSUnited StatesR01 AG064223AGNIA NIH HHSUnited StatesP01 AG031862AGNIA NIH HHSUnited StatesR01 AG028730AGNIA NIH HHSUnited StatesR01 AG016694AGNIA NIH HHSUnited StatesR00 AG055683AGNIA NIH HHSUnited StatesT32 HL007118HLNHLBI NIH HHSUnited StatesK99 AG070102AGNIA NIH HHSUnited StatesT32 AG023480AGNIA NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't20230112

United StatesCell04130660092-86740NucleoproteinsIMCell Metab. 2023 Mar 7;35(3):383-385. doi: 10.1016/j.cmet.2023.02.012.36889279Signal Transduct Target Ther. 2023 Mar 27;8(1):140. doi: 10.1038/s41392-023-01412-9.36973241Cell. 2024 Feb 29;187(5):1312-1313. doi: 10.1016/j.cell.2024.01.049.38428398AnimalsAginggeneticsDNA MethylationEpigenesis, GeneticEpigenomeMammalsgeneticsNucleoproteinsSaccharomyces cerevisiaegeneticsDNA damageRCMagingchromatinepigenetic clockepigenetic reprogrammingrelocalization of chromatin modifiersenescenceDeclaration of interests 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.202191420228920221215202311460202312560202311318422024119ppublish36638792NIHMS1859595PMC1016613310.1016/j.cell.2022.12.027S0092-8674(22)01570-7Abdennur N., and Mirny LA. (2020). Cooler: scalable storage for Hi-C data and other genomically labeled arrays. Bioinformatics (Oxford, England) 36, 311–316. 10.1093/bioinformatics/btz540.10.1093/bioinformatics/btz540PMC820551631290943Ackert-Bicknell CL, Anderson LC, Sheehan S, Hill WG, Chang B, Churchill GA, Chesler EJ, Korstanje R, and Peters LL (2015). Aging Research Using Mouse Models. Current protocols in mouse biology 5, 95–133. 10.1002/9780470942390.mo140195.10.1002/9780470942390.mo140195PMC459077526069080Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, et al. (2014). Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science (New York, NY) 346, 89–93. 10.1126/science.1252945.10.1126/science.1252945PMC486932625147279Beggs ML, Nagarajan R, Taylor-Jones JM, Nolen G, Macnicol M, and Peterson CA (2004). Alterations in the TGFbeta signaling pathway in myogenic progenitors with age. Aging cell 3, 353–361. 10.1111/j.1474-9728.2004.00135.x.10.1111/j.1474-9728.2004.00135.x15569352Benayoun BA, Pollina EA, and Brunet A. (2015). Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nature reviews Molecular cell biology 16, 593–610. 10.1038/nrm4048.10.1038/nrm4048PMC473672826373265Benayoun BA, Pollina EA, Singh PP, Mahmoudi S, Harel I, Casey KM, Dulken BW, Kundaje A, and Brunet A. (2019). Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome research 29, 697–709. 10.1101/gr.240093.118.10.1101/gr.240093.118PMC644239130858345Berkovich E, Monnat RJ Jr., and Kastan MB (2007). Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nature cell biology 9, 683–690. 10.1038/ncb1599.10.1038/ncb159917486112Birkisdottir MB, Jaarsma D, Brandt RMC, Barnhoorn S, van Vliet N, Imholz S, van Oostrom CT, Nagarajah B, Portilla Fernandez E, Roks AJM, et al. (2021). Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice. Aging cell 20, e13302. 10.1111/acel.13302.10.1111/acel.13302PMC788404833484480Boisvert MM, Erikson GA, Shokhirev MN, and Allen NJ (2018). The Aging Astrocyte Transcriptome from Multiple Regions of the Mouse Brain. Cell reports 22, 269–285. 10.1016/j.celrep.2017.12.039.10.1016/j.celrep.2017.12.039PMC578320029298427Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, and Rando TA (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science (New York, NY) 317, 807–810. 10.1126/science.1144090.10.1126/science.114409017690295Brown MF, and Stuart JA (2007). Correlation of mitochondrial superoxide dismutase and DNA polymerase beta in mammalian dermal fibroblasts with species maximal lifespan. Mechanisms of ageing and development 128, 696–705. 10.1016/j.mad.2007.10.004.10.1016/j.mad.2007.10.00418045656Budovskaya YV, Wu K, Southworth LK, Jiang M, Tedesco P, Johnson TE, and Kim SK (2008). An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134, 291–303. 10.1016/j.cell.2008.05.044.10.1016/j.cell.2008.05.044PMC471905318662544Bunn AG (2008). A dendrochronology program library in R (dplR). Dendrochronologia 26, 115–124. 10.1016/j.dendro.2008.01.002.10.1016/j.dendro.2008.01.002Bunn AG (2010). Statistical and visual crossdating in R using the dplR library. Dendrochronologia 28, 251–258. 10.1016/j.dendro.2009.12.001.10.1016/j.dendro.2009.12.001Burgstaller JP, and Brem G. (2017). Aging of Cloned Animals: A Mini-Review. Gerontology 63, 417–425. 10.1159/000452444.10.1159/00045244427820924Calkins DJ. (2013). Age-related changes in the visual pathways: blame it on the axon. Investigative ophthalmology & visual science 54, Orsf37–41. 10.1167/iovs.13-12784.10.1167/iovs.13-12784PMC386437724335066Carrero D, Soria-Valles C, and López-Otín C. (2016). Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells. Disease Models & Mechanisms 9, 719–735. 10.1242/dmm.024711.10.1242/dmm.024711PMC495830927482812Cawthon RM (2009). Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic acids research 37, e21. 10.1093/nar/gkn1027.10.1093/nar/gkn1027PMC264732419129229Chailleux C, Aymard F, Caron P, Daburon V, Courilleau C, Canitrot Y, Legube G, and Trouche D. (2014). Quantifying DNA double-strand breaks induced by site-specific endonucleases in living cells by ligation-mediated purification. Nature protocols 9, 517–528. 10.1038/nprot.2014.031.10.1038/nprot.2014.03124504477Changolkar LN, Singh G, and Pehrson JR (2008). macroH2A1-dependent silencing of endogenous murine leukemia viruses. Molecular and cellular biology 28, 2059–2065. 10.1128/mcb.01362-07.10.1128/mcb.01362-07PMC226840818195046Cheung P, Vallania F, Warsinske HC, Donato M, Schaffert S, Chang SE, Dvorak M, Dekker CL, Davis MM, Utz PJ, et al. (2018). Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell 173, 1385–1397 e1314. 10.1016/j.cell.2018.03.079.10.1016/j.cell.2018.03.079PMC598418629706550Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, Ho YJ, Myers DR, Choi VW, Compagno M, Malkin DJ, et al. (2011). Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147, 107–119. 10.1016/j.cell.2011.07.049.10.1016/j.cell.2011.07.049PMC318693921962511Choudhury AR., Ju Z., Djojosubroto MW., Schienke A., Lechel A., Schaetzlein S., Jiang H., Stepczynska A., Wang C., Buer J., et al. (2007). Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature genetics 39, 99–105. 10.1038/ng1937.10.1038/ng193717143283Conant D, Hsiau T, Rossi N, Oki J, Maures T, Waite K, Yang J, Joshi S, Kelso R, Holden K, et al. (2022). Inference of CRISPR Edits from Sanger Trace Data. CRISPR J 5, 123–130. 10.1089/crispr.2021.0113.10.1089/crispr.2021.011335119294Cunningham F, Achuthan P, Akanni W, Allen J, Amode MR, Armean IM, Bennett R, Bhai J, Billis K, Boddu S, et al. (2019). Ensembl 2019. Nucleic acids research 47, D745–D751. 10.1093/nar/gky1113.10.1093/nar/gky1113PMC632396430407521Cutler RG (1982). The dysdifferentiative hypothesis of mammalian aging and longevity. The aging brain 20, 1–18.Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, and Berger SL (2009). Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807. 10.1038/nature08085.10.1038/nature08085PMC270215719516333Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne B, Joshi S, Lu Y, et al. (2019). Impairment of an Endothelial NAD(+)−H2S Signaling Network Is a Reversible Cause of Vascular Aging. Cell 176, 944–945. 10.1016/j.cell.2019.01.026.10.1016/j.cell.2019.01.026PMC642995330735637De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J, Peterson AL, Kreiling JA, Neretti N, and Sedivy JM (2013). Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging cell 12, 247–256. 10.1111/acel.12047.10.1111/acel.12047PMC361868223360310De Cecco M., Ito T., Petrashen AP., Elias AE., Skvir NJ., Criscione SW., Caligiana A., Brocculi G., Adney EM., Boeke JD., et al. (2019). L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78. 10.1038/s41586-018-0784-9.10.1038/s41586-018-0784-9PMC651996330728521De Majo F, Martens L, Hegenbarth JC, Rühle F, Hamczyk MR, Nevado RM, Andrés V, Hilbold E, Bär C, Thum T, et al. (2021). Genomic instability in the naturally and prematurely aged myocardium. Proceedings of the National Academy of Sciences of the United States of America 118. 10.1073/pnas.2022974118.10.1073/pnas.2022974118PMC843352234465617Demontis F, Piccirillo R, Goldberg AL, and Perrimon N. (2013). Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Disease Models & Mechanisms 6, 1339–1352. 10.1242/dmm.012559.10.1242/dmm.012559PMC382025824092876Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao PC, Qiu Y, Zhao Y, et al. (2013). SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nature neuroscience 16, 1008–1015. 10.1038/nn.3460.10.1038/nn.3460PMC475813423852118Downs JC (2015). Optic nerve head biomechanics in aging and disease. Experimental eye research 133, 19–29. 10.1016/j.exer.2015.02.011.10.1016/j.exer.2015.02.011PMC437944525819451Durand NC, Shamim MS, Machol I, Rao SS, Huntley MH, Lander ES, and Aiden EL (2016). Juicer Provides a One-Click System for Analyzing Loop-Resolution Hi-C Experiments. Cell systems 3, 95–98. 10.1016/j.cels.2016.07.002.10.1016/j.cels.2016.07.002PMC584646527467249El Andari J., Renaud-Gabardos E., Tulalamba W., Weinmann J., Mangin L., Pham QH., Hille S., Bennett A., Attebi E., Bourges E., et al. (2022). Semirational bioengineering of AAV vectors with increased potency and specificity for systemic gene therapy of muscle disorders. Science advances 8, eabn4704. 10.1126/sciadv.abn4704.10.1126/sciadv.abn4704PMC949171436129972Feltes BC (2019). Architects meets Repairers: The interplay between homeobox genes and DNA repair. DNA repair 73, 34–48. 10.1016/j.dnarep.2018.10.007.10.1016/j.dnarep.2018.10.00730448208Feng J, Liu T, Qin B, Zhang Y, and Liu XS (2012). Identifying ChIP-seq enrichment using MACS. Nature protocols 7, 1728–1740. 10.1038/nprot.2012.101.10.1038/nprot.2012.101PMC386821722936215Ferguson VL, Ayers RA, Bateman TA, and Simske SJ (2003). Bone development and age-related bone loss in male C57BL/6J mice. Bone 33, 387–398.13678781Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, and Tyler JK (2010). Elevated histone expression promotes life span extension. Molecular cell 39, 724–735. 10.1016/j.molcel.2010.08.015.10.1016/j.molcel.2010.08.015PMC396607520832724Florian MC, Nattamai KJ, Dorr K, Marka G, Uberle B, Vas V, Eckl C, Andra I, Schiemann M, Oostendorp RA, et al. (2013). A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503, 392–396. 10.1038/nature12631.10.1038/nature12631PMC407899224141946Freund A, Laberge RM, Demaria M, and Campisi J. (2012). Lamin B1 loss is a senescence-associated biomarker. Molecular biology of the cell 23, 2066–2075. 10.1091/mbc.E11-10-0884.10.1091/mbc.E11-10-0884PMC336417222496421Gallagher M, Bakker A, Yassa MA, and Stark CE (2010). Bridging neurocognitive aging and disease modification: targeting functional mechanisms of memory impairment. Current Alzheimer research 7, 197–199. 10.2174/156720510791050867.10.2174/156720510791050867PMC300859220088811Gao J., Wang WY., Mao YW., Graff J., Guan JS., Pan L., Mak G., Kim D., Su SC., and Tsai LH. (2010). A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature 466, 1105–1109. 10.1038/nature09271.10.1038/nature09271PMC292887520622856Garlick PJ, McNurlan MA, and Preedy VR (1980). A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [3H]phenylalanine. The Biochemical journal 192, 719–723. 10.1042/bj1920719.10.1042/bj1920719PMC11623896786283Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, and Kellis M. (2015). Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369. 10.1038/nature14252.10.1038/nature14252PMC453058325693568Gorkin DU, Leung D, and Ren B. (2014). The 3D genome in transcriptional regulation and pluripotency. Cell stem cell 14, 762–775. 