Attaining Epigenetic Rejuvenation: Challenges Ahead

  • Jogeswar S. Purohit
  • Neetika Singh
  • Shah S. Hussain
  • Madan M. ChaturvediEmail author


Recent studies from a number of model organisms have indicated that aging is mediated by genetic and epigenetic mechanisms. Few recent experiments also demonstrate that modulation in the chromatin modifying agents also affect the life span of an organism, and these chromatin modifications have a metabolic linkage. Further, the aging clock of an organism can be reset by reversal of aging. Aged cells can be reprogrammed to young ones by direct reprogramming by epigenetic rejuvenation or young cells can be obtained from them by passing through a dedifferentiated state. In the present report, we discuss the chromatin organization and its changes during aging. Further, we discuss how metabolic reprogramming can be linked to aging reversals to obtain epigenetic rejuvenation and challenges ahead.


  1. 1.
    Watson JD. Celebrating the genetic jubilee: a conversation with James D. Watson. Interviewed by John Rennie. Sci Am. 2003;288(4):66–9.PubMedGoogle Scholar
  2. 2.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Weber CM, Henikoff S. Histone variants: dynamic punctuation in transcription. Genes Dev. 2014;28(7):672–82.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Sierra MI, Fernandez AF, Fraga MF. Epigenetics of aging. Curr Genomics. 2015;16(6):435–40.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Ashok BT, Ali R. Aging research in India. Exp Gerontol. 2003;38(6):597–603.PubMedGoogle Scholar
  6. 6.
    Pyhtila MJ, Sherman FG. Age-associated studies on thermal stability and template effectiveness of DNA and nucleoproteins from beef thymus. Biochem Biophys Res Commun. 1968;31(3):340–4.PubMedGoogle Scholar
  7. 7.
    Medvedev ZA, Medvedeva MN, Robson L. Tissue specificity and age changes for the pattern of the H1 group of histones in chromatin from mouse tissues. Gerontology. 1978;24(4):286–92.PubMedGoogle Scholar
  8. 8.
    Tas S, Tam CF, Walford RL. Disulfide bonds and the structure of the chromatin complex in relation to aging. Mech Ageing Dev. 1980;12(1):65–80.PubMedGoogle Scholar
  9. 9.
    Chaturvedi MM, Kanungo MS. Analysis of conformation and function of the chromatin of the brain of young and old rats. Mol Biol Rep. 1985;10(4):215–9.PubMedGoogle Scholar
  10. 10.
    Gravina S, Vijg J. Epigenetic factors in aging and longevity. Pflugers Archiv: European J Physiol. 2010;459(2):247–58.Google Scholar
  11. 11.
    Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16(10):593–610.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jin B, Li Y, Robertson KD. DNA methylation: superior or subordinate in the epigenetic hierarchy? Genes Cancer. 2011;2(6):607–17.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci. 2006;31(2):89–97.PubMedGoogle Scholar
  15. 15.
    Pal S, Tyler JK. Epigenetics and aging. Sci Adv. 2016;2(7):e1600584.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Jung M, Pfeifer GP. Aging and DNA methylation. BMC Biol. 2015;13(7):1–8.Google Scholar
  17. 17.
    Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. Genome structure, chromatin, and the nucleosome Molecular Biology of the gene. 6th ed. Pearson: CSHL Press; 2008. p. 135–93.Google Scholar
  18. 18.
    Davey CA, Sargent DF, Luger K, Maeder AW, Richmond TJ. Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 a resolution. J Mol Biol. 2002;319(5):1097–113.PubMedGoogle Scholar
  19. 19.
    Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381–95.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Feser J, Truong D, Das C, Carson JJ, Kieft J, Harkness T, et al. Elevated histone expression promotes life span extension. Mol Cell. 2010;39(5):724–35.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Tsuchiya M, Dang N, Kerr EO, Hu D, Steffen KK, Oakes JA, et al. Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell. 2006;5(6):505–14.PubMedGoogle Scholar
  23. 23.
    Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483(7388):218–21.PubMedGoogle Scholar
  24. 24.
    Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. 2010;328(5979):753–6.PubMedGoogle Scholar
  25. 25.
    Larson K, Yan SJ, Tsurumi A, Liu J, Zhou J, Gaur K, et al. Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet. 2012;8(1):e1002473.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Wood JG, Hillenmeyer S, Lawrence C, Chang C, Hosier S, Lightfoot W, et al. Chromatin remodeling in the aging genome of Drosophila. Aging Cell. 2010;9(6):971–8.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun. 2013;4:1868.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang CM, Tsai SN, Yew TW, Kwan YW, Ngai SM. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology. 2010;11(1):87–102.PubMedGoogle Scholar
  29. 29.
    Ni Z, Ebata A, Alipanahiramandi E, Lee SS. Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell. 2012;11(2):315–25.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Sen P, Dang W, Donahue G, Dai J, Dorsey J, Cao X, et al. H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev. 2015;29(13):1362–76.PubMedPubMedCentralGoogle Scholar
  31. 31.
    McCormick MA, Mason AG, Guyenet SJ, Dang W, Garza RM, Ting MK, et al. The SAGA histone deubiquitinase module controls yeast replicative lifespan via Sir2 interaction. Cell Rep. 2014;8(2):477–86.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Sharma R, Nakamura A, Takahashi R, Nakamoto H, Goto S. Carbonyl modification in rat liver histones: decrease with age and increase by dietary restriction. Free Radic Biol Med. 2006;40(7):1179–84.PubMedGoogle Scholar
  33. 33.
    Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle. 2011;10(3):457–68.PubMedGoogle Scholar
  34. 34.
    Cairns BR. Chromatin remodeling: insights and intrigue from single-molecule studies. Nat Struct Mol Biol. 2007;14(11):989–96.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Hargreaves DC, Crabtree GR. ATP-dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 2011;21(3):396–420.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Vaquero A, Loyola A, Reinberg D. The constantly changing face of chromatin. Sci Aging Knowledge Environ: SAGE KE. 2003;2003(14):RE4.PubMedGoogle Scholar
  37. 37.
    De Vaux V, Pfefferli C, Passannante M, Belhaj K, von Essen A, Sprecher SG, et al. The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation. Aging Cell. 2013;12(6):1012–20.PubMedGoogle Scholar
  38. 38.
    Dang W, Sutphin GL, Dorsey JA, Otte GL, Cao K, Perry RM, et al. Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response. Cell Metab. 2014;19(6):952–66.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Pegoraro G, Kubben N, Wickert U, Gohler H, Hoffmann K, Misteli T. Ageing-related chromatin defects through loss of the NURD complex. Nat Cell Biol. 2009;11(10):1261–7.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Henikoff S, Smith MM. Histone variants and epigenetics. Cold Spring Harb Perspect Biol. 2015;7(1):a019364.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Pina B, Suau P. Changes in histones H2A and H3 variant composition in differentiating and mature rat brain cortical neurons. Dev Biol. 1987;123(1):51–8.PubMedGoogle Scholar
  42. 42.
    Urban MK, Zweidler A. Changes in nucleosomal core histone variants during chicken development and maturation. Dev Biol. 1983;95(2):421–8.PubMedGoogle Scholar
  43. 43.
    Saade E, Pirozhkova I, Aimbetov R, Lipinski M, Ogryzko V. Molecular turnover, the H3.3 dilemma and organismal aging (hypothesis). Aging Cell. 2015;14(3):322–33.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, et al. DNA Hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Res. 2016;76(3):594–606.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007;128(1):36–44.PubMedGoogle Scholar
  46. 46.
    Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Saka K, Ide S, Ganley AR, Kobayashi T. Cellular senescence in yeast is regulated by rDNA noncoding transcription. Curr Biol. 2013;23(18):1794–8.PubMedGoogle Scholar
  48. 48.
    Mori MA, Raghavan P, Thomou T, Boucher J, Robida-Stubbs S, Macotela Y, et al. Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab. 2012;16(3):336–47.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M. Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell. 2006;5(3):235–46.PubMedGoogle Scholar
  50. 50.
