The achievement of animal cloning and subsequent development of cell reprogramming technology are having a profound impact on our view of the mechanisms of aging in complex organisms. The experimental evidence showing that an adult somatic nucleus implanted into an enucleated oocyte can give rise to a whole new individual strongly suggests that the integrity of the genome of an adult nucleus is fully preserved. Here, we will review recent experimental evidence showing that pluripotency gene-based cell reprogramming can erase the epigenetic marks of aging and rejuvenate cells from old individuals reversing most signs of aging and that when induced pluripotent stem cells are differentiated back to the cell type of origin, the rejuvenated cells share many of the features of wild-type counterparts from young donors. This evidence supports the idea that progressive epigenetic dysregulation may be the key driver of organismal aging and challenges the conventional view of aging as an irreversible process. The model of aging as an epigenetic process provides an elegant explanation of a number of age-related processes difficult to explain by conventional theories of aging.

Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126:663-676.
Gurdon JB: From nuclear transfer to nuclear reprogramming: the reversal of cell differentiation. Ann Rev Cell Dev Biol 2006;22:1-22.
Gurdon JB: The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 1962;10:622-640.
Wilmut I, Schnieke AE, McWhir J, Campbell KH: Viable offspring derived from fetal and adult mammalian cells. Nature 1997;385:810-813.
Hochedlinger K, Jaenisch R: Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 2002;415:1035-1038.
Meng L, Ely JJ, Stouffer RL, Wolf DP: Rhesus monkeys produced by nuclear transfer. Biol Reprod 1997;57:454-459.
Grisham J: Pigs cloned for first time. Nature Biotechnol 2000;18:365-367.
Davis RL, Weintraub H, Lassar AB: Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987;51:987-1000.
Choi J, Costa ML, Mermelstein CS, Chagas C, Holtzer S, Holtzer H: MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Proc Natl Acad Sci USA 1990;87:7988-7992.
Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD: Activation of muscle-specific genes in pigment, nerve, fat, liver and fibroblasts cell lines by forced expression of MyoD. Proc Natl Acad Sci USA 1989;86:5434-5438.
Bayart E, Cohen-Haguenauer O: Technological overview of iPS induction from human adult somatic cells. Curr Gene Ther 2013;13:73-92.
Nedelec S, Onteniente B, Peschanski M, Martinat C: Genetically-modified human pluripotent stem cells: new hopes for the understanding and the treatment of neurological diseases? Curr Gene Ther 2013;13:111-119.
Ames BN: Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun 1989;7:121-128.
Campisi J, Vijg J: Does damage to DNA and other macromolecules play a role in aging? If so, how? J Gerontol A Biol Sci Med Sci 2009;64:175-178.
Harman D: Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;11:298-300.
Van Remmen H, Richardson A: Oxidative damage to mitochondria and aging. Exp Gerontol 2001;36:957-968.
Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science 1996;273:59-63.
Rando TA1, Chang HY: Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 2012;148:46-57.
Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, Berger SL: Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 2009;459:802-807.
Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, Tyler JK: Elevated histone expression promotes life span extension. Mol Cell 2010;39:724-735.
Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A: Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 2010;466:383-387.
Sen P, Dang W, Donahue G, Dai J, Dorsey J, Cao X, Liu W, Cao K, Perry R, Lee JY, Wasko BM, Carr DT, He C, Robison B, Wagner J, Gregory BD, Kaeberlein M, Kennedy BK, Boeke JD, Berger SL: H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev 2015;29:1362-1376.
Han S, Brunet A: Histone methylation makes its mark on longevity. Trends Cell Biol 2012;22:42-49.
Benayoun BA, Pollina EA, Brunet A: Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 2015;16:593-610.
Sen P, Shah PP, Nativio R, Berger SL: Epigenetic mechanisms of longevity and aging. Cell 2016;166:822-839.
Jung M, Pfeifer GP: Aging and DNA methylation. BMC Biol 2015;13:7.
Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP: Intra-individual change over time in DNA methylation with familial clustering. JAMA 2008;299:2877-2883.
Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A: Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Age Dev 2009;130:234-239.
Bormann F, Rodríguez-Paredes M, Hagemann S, Manchanda H, Kristof B, Gutekunst J, Raddatz G, Haas R, Terstegen L, Wenck H, Kaderali L, Winnefeld M, Lyko F: Reduced DNA methylation patterning and transcriptional connectivity define human skin aging. Aging Cell 2016;15:563-571.
Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbacker DJ, Yeh RF, Wiencke JK, Kelsey KT: Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLOS Genet 2009;5:e1000602.
Horvath S: DNA methylation age of human tissues and cell types. Genome Biol 2013;14:R115.
Aalfs JD, Kingston RE: What does “chromatin remodeling” mean? Trends Biochem Sci 2000;25:548-555.
Saka K, Ide S, Ganley ARD, Kobayashi T: Cellular senescence in yeast is regulated by rDNA noncoding transcription. Curr Biol 2013;23:1794-1798.
Pal S, Tyler JK: Epigenetics and aging. Sci Adv 2016;29:e1600584.
Mertens J, Paquola AC, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, Winkler J, Yao J, Hetzer MW, Gage FH: Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 2015;17:705-718.
Lapasset L1, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM: Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 2011;25:2248-2253.
Hashizume O, Ohnishi S, Mito T, Shimizu A, Ishikawa K, Nakada K, Soda M, Mano H, Togayachi S, Miyoshi H, Okita K, Hayashi J: Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep 2015;5:10.
Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Goto H, Zhu D, Nakayama-Hosoya K, Iriguchi S, Uemura Y, Shimizu T, Takayama N, Yamada D, Nishimura K, Ohtaka M, Watanabe N, Takahashi S, Iwamoto A, Koseki H, Nakanishi M, Eto K, Nakauchi H: Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 2013;12:114-126.
Wahlestedt M, Erlandsson E, Kristiansen T, Lu R, Brakebusch C, Weissman IL, Yuan J, Martin-Gonzalez J, Bryder D: Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate. Nat Commun 2017;22:14533.
Mistriotis P, Bajpai VK, Wang X, Rong N, Shahini A, Asmani M, Liang MS, Wang J, Lei P, Liu S, Zhao R, Andreadis ST: NANOG reverses the myogenic differentiation potential of senescent stem cells by restoring Actin filamentous organization and SRF-dependent gene expression. Stem Cells 2017;35:207-221.
Dawkins R, Wong Y: The Ancestor's Tale: A Pilgrimage to the Dawn of Life, ed 2. New York, Mariner Books Ltd, 2016.
Kubota C, Tian XC, Yang X: Serial bull cloning by somatic cell nuclear transfer. Nat Biotechnol 2004;22:693-694.
Cho SK, Kim JH, Park JY, Choi YJ, Bang JI, Hwang KC, Cho EJ, Sohn SH, Uhm SJ, Koo DB: Serial cloning of pigs by somatic cell nuclear transfer: restoration of phenotypic normality during serial cloning. Dev Dyn 2007;236:3369-3382.
Kurome, M, Hisatomi H, Matsumoto S, Tomii R, Ueno S, Hiruma K, Saito H, Nakamura K, Okumura K, Matsumoto M: Production efficiency and telomere length of the cloned pigs following serial somatic cell nuclear transfer. J Reprod Devel 2008;54:254-258.
Yin XJ, Lee HS, Yu XF, Kim LH, Shin Hd, Cho SJ, Choi EG, Kong IK: Production of second generation cloned cats by somatic cell nuclear transfer. Theriogenology 2008;69:1001-1006.
Wakayama S, Kohda T, Obokata H, Tokoro M, Li C, Terashita Y, Mizutani E, Nguyen VT, Kishigami S, Ishino F, Wakayama T: Successful serial recloning in the mouse over multiple generations. Cell Stem Cell 2013;12:293-397.
Ocampo 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, Roman JL Xu J, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua Belmonte JC: In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 2016;167:1719-1733.
Abad M, Mosteiro L, Pantoja C, Cañamero M, Rayon T, Ors I, Graña O, Megías D, Domínguez O, Martínez D, Manzanares M, Ortega S, Serrano M: Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 2013;502:340-345.
Srivastava D, DeWitt N: In vivo cellular reprogramming: the next generation. Cell 2016;166:1386-1396.
Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J: An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014;31:722-733.
Chiche A, Le Roux I, von Joest M, Sakai H, Aguín SB, Cazin C, Salam R, Fiette L, Alegria O, Flamant P, Tajbakhsh S, Li H: Injury-induced senescence enables in vivo reprogramming in skeletal muscle. Cell Stem Cell 2017;20:407-414.
Lau CH, Suh Y: Genome and epigenome editing in mechanistic studies of human aging and aging-related disease. Gerontology 2017;63:103-117.
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