10.1016/j.stem.2014.05.017.10.1016/j.stem.2014.05.017PMC410721424905166Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, and Brunet A. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466, 383–387. 10.1038/nature09195.10.1038/nature09195PMC307500620555324Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, and Brunet A. (2011). Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479, 365–371. 10.1038/nature10572.10.1038/nature10572PMC336812122012258Hannum G., Guinney J., Zhao L., Zhang L., Hughes G., Sadda S., Klotzle B., Bibikova M., Fan JB., Gao Y., et al. (2013). Genome-wide methylation profiles reveal quantitative views of human aging rates. Molecular cell 49, 359–367. 10.1016/j.molcel.2012.10.016.10.1016/j.molcel.2012.10.016PMC378061123177740Harkema L, Youssef SA, and de Bruin A. (2016). Pathology of Mouse Models of Accelerated Aging. Veterinary pathology 53, 366–389. 10.1177/0300985815625169.10.1177/030098581562516926864891Heinz S, Romanoski CE, Benner C, and Glass CK (2015). The selection and function of cell type-specific enhancers. Nature reviews Molecular cell biology 16, 144–154. 10.1038/nrm3949.10.1038/nrm3949PMC451760925650801Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-Andre V, Sigova AA, Hoke HA, and Young RA (2013). Super-enhancers in the control of cell identity and disease. Cell 155, 934–947. 10.1016/j.cell.2013.09.053.10.1016/j.cell.2013.09.053PMC384106224119843Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, Hubbard GB, Ikeno Y, Zhang Y, Feng B, et al. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell 160, 477–488. 10.1016/j.cell.2014.12.016.10.1016/j.cell.2014.12.016PMC462492125619689Hofstatter EW, Horvath S, Dalela D, Gupta P, Chagpar AB, Wali VB, Bossuyt V, Storniolo AM, Hatzis C, Patwardhan G, et al. (2018). Increased epigenetic age in normal breast tissue from luminal breast cancer patients. Clinical epigenetics 10, 112. 10.1186/s13148-018-0534-8.10.1186/s13148-018-0534-8PMC611471730157950Horvath S. (2013). DNA methylation age of human tissues and cell types. Genome biology 14, R115. 10.1186/gb-2013-14-10-r115.10.1186/gb-2013-14-10-r115PMC401514324138928Horvath S, and Levine AJ (2015). HIV-1 Infection Accelerates Age According to the Epigenetic Clock. The Journal of infectious diseases 212, 1563–1573. 10.1093/infdis/jiv277.10.1093/infdis/jiv277PMC462125325969563Houtkooper RH., Argmann C., Houten SM., Canto C., Jeninga EH., Andreux PA., Thoma C., Doenlen R., Schoonjans K., and Auwerx J. (2011). The metabolic footprint of aging in mice. Scientific reports 1, 134. 10.1038/srep00134.10.1038/srep00134PMC321661522355651Hu Z, Chen K, Xia Z, Chavez M, Pal S, Seol JH, Chen CC, Li W, and Tyler JK (2014). Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes & development 28, 396–408. 10.1101/gad.233221.113.10.1101/gad.233221.113PMC393751724532716Idelevich A, Sato K, Nagano K, Rowe G, Gori F, and Baron R. (2018). Neuronal hypothalamic regulation of body metabolism and bone density is galanin dependent. The Journal of clinical investigation 128, 2626–2641. 10.1172/jci99350.10.1172/jci99350PMC598333729596063Imai S, and Kitano H. (1998). Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Experimental gerontology 33, 555–570. 10.1016/s0531-5565(98)00037-0.10.1016/s0531-5565(98)00037-09789733Jiang N, Du G, Tobias E, Wood JG, Whitaker R, Neretti N, and Helfand SL (2013). Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging. Aging 5, 813–824. 10.18632/aging.100614.10.18632/aging.100614PMC386872424243774Johnson S, Wozniak DF, and Imai S. (2018). CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. NPJ aging and mechanisms of disease 4, 10. 10.1038/s41514-018-0029-z.10.1038/s41514-018-0029-zPMC622450430416740Kabacik S, Lowe D, Fransen L, Leonard M, Ang S-L, Whiteman C, Corsi S, Cohen H, Felton S, Bali R, et al. (2022). The relationship between epigenetic age and the hallmarks of ageing in human cells. Nature Aging. 10.1038/s43587-022-00220-0.10.1038/s43587-022-00220-0PMC1007797137034474Kaeberlein M., McVey M., and Guarente L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes & development 13, 2570–2580. 10.1101/gad.13.19.2570.10.1101/gad.13.19.2570PMC31707710521401Kane AE, and Sinclair DA (2019). Epigenetic changes during aging and their reprogramming potential. Critical reviews in biochemistry and molecular biology 54, 61–83. 10.1080/10409238.2019.1570075.10.1080/10409238.2019.1570075PMC642462230822165Katzman WB, Wanek L, Shepherd JA, and Sellmeyer DE (2010). Age-related hyperkyphosis: its causes, consequences, and management. The Journal of orthopaedic and sports physical therapy 40, 352–360. 10.2519/jospt.2010.3099.10.2519/jospt.2010.3099PMC290735720511692Kaya A, Lobanov AV, and Gladyshev VN (2015). Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae. Aging cell 14, 366–371. 10.1111/acel.12290.10.1111/acel.12290PMC440666525702753Keller EF (2009). Knowing As Making, Making As Knowing: The Many Lives of Synthetic Biology. Biological Theory 4, 333–339. 10.1162/BIOT_a_00005.10.1162/BIOT_a_00005Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabb DS, Murthy M, Pak SM, Laroche T, Gasser SM, and Guarente L. (1997). Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89, 381–391. 10.1016/s0092-8674(00)80219-6.10.1016/s0092-8674(00)80219-69150138Kent WJ, Zweig AS, Barber G, Hinrichs AS, and Karolchik D. (2010). BigWig and BigBed: enabling browsing of large distributed datasets. Bioinformatics (Oxford, England) 26, 2204–2207. 10.1093/bioinformatics/btq351.10.1093/bioinformatics/btq351PMC292289120639541Kim D, Langmead B, and Salzberg SL (2015). HISAT: a fast spliced aligner with low memory requirements. Nature methods 12, 357–360. 10.1038/nmeth.3317.10.1038/nmeth.3317PMC465581725751142Klemm SL., Shipony Z., and Greenleaf WJ. (2019). Chromatin accessibility and the regulatory epigenome. Nature reviews Genetics 20, 207–220. 