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The ageing epigenome and its rejuvenation


Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several ‘rejuvenating’ interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes.

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Fig. 1: The epigenetic bases of ageing and rejuvenation.
Fig. 2: Caloric restriction regulates epigenetic pathways.
Fig. 3: Reprogramming overcomes senescence barriers and rejuvenates aged cells.
Fig. 4: Model of mitochondria as nodes linking intervention strategies to epigenetic regulation.
Fig. 5: Repeating sequences form ‘blocks’ to maintain chromatin structure.
Fig. 6: The sequence of heterochromatin loss, retrotransposon activation and inflammation is a critical target for rejuvenation.
Fig. 7: Epigenetic regulation is at the nexus of ageing rejuvenation.


  1. 1.

    Gravina, S., Dong, X., Yu, B. & Vijg, J. Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 17, 150 (2016).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Crimmins, E. M. Lifespan and healthspan: past, present, and promise. Gerontologist 55, 901–911 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic mechanisms of longevity and aging. Cell 166, 822–839 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Li, E. & Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol. (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).

    CAS  PubMed  Google Scholar 

  6. 6.

    Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, 3156 (2013).

    Google Scholar 

  7. 7.

    Bocklandt, S. et al. Epigenetic predictor of age. PLoS One 6, e14821 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).

    CAS  PubMed  Google Scholar 

  9. 9.

    Jambhekar, A., Dhall, A. & Shi, Y. Roles and regulation of histone methylation in animal development. Nat. Rev. Mol. Cell Biol. 20, 625–641 (2019).

    CAS  PubMed  Google Scholar 

  10. 10.

    Sabari, B. R., Zhang, D., Allis, C. D. & Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 18, 90–101 (2017).

    CAS  PubMed  Google Scholar 

  11. 11.

    Prado, F., Jimeno-González, S. & Reyes, J. C. Histone availability as a strategy to control gene expression. RNA Biol. 14, 281–286 (2017).

    PubMed  Google Scholar 

  12. 12.

    Celona, B. et al. Substantial histone reduction modulates genomewide nucleosomal occupancy and global transcriptional output. PLoS Biol. 9, e1001086 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zhang, W., Song, M., Qu, J. & Liu, G.-H. Epigenetic modifications in cardiovascular aging and diseases. Circ. Res. 123, 773–786 (2018).

    CAS  PubMed  Google Scholar 

  14. 14.

    Trojer, P. & Reinberg, D. Facultative heterochromatin: is there a distinctive molecular signature? Mol. Cell 28, 1–13 (2007).

    CAS  PubMed  Google Scholar 

  15. 15.

    Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Rando, Thomas A. & Chang, Howard Y. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46–57 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Feser, J. et al. Elevated histone expression promotes life span extension. Mol. Cell 39, 724–735 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Mahmoudi, S., Xu, L. & Brunet, A. Turning back time with emerging rejuvenation strategies. Nat. Cell Biol. 21, 32–43 (2019).

    CAS  PubMed  Google Scholar 

  20. 20.

    Grewal, S. I. S. & Jia, S. Heterochromatin revisited. Nat. Rev. Genet. 8, 35 (2007).

    CAS  PubMed  Google Scholar 

  21. 21.

    Mattson, M. P. & Arumugam, T. V. Hallmarks of brain aging: adaptive and pathological modification by metabolic states. Cell Metab. 27, 1176–1199 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Booth, Lauren N. & Brunet, A. The aging epigenome. Mol. Cell 62, 728–744 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Avgustinova, A. & Benitah, S. A. Epigenetic control of adult stem cell function. Nat. Rev. Mol. Cell Biol. 17, 643 (2016).

    CAS  PubMed  Google Scholar 

  24. 24.

    Benayoun, B. A., Pollina, E. A. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat. Rev. Mol. Cell Biol. 16, 593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Ermolaeva, M., Neri, F., Ori, A. & Rudolph, K. L. Cellular and epigenetic drivers of stem cell ageing. Nat. Rev. Mol. Cell Biol. 19, 594–610 (2018).