    Kato M, Chen X, Inukai S, Zhao H, Slack FJ. Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans. RNA. 2011;17(10):1804–20.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Boehm M, Slack F. A developmental timing microRNA and its target regulate life span in C. elegans. Science. 2005;310(5756):1954–7.PubMedGoogle Scholar
  52. 52.
    de Lencastre A, Pincus Z, Zhou K, Kato M, Lee SS, Slack FJ. MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol. 2010;20(24):2159–68.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Szafranski K, Abraham KJ, Mekhail K. Non-coding RNA in neural function, disease, and aging. Front Genet. 2015;6:87.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Liu N, Landreh M, Cao K, Abe M, Hendriks GJ, Kennerdell JR, et al. The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature. 2012;482(7386):519–23.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, et al. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem. 2010;285(17):12604–11.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Jung HJ, Suh Y. MicroRNA in aging: from discovery to biology. Curr Genomics. 2012;13(7):548–57.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Meier I, Fellini L, Jakovcevski M, Schachner M, Morellini F. Expression of the snoRNA host gene gas5 in the hippocampus is upregulated by age and psychogenic stress and correlates with reduced novelty-induced behavior in C57BL/6 mice. Hippocampus. 2010;20(9):1027–36.PubMedGoogle Scholar
  58. 58.
    Castel SE, Martienssen RA. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat Rev Genet. 2013;14(2):100–12.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Allis CD, Bowen JK, Abraham GN, Glover CV, Gorovsky MA. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell. 1980;20(1):55–64.PubMedGoogle Scholar
  60. 60.
    Purohit JS, Chaturvedi MM, Panda P. Histone protease: the tale of tail clippers. Int J Integr Sci, Innov Technol. 2012;1(1):51–60.Google Scholar
  61. 61.
    Lin R, Cook RG, Allis CD. Proteolytic removal of core histone amino termini and dephosphorylation of histone H1 correlate with the formation of condensed chromatin and transcriptional silencing during Tetrahymena macronuclear development. Genes Dev. 1991;5(9):1601–10.PubMedGoogle Scholar
  62. 62.
    Satchidananda PJ, Mohan CM. Chromatin and aging. In: Rath PS PC, Sharma S, editors. Topics in biomedical gerontology. Singapore: Springer; 2017. p. 205.Google Scholar
  63. 63.
    Mahendra G, Gupta S, Kanungo MS. Effect of 17beta estradiol and progesterone on the conformation of the chromatin of the liver of female Japanese quail during aging. Arch Gerontol Geriatr. 1999;28(2):149–58.PubMedGoogle Scholar
  64. 64.
    Mahendra G, Kanungo MS. Age-related and steroid induced changes in the histones of the quail liver. Arch Gerontol Geriatr. 2000;30(2):109–14.PubMedGoogle Scholar
  65. 65.
    Panda P, Chaturvedi MM, Panda AK, Suar M, Purohit JS. Purification and characterization of a novel histone H2A specific protease (H2Asp) from chicken liver nuclear extract. Gene. 2013;512(1):47–54.PubMedGoogle Scholar
  66. 66.
    Purohit JS, Tomar RS, Panigrahi AK, Pandey SM, Singh D, Chaturvedi MM. Chicken liver glutamate dehydrogenase (GDH) demonstrates a histone H3 specific protease (H3ase) activity in vitro. Biochimie. 2013;95(11):1999–2009.PubMedGoogle Scholar
  67. 67.
    Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Barzilai N, Huffman DM, Muzumdar RH, Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315–22.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Bratic I, Trifunovic A. Mitochondrial energy metabolism and ageing. Biochim Biophys Acta. 2010;1797(6–7):961–7.PubMedGoogle Scholar
  70. 70.
    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–34.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016;18(10):1090–101.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–9.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bowling AC, Schulz JB, Brown RH Jr, Beal MF. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1993;61(6):2322–5.PubMedGoogle Scholar
  74. 74.