10.1038/s41576-018-0089-8.10.1038/s41576-018-0089-830675018Koks S, Dogan S, Tuna BG, Gonzalez-Navarro H, Potter P, and Vandenbroucke RE (2016). Mouse models of ageing and their relevance to disease. Mechanisms of ageing and development 160, 41–53. 10.1016/j.mad.2016.10.001.10.1016/j.mad.2016.10.00127717883Krueger F, and Andrews SR (2011). Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics (Oxford, England) 27, 1571–1572. 10.1093/bioinformatics/btr167.10.1093/bioinformatics/btr167PMC310222121493656Kundu S, Ji F, Sunwoo H, Jain G, Lee JT, Sadreyev RI, Dekker J, and Kingston RE (2017). Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation. Molecular cell 65, 432–446.e435. 10.1016/j.molcel.2017.01.009.10.1016/j.molcel.2017.01.009PMC542137528157505Landt SG, Marinov GK, Kundaje A, Kheradpour P, Pauli F, Batzoglou S, Bernstein BE, Bickel P, Brown JB, Cayting P, et al. (2012). ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia. Genome research 22, 1813–1831. 10.1101/gr.136184.111.10.1101/gr.136184.111PMC343149622955991Langmead B, and Salzberg SL (2012). Fast gapped-read alignment with Bowtie 2. Nature methods 9, 357–359. 10.1038/nmeth.1923.10.1038/nmeth.1923PMC332238122388286Le Couteur DG, Cogger VC, Markus AM, Harvey PJ, Yin ZL, Ansselin AD, and McLean AJ (2001). Pseudocapillarization and associated energy limitation in the aged rat liver. Hepatology (Baltimore, Md) 33, 537–543. 10.1053/jhep.2001.22754.10.1053/jhep.2001.2275411230732Leduc-Gaudet JP., Picard M., St-Jean Pelletier F., Sgarioto N., Auger MJ., Vallee J., Robitaille R., St-Pierre DH., and Gouspillou G. (2015). Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. Oncotarget 6, 17923–17937. 10.18632/oncotarget.4235.10.18632/oncotarget.4235PMC462722626053100Li H, Coghlan A, Ruan J, Coin LJ, Heriche JK, Osmotherly L, Li R, Liu T, Zhang Z, Bolund L, et al. (2006). TreeFam: a curated database of phylogenetic trees of animal gene families. Nucleic acids research 34, D572–580. 10.1093/nar/gkj118.10.1093/nar/gkj118PMC134748016381935Li H, and Durbin R. (2009). Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England) 25, 1754–1760. 10.1093/bioinformatics/btp324.10.1093/bioinformatics/btp324PMC270523419451168Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, and Genome Project Data Processing, S. (2009). The Sequence Alignment/Map format and SAMtools. Bioinformatics (Oxford, England) 25, 2078–2079. 10.1093/bioinformatics/btp352.10.1093/bioinformatics/btp352PMC272300219505943Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, et al. (2015). Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell stem cell 17, 195–203. 10.1016/j.stem.2015.06.003.10.1016/j.stem.2015.06.00326253201Li Z, Zhang W, Chen Y, Guo W, Zhang J, Tang H, Xu Z, Zhang H, Tao Y, Wang F, et al. (2016). Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans. Cell death and differentiation 23, 1765–1777. 10.1038/cdd.2016.65.10.1038/cdd.2016.65PMC507156827391797Liao Y, Smyth GK, and Shi W. (2013). The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote. Nucleic acids research 41, e108. 10.1093/nar/gkt214.10.1093/nar/gkt214PMC366480323558742Lieberman-Aiden E., van Berkum NL., Williams L., Imakaev M., Ragoczy T., Telling A., Amit I., Lajoie BR., Sabo PJ., Dorschner MO., et al. (2009). Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science (New York, NY) 326, 289–293. 10.1126/science.1181369.10.1126/science.1181369PMC285859419815776Lim MA, Defensor EB, Mechanic JA, Shah PP, Jaime EA, Roberts CR, Hutto DL, and Schaevitz LR (2019). Retrospective Analysis of the Effects of Identification Procedures and Cage Changing by Using Data from Automated, Continuous Monitoring. Journal of the American Association for Laboratory Animal Science : JAALAS 58, 126–141. 10.30802/aalas-jaalas-18-000056.10.30802/aalas-jaalas-18-000056PMC643335530764898Lim MA, Louie B, Ford D, Heath K, Cha P, Betts-Lacroix J, Lum PY, Robertson TL, and Schaevitz L. (2017). Development of the Digital Arthritis Index, a Novel Metric to Measure Disease Parameters in a Rat Model of Rheumatoid Arthritis. Frontiers in pharmacology 8, 818. 10.3389/fphar.2017.00818.10.3389/fphar.2017.00818PMC569444329184498Lin IH, Chang JL, Hua K, Huang WC, Hsu MT, and Chen YF (2018). Skeletal muscle in aged mice reveals extensive transformation of muscle gene expression. BMC genetics 19, 55. 10.1186/s12863-018-0660-5.10.1186/s12863-018-0660-5PMC608349630089464Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, et al. (2007). Augmented Wnt signaling in a mammalian model of accelerated aging. Science (New York, NY) 317, 803–806. 10.1126/science.1143578.10.1126/science.114357817690294Liu N, Matsumura H, Kato T, Ichinose S, Takada A, Namiki T, Asakawa K, Morinaga H, Mohri Y, De Arcangelis A, et al. (2019). Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350. 10.1038/s41586-019-1085-7.10.1038/s41586-019-1085-730944469Love MI, Huber W, and Anders S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology 15, 550. 10.1186/s13059-014-0550-8.10.1186/s13059-014-0550-8PMC430204925516281Lu AT., Fei Z., Haghani A., Robeck TR., Zoller JA., Li CZ., Zhang J., Ablaeva J., Adams DM., Almunia J., et al. (2021). Universal DNA methylation age across mammalian tissues. bioRxiv, 2021.2001.2018.426733. 10.1101/2021.01.18.426733.10.1101/2021.01.18.426733Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, et al. (2014). REST and stress resistance in ageing and Alzheimer’s disease. Nature 507, 448–454. 10.1038/nature13163.10.1038/nature13163PMC411097924670762Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, et al. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129. 10.1038/s41586-020-2975-4.10.1038/s41586-020-2975-4PMC775213433268865Lu Y, Krishnan A, Brommer B, Tian X, Meer M, Vera DL, Wang C, Zeng Q, Yu D, Bonkowski MS, et al. (2019). Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming. bioRxiv, 710210. 10.1101/710210.10.1101/710210Luense LJ, Wang X, Schon SB, Weller AH, Lin Shiao E, Bryant JM, Bartolomei MS, Coutifaris C, Garcia BA, and Berger SL (2016). Comprehensive analysis of histone post-translational modifications in mouse and human male germ cells. Epigenetics & chromatin 9, 24. 10.1186/s13072-016-0072-6.10.1186/s13072-016-0072-6PMC491517727330565Luna LG (1968). Manual of histologic staining methods of the Armed Forces Institute of Pathology (Third edition. New York: : Blakiston Division, McGraw-Hill, [1968] ©1968).Maccormick RE (2006). Possible acceleration of aging by adjuvant chemotherapy: a cause of early onset frailty? Medical hypotheses 67, 212–215. 10.1016/j.mehy.2006.01.045.10.1016/j.mehy.2006.01.04516546325Mapuskar KA., Flippo KH., Schoenfeld JD., Riley DP., Strack S., Hejleh TA., Furqan M., Monga V., Domann FE., Buatti JM., et al. (2017). Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy. Cancer research 77, 5054–5067. 10.1158/0008-5472.can-17-0106.10.1158/0008-5472.can-17-0106PMC560086328765155Martin SG, Laroche T, Suka N, Grunstein M, and Gasser SM (1999). Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97, 621–633. 10.1016/s0092-8674(00)80773-4.10.1016/s0092-8674(00)80773-410367891Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, and Nishimura EK (2016). Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science (New York, NY) 351, aad4395. 10.1126/science.aad4395.10.1126/science.aad439526912707McAinsh AD, Scott-Drew S, Murray JA, and Jackson SP (1999). DNA damage triggers disruption of telomeric silencing and Mec1p-dependent relocation of Sir3p. Current biology : CB 9, 963–966. 10.1016/s0960-9822(99)80424-2.10.1016/s0960-9822(99)80424-210508591McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, et al. (2009). SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging 1, 109–121. 10.18632/aging.100011.10.18632/aging.100011PMC281576820157594McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, et al. (2010). The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research 20, 1297–1303. 10.1101/gr.107524.110.10.1101/gr.107524.110PMC292850820644199McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, and Bejerano G. (2010). GREAT improves functional interpretation of cis- regulatory regions. Nature biotechnology 28, 495–501. 10.1038/nbt.1630.10.1038/nbt.1630PMC484023420436461Medawar PB. (1952). An unsolved problem of biology (Published for the College; by Lewis HK).Meer MV, Podolskiy DI, Tyshkovskiy A, and Gladyshev VN (2018). A whole lifespan mouse multi-tissue DNA methylation clock. eLife 7. 10.7554/eLife.40675.10.7554/eLife.40675PMC628794530427307Miller DB, and O’Callaghan JP (2005). Aging, stress and the hippocampus. Ageing research reviews 4, 123–140. 10.1016/j.arr.2005.03.002.10.1016/j.arr.2005.03.00215964248Mills KD, Sinclair DA, and Guarente L. (1999). MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 97, 609– 620. 10.1016/s0092-8674(00)80772-2.10.1016/s0092-8674(00)80772-210367890Miyoshi N, Oubrahim H, Chock PB, and Stadtman ER (2006). Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis. Proceedings of the National Academy of Sciences of the United States of America 103, 1727–1731. 10.1073/pnas.0510346103.10.1073/pnas.0510346103PMC141365216443681Monnat RJ Jr., Hackmann AF, and Cantrell MA (1999). Generation of highly site- specific DNA double-strand breaks in human cells by the homing endonucleases I-PpoI and I-CreI. Biochemical and biophysical research communications 255, 88–93. 10.1006/bbrc.1999.0152.10.1006/bbrc.1999.015210082660Mosammaparast N, Kim H, Laurent B, Zhao Y, Lim HJ, Majid MC, Dango S, Luo Y, Hempel K, Sowa ME, et al. (2013). The histone demethylase LSD1/KDM1A promotes the DNA damage response. The Journal of cell biology 203, 457–470. 10.1083/jcb.201302092.10.1083/jcb.201302092PMC382400724217620Mumbach MR, Rubin AJ, Flynn RA, Dai C, Khavari PA, Greenleaf WJ, and Chang HY (2016). HiChIP: efficient and sensitive analysis of protein-directed genome architecture. Nature methods 13, 919–922. 10.1038/nmeth.3999.10.1038/nmeth.3999PMC550117327643841Nance MA., and Berry SA. (1992). Cockayne syndrome: Review of 140 cases. American Journal of Medical Genetics 42, 68–84. 10.1002/ajmg.1320420115.10.1002/ajmg.13204201151308368Narayanan L, Fritzell JA, Baker SM, Liskay RM, and Glazer PM (1997). Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proceedings of the National Academy of Sciences of the United States of America 94, 3122–3127. 10.1073/pnas.94.7.3122.10.1073/pnas.94.7.3122PMC203329096356Narendra V, Rocha PP, An D, Raviram R, Skok JA, Mazzoni EO, and Reinberg D. (2015). CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science (New York, NY) 347, 1017–1021. 10.1126/science.1262088.10.1126/science.1262088PMC442814825722416Nishimura EK, Granter SR, and Fisher DE (2005). Mechanisms of Hair Graying: Incomplete Melanocyte Stem Cell Maintenance in the Niche. Science (New York, NY) 307, 720–724. 10.1126/science.1099593.10.1126/science.109959315618488Norden DM, and Godbout JP (2013). Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathology and applied neurobiology 39, 19–34. 10.1111/j.1365-2990.2012.01306.x.10.1111/j.1365-2990.2012.01306.xPMC355325723039106O’Hagan HM, Mohammad HP, and Baylin SB (2008). Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS genetics 4, e1000155. 10.1371/journal.pgen.1000155.10.1371/journal.pgen.1000155PMC249172318704159Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK, Hartlerode A, Stegmuller J, Hafner A, Loerch P, et al. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918. 10.1016/j.cell.2008.10.025.10.1016/j.cell.2008.10.025PMC285397519041753Oberdoerffer P., and Sinclair DA. (2007). The role of nuclear architecture in genomic instability and ageing. Nature reviews Molecular cell biology 8, 692–702. 