    CAS  PubMed  Google Scholar 

  26. 26.

    Sidler, C., Kovalchuk, O. & Kovalchuk, I. Epigenetic regulation of cellular senescence and aging. Front. Genet. (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Bollati, V. et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech. Ageing Dev. 130, 234–239 (2009).

    CAS  PubMed  Google Scholar 

  28. 28.

    Ren, R., Ocampo, A., Liu, G.-H. & Izpisua Belmonte, J. C. Regulation of stem cell aging by metabolism and epigenetics. Cell Metab. 26, 460–474 (2017).

    CAS  PubMed  Google Scholar 

  29. 29.

    Ucar, D. & Benayoun, B. A. Aging epigenetics: changes and challenges, in Epigenetics of Aging and Longevity Vol. 4 (eds. Moskalev, A. & Vaiserman, A. M.) Ch.1, 3–32 (Academic Press, Boston, 2018).

  30. 30.

    Zhang, W. et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348, 1160 (2015). Zhang et al. highlight heterochromatin disorganization as a potential determinant of human stem cell ageing.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e1712 (2016). Ocampo et al. demonstrate that in vivo reprogramming ameliorates signs of ageing and extends lifespan.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ecker, S., Pancaldi, V., Valencia, A., Beck, S. & Paul, D. S. Epigenetic and transcriptional variability shape phenotypic plasticity. Bioessays 40, 1700148 (2018).

    Google Scholar 

  33. 33.

    Tan, Q. et al. Epigenetic drift in the aging genome: a ten-year follow-up in an elderly twin cohort. Int. J. Epidemiol. 45, 1146–1158 (2016).

    PubMed  Google Scholar 

  34. 34.

    Enge, M. et al. Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171, 321–330.e314 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Liu, P., Song, R., Elison, G. L., Peng, W. & Acar, M. Noise reduction as an emergent property of single-cell aging. Nat. Commun. 8, 680 (2017).

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Raser, J. M. & O’Shea, E. K. Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Salzer, M. C. et al. Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175, 1575–1590.e1522 (2018).

    CAS  PubMed  Google Scholar 

  38. 38.

    Swisa, A., Kaestner, K. H. & Dor, Y. Transcriptional noise and somatic mutations in the aging pancreas. Cell Metab. 26, 809–811 (2017).

    CAS  PubMed  Google Scholar 

  39. 39.

    Hernando-Herraez, I. et al. Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nat. Commun. 10, 4361 (2019).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Cheung, P. et al. Single-cell chromatin modification profiling reveals increased epigenetic variations with aging. Cell 173, 1385–1397.e1314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Martin, G. M. Epigenetic drift in aging identical twins. Proc. Natl Acad. Sci. USA 102, 10413–10414 (2005).

    CAS  PubMed  Google Scholar 

  43. 43.

    Kaminsky, Z. A. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat. Genet. 41, 240 (2009).

    CAS  PubMed  Google Scholar 

  44. 44.

    Kim, S. et al. DNA methylation associated with healthy aging of elderly twins. Geroscience 40, 469–484 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Fraga, M. F. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc. Natl Acad. Sci. USA 102, 10604 (2005).

    CAS  PubMed  Google Scholar 

  46. 46.

    Fraga, M. F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413–418 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Pal, S. & Tyler, J. K. Epigenetics and aging. Sci. Adv. 2, e1600584 (2016).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Xie, K. et al. Epigenetic alterations in longevity regulators, reduced life span, and exacerbated aging-related pathology in old father offspring mice. Proc. Natl Acad. Sci. USA 115, E2348 (2018).

    CAS  PubMed  Google Scholar 

  49. 49.

    Öst, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014).

    PubMed  Google Scholar 

  50. 50.

    Laker, R. C. et al. Exercise prevents maternal high-fat diet–induced hypermethylation of the Pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes 63, 1605 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Ng, S.-F. et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010).

    CAS  PubMed  Google Scholar 

  52. 52.