    Hagen TM, Yowe DL, Bartholomew JC, Wehr CM, Do KL, Park JY, et al. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci U S A. 1997;94(7):3064–9.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Wallace DC, Fan W, Procaccio V. Mitochondrial energetics and therapeutics. Annu Rev Pathol. 2010;5:297–348.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N Engl J Med. 2012;366(12):1132–41.PubMedGoogle Scholar
  77. 77.
    Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013;123(3):951–7.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61(5):654–66.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–41.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Ren J, Pulakat L, Whaley-Connell A, Sowers JR. Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med. 2010;88(10):993–1001.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Turner N, Heilbronn LK. Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol Metab. 2008;19(9):324–30.PubMedGoogle Scholar
  82. 82.
    Su B, Wang X, Zheng L, Perry G, Smith MA, Zhu X. Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta. 2010;1802(1):135–42.PubMedGoogle Scholar
  83. 83.
    Mammucari C, Rizzuto R. Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev. 2010;131(7–8):536–43.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208–13.PubMedGoogle Scholar
  85. 85.
    Scheibye-Knudsen M, Mitchell SJ, Fang EF, Iyama T, Ward T, Wang J, et al. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab. 2014;20(5):840–55.PubMedPubMedCentralGoogle Scholar
  86. 86.
    German NJ, Haigis MC. Sirtuins and the metabolic hurdles in Cancer. Curr Biol. 2015;25(13):R569–83.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Vassilopoulos A, Fritz KS, Petersen DR, Gius D. The human sirtuin family: evolutionary divergences and functions. Hum Genomics. 2011;5(5):485–96.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Madeo F, Zimmermann A, Maiuri MC, Kroemer G. Essential role for autophagy in life span extension. J Clin Invest. 2015;125(1):85–93.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science. 2009;325(5937):201–4.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Fontana L, Partridge L, Longo VD. Extending healthy life span--from yeast to humans. Science. 2010;328(5976):321–6.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Wang L, Karpac J, Jasper H. Promoting longevity by maintaining metabolic and proliferative homeostasis. J Exp Biol. 2014;217(Pt 1):109–18.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci U S A. 2002;99(23):14988–93.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Higami Y, Pugh TD, Page GP, Allison DB, Prolla TA, Weindruch R. Adipose tissue energy metabolism: altered gene expression profile of mice subjected to long-term caloric restriction. FASEB J: Off Pub Fed Am Soc Exp Biol. 2004;18(2):415–7.Google Scholar
  94. 94.
    Higami Y, Barger JL, Page GP, Allison DB, Smith SR, Prolla TA, et al. Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr. 2006;136(2):343–52.PubMedGoogle Scholar
  95. 95.
    Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986;116(4):641–54.PubMedGoogle Scholar
  96. 96.
    Anderson RM, Weindruch R. Metabolic reprogramming in dietary restriction. Interdiscip Top Gerontol. 2007;35:18–38.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Solon-Biet SM, Mitchell SJ, Coogan SC, Cogger VC, Gokarn R, McMahon AC, et al. Dietary protein to carbohydrate ratio and caloric restriction: comparing metabolic outcomes in mice. Cell Rep. 2015;11(10):1529–34.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 2014;19(3):418–30.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Charville GW, Rando TA. Stem cell ageing and non-random chromosome segregation. Philos Trans R Soc Lond Ser B Biol Sci. 2011;366(1561):85–93.Google Scholar
  100. 100.
    Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. Daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997;277(5328):942–6.PubMedGoogle Scholar
  101. 101.
    Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol. 2004;14(10):885–90.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Apfeld J, O'Connor G, McDonagh T, DiStefano PS, Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 2004;18(24):3004–9.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Fielenbach N, Antebi A. C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 2008;22(16):2149–65.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Sallon S, Solowey E, Cohen Y, Korchinsky R, Egli M, Woodhatch I, et al. Germination, genetics, and growth of an ancient date seed. Science. 2008;320(5882):1464.PubMedGoogle Scholar
  105. 105.
    Cano RJ, Borucki MK. Revival and identification of bacterial spores in 25- to 40-million-year-old Dominican amber. Science. 1995;268(5213):1060–4.PubMedGoogle Scholar
  106. 106.
    Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell. 2012;148(1–2):46–57.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Briggs R, King TJ. Transplantation of living nuclei from blastula cells into enucleated Frogs' eggs. Proc Natl Acad Sci U S A. 1952;38(5):455–63.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol. 1962;10:622–40.PubMedGoogle Scholar
  109. 109.
    Campbell KH, McWhir J, Ritchie WA, Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature. 1996;380(6569):64–6.PubMedGoogle Scholar
  110. 110.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.PubMedGoogle Scholar
  111. 111.
    Stadtfeld M, Hochedlinger K. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 2010;24(20):2239–63.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Rossant J. Stem cells from the mammalian blastocyst. Stem Cells. 2001;19(6):477–82.PubMedGoogle Scholar
  113. 113.
    Loh KM, Lim B. Recreating pluripotency? Cell Stem Cell. 2010;7(2):137–9.PubMedGoogle Scholar
  114. 114.
    Bunster E, Meyer RK. An improved method of parabiosis. Anat Rec. 1933;57(4):339–43.Google Scholar
  115. 115.
    Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433(7027):760–4.PubMedGoogle Scholar
  116. 116.
    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–4.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev. 2007;21(24):3244–57.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–5.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Chen C, Liu Y, Liu Y, Zheng P. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signaling. 2009;2(98):ra75.Google Scholar
  120. 120.
    Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science. 2010;330(6004):622–7.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Meissner A. Epigenetic modifications in pluripotent and differentiated cells. Nat Biotechnol. 2010;28(10):1079–88.PubMedGoogle Scholar
  122. 122.
    Mikkelsen TS, Hanna J, Zhang X, Ku M, Wernig M, Schorderet P, et al. Dissecting direct reprogramming through integrative genomic analysis. Nature. 2008;454(7200):49–55.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Vastenhouw NL, Zhang Y, Woods IG, Imam F, Regev A, Liu XS, et al. Chromatin signature of embryonic pluripotency is established during genome activation. Nature. 2010;464(7290):922–6.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010;107(50):21931–6.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Krizhanovsky V, Lowe SW. Stem cells: the promises and perils of p53. Nature. 2009;460(7259):1085–6.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature. 2011;479(7373):365–71.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113(6):703–16.PubMedGoogle Scholar
  128. 128.
    Van Den Bogaert A, De Zutter S, Heyrman L, Mendlewicz J, Adolfsson R, Van Broeckhoven C, et al. Response to Zhang et al (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major Depression. Neuron 45, 11–16. Neuron. 2005;48(5):704; author reply 5-6.Google Scholar
  129. 129.
    Gao S, Chung YG, Parseghian MH, King GJ, Adashi EY, Latham KE. Rapid H1 linker histone transitions following fertilization or somatic cell nuclear transfer: evidence for a uniform developmental program in mice. Dev Biol. 2004;266(1):62–75.PubMedGoogle Scholar
  130. 130.
    Apostolou E, Hochedlinger K. Chromatin dynamics during cellular reprogramming. Nature. 2013;502(7472):462–71.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Ait-Hamou N, et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 2011;25(21):2248–53.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Li H, Collado M, Villasante A, Strati K, Ortega S, Canamero M, et al. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature. 2009;460(7259):1136–9.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Mahmoudi S, Brunet A. Aging and reprogramming: a two-way street. Curr Opin Cell Biol. 2012;24(6):744–56.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Kim K, Doi A, Wen B, Ng K, Zhao R, Cahan P, et al. Epigenetic memory in induced pluripotent stem cells. Nature. 2010;467(7313):285–90.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Jogeswar S. Purohit
    • 1
  • Neetika Singh
    • 2
  • Shah S. Hussain
    • 2
  • Madan M. Chaturvedi
    • 2
    Email author
  1. 1.Cluster Innovation Centre, University Stadium, G.C. Narang Marg, North Campus, Delhi UniversityDelhiIndia
  2. 2.Laboratory for Chromatin Biology, Department of ZoologyUniversity of DelhiDelhiIndia

Personalised recommendations