10.1038/nrm2238.10.1038/nrm223817700626Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, et al. (2016). In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell 167, 1719–1733.e1712. 10.1016/j.cell.2016.11.052.10.1016/j.cell.2016.11.052PMC567927927984723Ohse T, Vaughan MR, Kopp JB, Krofft RD, Marshall CB, Chang AM, Hudkins KL, Alpers CE, Pippin JW, and Shankland SJ (2010). De novo expression of podocyte proteins in parietal epithelial cells during experimental glomerular disease. Am J Physiol Renal Physiol 298, F702–711. 10.1152/ajprenal.00428.2009.10.1152/ajprenal.00428.2009PMC283859620007346Orlando DA, Chen MW, Brown VE, Solanki S, Choi YJ, Olson ER, Fritz CC, Bradner JE, and Guenther MG (2014). Quantitative ChIP-Seq normalization reveals global modulation of the epigenome. Cell reports 9, 1163–1170. 10.1016/j.celrep.2014.10.018.10.1016/j.celrep.2014.10.01825437568Pal S, and Tyler JK (2016). Epigenetics and aging. Science advances 2, e1600584. 10.1126/sciadv.1600584.10.1126/sciadv.1600584PMC496688027482540Park DC, and Reuter-Lorenz P. (2009). The adaptive brain: aging and neurocognitive scaffolding. Annual review of psychology 60, 173–196. 10.1146/annurev.psych.59.103006.093656.10.1146/annurev.psych.59.103006.093656PMC335912919035823Park PU., Defossez PA., and Guarente L. (1999). Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae. Molecular and cellular biology 19, 3848–3856. 10.1128/mcb.19.5.3848.10.1128/mcb.19.5.3848PMC8423610207108Petkovich DA, Podolskiy DI, Lobanov AV, Lee SG, Miller RA, and Gladyshev VN (2017). Using DNA Methylation Profiling to Evaluate Biological Age and Longevity Interventions. Cell metabolism 25, 954–960 e956. 10.1016/j.cmet.2017.03.016.10.1016/j.cmet.2017.03.016PMC557845928380383Quinlan AR, and Hall IM (2010). BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics (Oxford, England) 26, 841–842. 10.1093/bioinformatics/btq033.10.1093/bioinformatics/btq033PMC283282420110278Ramirez F, Ryan DP, Gruning B, Bhardwaj V, Kilpert F, Richter AS, Heyne S, Dundar F, and Manke T. (2016). deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic acids research 44, W160–165. 10.1093/nar/gkw257.10.1093/nar/gkw257PMC498787627079975Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, et al. (2015). Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330. 10.1038/nature14248.10.1038/nature14248PMC453001025693563Robinson PS, Coorens THH, Palles C, Mitchell E, Abascal F, Olafsson S, Lee BCH, Lawson ARJ, Lee-Six H, Moore L, et al. (2021). Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nature genetics 53, 1434–1442. 10.1038/s41588-021-00930-y.10.1038/s41588-021-00930-yPMC849247434594041Roeder SS, Stefanska A, Eng DG, Kaverina N, Sunseri MW, McNicholas BA, Rabinovitch P, Engel FB, Daniel C, Amann K, et al. (2015). Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age. Am J Physiol Renal Physiol 309, F164–178. 10.1152/ajprenal.00144.2015.10.1152/ajprenal.00144.2015PMC459673126017974Rogina ,B, and Helfand ,SL (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proceedings of the National Academy of Sciences of the United States of America 101, 15998–16003. 10.1073/pnas.0404184101.10.1073/pnas.0404184101PMC52875215520384Ross JM. (2011). Visualization of mitochondrial respiratory function using cytochrome c oxidase/succinate dehydrogenase (COX/SDH) double-labeling histochemistry. Journal of visualized experiments : JoVE, e3266. 10.3791/3266.10.3791/3266PMC330859322143245Ruan J, Li H, Chen Z, Coghlan A, Coin LJ, Guo Y, Heriche JK, Hu Y, Kristiansen K, Li R, et al. (2008). TreeFam: 2008 Update. Nucleic acids research 36, D735–740. 10.1093/nar/gkm1005.10.1093/nar/gkm1005PMC223885618056084Rubin E, Wu X, Zhu T, Cheung JC, Chen H, Lorincz A, Pandita RK, Sharma GG, Ha HC, Gasson J, et al. (2007). A role for the HOXB7 homeodomain protein in DNA repair. Cancer research 67, 1527–1535. 10.1158/0008-5472.Can-06-4283.10.1158/0008-5472.Can-06-428317308091Russell-Goldman E, and Murphy GF (2020). The Pathobiology of Skin Aging: New Insights into an Old Dilemma. The American journal of pathology 190, 1356–1369. 10.1016/j.ajpath.2020.03.007.10.1016/j.ajpath.2020.03.007PMC748175532246919Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, and Brown EJ (2007). Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell stem cell 1, 113–126. 10.1016/j.stem.2007.03.002.10.1016/j.stem.2007.03.002PMC292060318371340Ryu HY, Rhie BH, and Ahn SH (2014). Loss of the Set2 histone methyltransferase increases cellular lifespan in yeast cells. Biochemical and biophysical research communications 446, 113–118. 10.1016/j.bbrc.2014.02.061.10.1016/j.bbrc.2014.02.06124607280Salk D., Fujiwara Y., and Martin GM. (1985). Werner’s Syndrome and Human Aging. 10.1007/978-1-4684-7853-2_9.10.1007/978-1-4684-7853-2_9Salzer MC, Lafzi A, Berenguer-Llergo A, Youssif C, Castellanos A, Solanas G, Peixoto FO, Stephan-Otto Attolini C, Prats N, Aguilera M, et al. (2018). Identity Noise and Adipogenic Traits Characterize Dermal Fibroblast Aging. Cell 175, 1575–1590 e1522. 10.1016/j.cell.2018.10.012.10.1016/j.cell.2018.10.01230415840Samuel MA, Zhang Y, Meister M, and Sanes JR (2011). Age-related alterations in neurons of the mouse retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 16033–16044. 10.1523/jneurosci.3580-11.2011.10.1523/jneurosci.3580-11.2011PMC323839322049445Sarkar TJ, Quarta M, Mukherjee S, Colville A, Paine P, Doan L, Tran CM, Chu CR, Horvath S, Qi LS, et al. (2020). Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. Nature communications 11, 1545. 10.1038/s41467-020-15174-3.10.1038/s41467-020-15174-3PMC709339032210226Schneider RR, Eng DG, Kutz JN, Sweetwyne MT, Pippin JW, and Shankland SJ (2017). Compound effects of aging and experimental FSGS on glomerular epithelial cells. Aging 9, 524–546. 