    Sandovici, I. et al. Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4 α gene in rat pancreatic islets. Proc. Natl Acad. Sci. USA 108, 5449–5454 (2011).

    CAS  PubMed  Google Scholar 

  53. 53.

    Radford, E. J. et al. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

    PubMed  PubMed Central  Google Scholar 

  54. 54.

    Kishimoto, S., Uno, M., Okabe, E., Nono, M. & Nishida, E. Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in caenorhabditis elegans. Nat. Commun. 8, 14031 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Finkel, T. The metabolic regulation of aging. Nat. Med. 21, 1416–1423 (2015).

    CAS  PubMed  Google Scholar 

  56. 56.

    Houtkooper, R. H., Williams, R. W. & Auwerx, J. Metabolic networks of longevity. Cell 142, 9–14 (2010).

    CAS  PubMed  Google Scholar 

  57. 57.

    Weimer, S. et al. D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat. Commun. 5, 3563 (2014).

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Johnson, L. C. et al. Amino acid and lipid associated plasma metabolomic patterns are related to healthspan indicators with aging in humans. Clin. Sci. 132, 1765–1777 (2018).

    CAS  PubMed  Google Scholar 

  59. 59.

    Mihaylova, M. M. et al. Fasting activates fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell 22, 769–778.e764 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Han, S. et al. Mono-unsaturated fatty acids link H3K4me3 modifiers to C. elegans lifespan. Nature 544, 185 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Redman, L. M. et al. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab. 27, 805–815.e804 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Valdez, G. et al. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc. Natl Acad. Sci. USA 107, 14863–14868 (2010).

    CAS  PubMed  Google Scholar 

  65. 65.

    Cerletti, M. et al. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell 10, 515–519 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Igarashi, M. & Guarente, L. mTORC1 and SIRT1 cooperate to foster expansion of gut adult stem cells during calorie restriction. Cell 166, 436–450 (2016).

    CAS  PubMed  Google Scholar 

  67. 67.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Hahn, O. et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 18, 56 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Sae-Lee, C. et al. Dietary intervention modifies DNA methylation age assessed by the epigenetic clock. Mol. Nutr. Food Res. (2018).

    Article  PubMed  Google Scholar 

  70. 70.

    Maegawa, S. et al. Caloric restriction delays age-related methylation drift. Nat. Commun. 8, 539 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Unnikrishnan, A. et al. Revisiting the genomic hypomethylation hypothesis of aging. Ann. N. Y. Acad. Sci. 1418, 69–79 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Li, Y., Liu, L. & Tollefsbol, T. O. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J. 24, 1442–1453 (2009).

    PubMed  Google Scholar 

  73. 73.

    Smeal, T., Claus, J., Kennedy, B., Cole, F. & Guarente, L. Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae. Cell 84, 633–642 (1996).

    CAS  PubMed  Google Scholar 

  74. 74.

    Howitz, K. T. et al. Small molecule activators of sirtuins extend saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).

    CAS  PubMed  Google Scholar 

  75. 75.

    Imai, S.-i, Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000). Imai et. al. found that Sir2 (which extends lifespan in yeast) is a NAD-dependent epigenetic regulator, linking metabolism and longevity.

    CAS  PubMed  Google Scholar 

  76. 76.

    Lin, S.-J., Defossez, P.-A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in saccharomyces cerevisiae. Science 289, 2126 (2000).

    CAS  PubMed  Google Scholar 

  77. 77.

    Cohen, H. Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390 (2004).

    CAS  PubMed  Google Scholar 

  78. 78.

    Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).

    CAS  PubMed  Google Scholar 

  79. 79.

    Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).

    CAS  PubMed  Google Scholar 

  80. 80.

    Zhang, W. et al. SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 560, 661–665 (2018).

    CAS  PubMed  Google Scholar 

  81. 81.

    Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).

    CAS  PubMed  Google Scholar 

  82. 82.