10.18632/aging.101176.10.18632/aging.101176PMC536167928222042Schoenfelder S, Sugar R, Dimond A, Javierre BM, Armstrong H, Mifsud B, Dimitrova E, Matheson L, Tavares-Cadete F, Furlan-Magaril M, et al. (2015). Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome. Nature genetics 47, 1179–1186. 10.1038/ng.3393.10.1038/ng.3393PMC484763926323060Sen P, Dang W, Donahue G, Dai J, Dorsey J, Cao X, Liu W, Cao K, Perry R, Lee JY, et al. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes & development 29, 1362–1376. 10.1101/gad.263707.115.10.1101/gad.263707.115PMC451121226159996Sen P., Shah PP., Nativio R., and Berger SL. (2016). Epigenetic Mechanisms of Longevity and Aging. Cell 166, 822–839. 10.1016/j.cell.2016.07.050.10.1016/j.cell.2016.07.050PMC582124927518561Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Rai TS, McBryan T, et al. (2013). Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes & development 27, 1787–1799. 10.1101/gad.223834.113.10.1101/gad.223834.113PMC375969523934658Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, et al. (2019). LINE1 Derepression in Aged Wild-Type and SIRT6- Deficient Mice Drives Inflammation. Cell metabolism 29, 871–885 e875. 10.1016/j.cmet.2019.02.014.10.1016/j.cmet.2019.02.014PMC644919630853213Sinclair DA, and Guarente L. (1997). Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 91, 1033–1042. 10.1016/s0092-8674(00)80493-6.10.1016/s0092-8674(00)80493-69428525Sinclair DA, and LaPlante MD (2019). Lifespan: Why We Age—and Why We Don’t Have To (Atria Books; ).Sinclair DA, Mills K, and Guarente L. (1997). Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science (New York, NY) 277, 1313–1316. 10.1126/science.277.5330.1313.10.1126/science.277.5330.13139271578Smeal T, Claus J, Kennedy B, Cole F, and Guarente L. (1996). Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae. Cell 84, 633–642. 10.1016/s0092-8674(00)81038-7.10.1016/s0092-8674(00)81038-78598049Soto I., Graham LC., Richter HJ., Simeone SN., Radell JE., Grabowska W., Funkhouser WK., Howell MC., and Howell GR. (2015). APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction. PLoS biology 13, e1002279. 10.1371/journal.pbio.1002279.10.1371/journal.pbio.1002279PMC462609226512759Speir ML, Zweig AS, Rosenbloom KR, Raney BJ, Paten B, Nejad P, Lee BT, Learned K, Karolchik D, Hinrichs AS, et al. (2016). The UCSC Genome Browser database: 2016 update. Nucleic acids research 44, D717–725. 10.1093/nar/gkv1275.10.1093/nar/gkv1275PMC470290226590259Stubbs TM, Bonder MJ, Stark AK, Krueger F, von Meyenn F, Stegle O, and Reik W. (2017). Multi-tissue DNA methylation age predictor in mouse. Genome biology 18, 68. 10.1186/s13059-017-1203-5.10.1186/s13059-017-1203-5PMC538917828399939Szilard L. (1959). ON THE NATURE OF THE AGING PROCESS. Proceedings of the National Academy of Sciences of the United States of America 45, 30–45. 10.1073/pnas.45.1.30.10.1073/pnas.45.1.30PMC22250916590351Takahashi K, and Yamanaka S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676. 10.1016/j.cell.2006.07.024.10.1016/j.cell.2006.07.02416904174Tamburini BA, and Tyler JK (2005). Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. Molecular and cellular biology 25, 4903–4913. 10.1128/mcb.25.12.4903-4913.2005.10.1128/mcb.25.12.4903-4913.2005PMC114060815923609Tan L, Ke Z, Tombline G, Macoretta N, Hayes K, Tian X, Lv R, Ablaeva J, Gilbert M, Bhanu NV, et al. (2017). Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming. Stem cell reports 9, 1721–1734. 10.1016/j.stemcr.2017.10.001.10.1016/j.stemcr.2017.10.001PMC583105229107597Thompson MJ., Chwialkowska K., Rubb L., Lusi AJ., Davi RC., Srivastav A., Korstanje R., Churchill GA., Horvath S., and Pellegrini M. (2018). A multi-tissue full lifespan epigenetic clock for mice. Aging 10, 2832–2854. 10.18632/aging.101590.10.18632/aging.101590PMC622422630348905Tian X, Firsanov D, Zhang Z, Cheng Y, Luo L, Tombline G, Tan R, Simon M, Henderson S, Steffan J, et al. (2019). SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell 177, 622–638 e622. 10.1016/j.cell.2019.03.043.10.1016/j.cell.2019.03.043PMC649939031002797Tiku V, Jain C, Raz Y, Nakamura S, Heestand B, Liu W, Spath M, Suchiman HED, Muller RU, Slagboom PE, et al. (2017). Small nucleoli are a cellular hallmark of longevity. Nature communications 8, 16083. 10.1038/ncomms16083.10.1038/ncomms16083PMC558234928853436Tvardovskiy A, Schwämmle V, Kempf SJ, Rogowska-Wrzesinska A, and Jensen ON (2017). Accumulation of histone variant H3.3 with age is associated with profound changes in the histone methylation landscape. Nucleic acids research 45, 9272–9289. 10.1093/nar/gkx696.10.1093/nar/gkx696PMC576616328934504Ungvari Z, Tarantini S, Hertelendy P, Valcarcel-Ares MN, Fülöp GA, Logan S, Kiss T, Farkas E, Csiszar A, and Yabluchanskiy A. (2017). Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. GeroScience 39, 33–42. 10.1007/s11357-017-9964-z.10.1007/s11357-017-9964-zPMC535258828299642Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, et al. (2013). From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Current protocols in bioinformatics 43, 11.10.11–33. 10.1002/0471250953.bi1110s43.10.1002/0471250953.bi1110s43PMC424330625431634Venkatareddy M, Wang S, Yang Y, Patel S, Wickman L, Nishizono R, Chowdhury M, Hodgin J, Wiggins PA, and Wiggins RC (2014). Estimating podocyte number and density using a single histologic section. Journal of the American Society of Nephrology : JASN 25, 1118–1129. 10.1681/asn.2013080859.10.1681/asn.2013080859PMC400531524357669Vilenchik MM., and Knudson AG. (2003). Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer. Proceedings of the National Academy of Sciences 100, 12871–-12876.. 