    Mitchell, Sarah J. et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep. 6, 836–843 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Minor, R. K. et al. SRT1720 improves survival and healthspan of obese mice. Sci. Rep. 1, 70 (2011).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Satoh, A., Imai, S.-i & Guarente, L. The brain, sirtuins, and ageing. Nat. Rev. Neurosci. 18, 362–374 (2017).

    CAS  PubMed  Google Scholar 

  85. 85.

    Fusco, S. et al. A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability. Cell Rep. 14, 1195–1205 (2016).

    CAS  PubMed  Google Scholar 

  86. 86.

    Cao, T. et al. Histone deacetylase inhibitor alleviates the neurodegenerative phenotypes and histone dysregulation in presenilins-deficient mice. Front. Aging Neurosci. (2018).

  87. 87.

    Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546.e535 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Evason, K., Collins, J. J., Huang, C., Hughes, S. & Kornfeld, K. Valproic acid extends caenorhabditis elegans lifespan. Aging Cell 7, 305–317 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Edwards, C. et al. D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging 6, 621–644 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Dang, W. et al. Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response. Cell Metab. 19, 952–966 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Rhoads, T. W. et al. Caloric restriction engages hepatic rna processing mechanisms in rhesus monkeys. Cell Metab. 27, 677–688.e675 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Heintz, C. et al. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102 (2016).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Mellor, J. The molecular basis of metabolic cycles and their relationship to circadian rhythms. Nat. Struct. Mol. Biol. 23, 1035 (2016).

    CAS  PubMed  Google Scholar 

  94. 94.

    Wang, H. et al. Time-restricted feeding shifts the skin circadian clock and alters UVB-induced DNA damage. Cell Rep. 20, 1061–1072 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Mure, L. S. et al. Diurnal transcriptome atlas of a primate across major neural and peripheral tissues. Science 359, eaao0318 (2018).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Solanas, G. et al. Aged stem cells reprogram their daily rhythmic functions to adapt to stress. Cell 170, 678–692.e620 (2017).

    CAS  PubMed  Google Scholar 

  97. 97.

    Masri, S. & Sassone-Corsi, P. Sirtuins and the circadian clock: bridging chromatin and metabolism. Sci. Signal. 7, re6 (2014).

    PubMed  Google Scholar 

  98. 98.

    Satoh, A. & Imai, S.-i. Systemic regulation of mammalian ageing and longevity by brain sirtuins. Nat. Commun. 5, 4211 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Sato, S. et al. Circadian reprogramming in the liver identifies metabolic pathways of aging. Cell 170, 664–677.e611 (2017).

    CAS  PubMed  Google Scholar 

  100. 100.

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). Takahashi and Yamanaka reported the ground-breaking discovery that induced pluripotent stem cells (iPSCs) can be obtained from mouse fibroblasts by expressing a defined set of transcription factors.

    CAS  Google Scholar 

  101. 101.

    Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).

    CAS  PubMed  Google Scholar 

  102. 102.

    Yagi, T. et al. Establishment of induced pluripotent stem cells from centenarians for neurodegenerative disease research. PLoS One 7, e41572 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Soria-Valles, C. & López-Otín, C. iPSCs: on the road to reprogramming aging. Trends Mol. Med. 22, 713–724 (2016).

    PubMed  Google Scholar 

  104. 104.

    Lapasset, L. et al. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes. Dev. 25, 2248–2253 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Wang, S. et al. Ectopic hTERT expression facilitates reprograming of fibroblasts derived from patients with Werner syndrome as a WS cellular model. Cell Death Dis. 9, 923 (2018).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Wang, S. et al. Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction. Protein Cell 11, 1–22 (2019).

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Zhang, W., Qu, J., Suzuki, K., Liu, G.-H. & Belmonte, J. C. I. Concealing cellular defects in pluripotent stem cells. Trends Cell Biol. 23, 587–592 (2013).

    CAS  PubMed  Google Scholar 

  108. 108.

    Brunauer, R. & Kennedy, B. K. Progeria accelerates adult stem cell aging. Science 348, 1093 (2015).