10.1073/pnas.2135498100.10.1073/pnas.2135498100PMC24071114566050Waddington CH (1957). The strategy of the genes; a discussion of some aspects of theoretical biology (London,: Allen & Unwin; ).Wakayama S, Kohda T, Obokata H, Tokoro M, Li C, Terashita Y, Mizutani E, Nguyen VT, Kishigami S, Ishino F, et al. (2013). Successful serial recloning in the mouse over multiple generations. Cell stem cell 12, 293–297. 10.1016/j.stem.2013.01.005.10.1016/j.stem.2013.01.00523472871Weidner CI, Lin Q, Koch CM, Eisele L, Beier F, Ziegler P, Bauerschlag DO, Jockel KH, Erbel R, Muhleisen TW, et al. (2014). Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome biology 15, R24. 10.1186/gb-2014-15-2-r24.10.1186/gb-2014-15-2-r24PMC405386424490752Welch RP, Lee C, Imbriano PM, Patil S, Weymouth TE, Smith RA, Scott LJ, and Sartor MA (2014). ChIP-Enrich: gene set enrichment testing for ChIP-seq data. Nucleic acids research 42, e105. 10.1093/nar/gku463.10.1093/nar/gku463PMC411774424878920Welle S, Brooks AI, Delehanty JM, Needler N, Bhatt K, Shah B, and Thornton CA (2004). Skeletal muscle gene expression profiles in 20–29 year old and 65–71 year old women. Experimental gerontology 39, 369–377. 10.1016/j.exger.2003.11.011.10.1016/j.exger.2003.11.01115036396Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, and Moraes CT (2009). Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences 106, 20405–20410. 10.1073/pnas.0911570106.10.1073/pnas.0911570106PMC278715219918075White RR., and Vijg J. (2016). Do DNA Double-Strand Breaks Drive Aging? Molecular cell 63, 729–738. 10.1016/j.molcel.2016.08.004.10.1016/j.molcel.2016.08.004PMC501231527588601Whitehead JC, Hildebrand BA, Sun M, Rockwood MR, Rose RA, Rockwood K, and Howlett SE (2013). A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans. The Journals of Gerontology: Series A 69, 621–632. 10.1093/gerona/glt136.10.1093/gerona/glt136PMC402209924051346Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, and Young RA (2013). Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319. 10.1016/j.cell.2013.03.035.10.1016/j.cell.2013.03.035PMC365312923582322Williams GC (1957). Pleiotropy, Natural Selection, and the Evolution of Senescence. Evolution 11, 398–411. 10.2307/2406060.10.2307/2406060Wittmayer PK, McKenzie JL, and Raines RT (1998). Degenerate DNA recognition by I-PpoI endonuclease. Gene 206, 11–21. 10.1016/s0378-1119(97)00563-5.10.1016/s0378-1119(97)00563-59461409Wolf N, Pendergrass W, Singh N, Swisshelm K, and Schwartz J. (2008). Radiation cataracts: mechanisms involved in their long delayed occurrence but then rapid progression. Molecular vision 14, 274–285.PMC225496618334943Wolf NS, Li Y, Pendergrass W, Schmeider C, and Turturro A. (2000). Normal mouse and rat strains as models for age-related cataract and the effect of caloric restriction on its development. Experimental eye research 70, 683–692. 10.1006/exer.2000.0835.10.1006/exer.2000.083510870527Wood JG., Jone BC., Jian N., Chang C., Hosier S., Wickremesinghe P., Garcia M., Hartnett DA., Burhenn L., Neretti N., et al. (2016). Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 113, 11277–11282. 10.1073/pnas.1604621113.10.1073/pnas.1604621113PMC505604527621458Yang JH, Song Y, Seol JH, Park JY, Yang YJ, Han JW, Youn HD, and Cho EJ (2011). Myogenic transcriptional activation of MyoD mediated by replication-independent histone deposition. Proceedings of the National Academy of Sciences of the United States of America 108, 85–90. 10.1073/pnas.1009830108.10.1073/pnas.1009830108PMC301720821173268Yang T, Zhang F, Yardimci GG, Song F, Hardison RC, Noble WS, Yue F, and Li Q. (2017). HiCRep: assessing the reproducibility of Hi-C data using a stratum-adjusted correlation coefficient. Genome research 27, 1939–1949. 10.1101/gr.220640.117.10.1101/gr.220640.117PMC566895028855260Ye X, Zerlanko B, Kennedy A, Banumathy G, Zhang R, and Adams PD (2007). Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Molecular cell 27, 183–196. 10.1016/j.molcel.2007.05.034.10.1016/j.molcel.2007.05.034PMC269809617643369Yoshihama S, Roszik J, Downs I, Meissner TB, Vijayan S, Chapuy B, Sidiq T, Shipp MA, Lizee GA, and Kobayashi KS (2016). NLRC5/MHC class I transactivator is a target for immune evasion in cancer. Proceedings of the National Academy of Sciences of the United States of America 113, 5999–6004. 10.1073/pnas.1602069113.10.1073/pnas.1602069113PMC488938827162338Zeng Q, Chen X, Ning C, Zhu Q, Yao Y, Zhao Y, and Luan F. (2018). Methylation of the genes ROD1, NLRC5, and HKR1 is associated with aging in Hainan centenarians. BMC medical genomics 11, 7. 10.1186/s12920-018-0334-1.10.1186/s12920-018-0334-1PMC579741429394898Zhang J., Pippin JW., Krofft RD., Naito S., Liu ZH., and Shankland SJ. (2013). Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS. Am J Physiol Renal Physiol 304, F1375–1389. 10.1152/ajprenal.00020.2013.10.1152/ajprenal.00020.2013PMC368069023486009Zhang X, Brann TW, Zhou M, Yang J, Oguariri RM, Lidie KB, Imamichi H, Huang DW, Lempicki RA, Baseler MW, et al. (2011). Cutting edge: Ku70 is a novel cytosolic DNA sensor that induces type III rather than type I IFN. J Immunol 186, 4541–4545. 10.4049/jimmunol.1003389.10.4049/jimmunol.1003389PMC372067621398614Zhang Y, Hapala J, Brenner H, and Wagner W. (2017). Individual CpG sites that are associated with age and life expectancy become hypomethylated upon aging. Clinical epigenetics 9, 9. 10.1186/s13148-017-0315-9.10.1186/s13148-017-0315-9PMC528884628168006Zhao Y, Yi J, Tao L, Huang G, Chu X, Song H, and Chen L. (2018). Wnt signaling induces radioresistance through upregulating HMGB1 in esophageal squamous cell carcinoma. Cell death & disease 9, 433. 10.1038/s41419-018-0466-4.10.1038/s41419-018-0466-4PMC586495829567990Zirkel A, Nikolic M, Sofiadis K, Mallm JP, Brackley CA, Gothe H, Drechsel O, Becker C, Altmuller J, Josipovic N, et al. (2018). HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. Molecular cell 70, 730–744.e736. 10.1016/j.molcel.2018.03.030.10.1016/j.molcel.2018.03.03029706538