    CAS  PubMed  Google Scholar 

  109. 109.

    Kubben, N. et al. Repression of the antioxidant NRF2 pathway in premature aging. Cell 165, 1361–1374 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Yu, D. et al. In vivo cellular reprogramming for tissue regeneration and age reversal. Innov. Aging 2, 883–883 (2018).

    PubMed Central  Google Scholar 

  111. 111.

    Huh, C. J. et al. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. eLife 5, e18648 (2016).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Ahlenius, H. et al. FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice. Proc. Natl Acad. Sci. USA 113, 8514–8519 (2016).

    CAS  PubMed  Google Scholar 

  113. 113.

    Koche, R. P. et al. Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell 8, 96–105 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Chen, K. et al. Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming. EMBO J. 39, e99165 (2019).

    PubMed  Google Scholar 

  115. 115.

    Chen, J. et al. H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs. Nat. Genet. 45, 34–42 (2013).

    CAS  PubMed  Google Scholar 

  116. 116.

    Bhutani, N. et al. Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 463, 1042–1047 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Mertens, J. et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17, 705–718 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Banito, A. et al. Senescence impairs successful reprogramming to pluripotent stem cells. Genes. Dev. 23, 2134–2139 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Soria-Valles, C., Osorio, F. G. & López-Otín, C. Reprogramming aging through DOT1L inhibition. Cell Cycle 14, 3345–3346 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Kondo, H. et al. Blockade of senescence-associated microRNA-195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells. Aging Cell 15, 56–66 (2016).

    CAS  PubMed  Google Scholar 

  121. 121.

    Bernardes de Jesus, B. et al. Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency. Nat. Commun. 9, 94 (2018).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    Olova, N., Simpson, D. J., Marioni, R. E. & Chandra, T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell 0, e12877 (2018).

    Google Scholar 

  123. 123.

    Mahmoudi, S. & Brunet, A. Bursts of reprogramming: a path to extend lifespan? Cell 167, 1672–1674 (2016).

    CAS  PubMed  Google Scholar 

  124. 124.

    Sikora, E. Rejuvenation of senescent cells—the road to postponing human aging and age-related disease? Exp. Gerontol. 48, 661–666 (2013).

    CAS  PubMed  Google Scholar 

  125. 125.

    Koellhoffer Edward, C., Morales-Scheihing, D., d’Aigle, J. & McCullough Louise, D. Abstract WP122: heterochronic parabiosis reverses the epigenetic imbalance of the aged central nervous system. Stroke 48, AWP122 (2017).

    Google Scholar 

  126. 126.

    Gontier, G. et al. Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep. 22, 1974–1981 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Serrano, M. & Barzilai, N. Targeting senescence. Nat. Med. 24, 1092–1094 (2018).

    CAS  PubMed  Google Scholar 

  128. 128.

    Fontana, L. Interventions to promote cardiometabolic health and slow cardiovascular ageing. Nat. Rev. Cardiol. 15, 566–577 (2018).

    PubMed  Google Scholar 

  129. 129.

    Bridgeman, S. C., Ellison, G. C., Melton, P. E., Newsholme, P. & Mamotte, C. D. S. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes. Metab. 20, 1553–1562 (2018).

    PubMed  Google Scholar 

  130. 130.

    Wu, D. et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559, 637–641 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Pietrocola, F. et al. Aspirin recapitulates features of caloric restriction. Cell Rep. 22, 2395–2407 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Geng, L. et al. Chemical screen identifies a geroprotective role of quercetin in premature aging. Protein Cell 10, 417–435 (2018).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Li, Y. et al. Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein Cell 7, 478–488 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476 (2017).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Gil, J. & Withers, D. J. Out with the old. Nature 530, 164 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Baumann, K. Rejuvenating senolytics. Nat. Rev. Mol. Cell Biol. 19, 543–543 (2018).

    CAS  PubMed  Google Scholar 

  138. 138.

    Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184 (2016). Baker et al. report that the therapeutic removal of senescent cells extends healthy lifespan of mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Jeon, O. H. et al. Senescence cell–associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Muñoz-Espín, D. et al. A versatile drug delivery system targeting senescent cells. EMBO Mol. Med. 10, e9355 (2018).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1233 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Krimpenfort, P. & Berns, A. Rejuvenation by therapeutic elimination of senescent cells. Cell 169, 3–5 (2017).

    CAS  PubMed  Google Scholar 

  144. 144.

    Nguyen, P. et al. Elimination of age-associated hepatic steatosis and correction of aging phenotype by inhibition of cdk4-C/EBPα-p300 Axis. Cell Rep. 24, 1597–1609 (2018).

    CAS  PubMed  Google Scholar 

  145. 145.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). Xu et al. provide proof-of-concept evidence that senolytics can increase healthspan and lifespan in old mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Kedhari Sundaram, M., Hussain, A., Haque, S., Raina, R. & Afroze, N. Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. J. Cell. Biochem. 120, 18357–18369 (2019).

    CAS  PubMed  Google Scholar 

  148. 148.

    Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Weir, H. J. et al. Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab. 26, 884–896 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Labbadia, J. et al. Mitochondrial stress restores the heat shock response and prevents proteostasis collapse during aging. Cell Rep. 21, 1481–1494 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Galluzzi, L., Yamazaki, T. & Kroemer, G. Linking cellular stress responses to systemic homeostasis. Nat. Rev. Mol. Cell Biol. 19, 731–745 (2018).

    CAS  PubMed  Google Scholar 

  153. 153.

    Imai, S.-i. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Guarente, L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132, 171–176 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127, 1109–1122 (2006).

    CAS  PubMed  Google Scholar 

  156. 156.

    Masotti, A. et al. Aged iPSCs display an uncommon mitochondrial appearance and fail to undergo in vitro neurogenesis. Aging 6, 1094–1108 (2014).

    PubMed  PubMed Central  Google Scholar 

  157. 157.

    Sinha, I., Sinha-Hikim, A. P., Wagers, A. J. & Sinha-Hikim, I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 357, 815–821 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Li, X., Egervari, G., Wang, Y., Berger, S. L. & Lu, Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nat. Rev. Mol. Cell Biol. 19, 563–578 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Peleg, S., Feller, C., Ladurner, A. G. & Imhof, A. The metabolic impact on histone acetylation and transcription in ageing. Trends Biochem. Sci. 41, 700–711 (2016).

    CAS  PubMed  Google Scholar 

  160. 160.

    Merkwirth, C. et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165, 1209–1223 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).

    CAS  PubMed  Google Scholar 

  162. 162.

    Igarashi, M. et al. NAD+ supplementation rejuvenates aged gut adult stem cells. Aging Cell 18, e12935 (2019).

    PubMed  PubMed Central  Google Scholar 

  163. 163.

    Yoshino, J., Baur, J. A. & Imai, S.-i. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 27, 513–528 (2018).

    CAS  PubMed  Google Scholar 

  164. 164.

    Rajman, L., Chwalek, K. & Sinclair, D. A. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 27, 529–547 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Mitchell, S. J. et al. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab. 27, 667–676.e664 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Saini, J. S. et al. Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration. Cell Stem Cell 20, 635–647.e637 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Saint-Geniez, M. & Rosales, M. A. B. Eyeing the fountain of youth. Cell Stem Cell 20, 583–584 (2017).

    CAS  PubMed  Google Scholar 

  168. 168.

    Katsyuba, E. et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 563, 354–359 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).

    PubMed  PubMed Central  Google Scholar 

  170. 170.

    Shadel, Gerald S. & Horvath, Tamas L. Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560–569 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Schroeder, Elizabeth A., Raimundo, N. & Shadel, Gerald S. Epigenetic silencing mediates mitochondria stress-induced longevity. Cell Metab. 17, 954–964 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Maxwell, P. H., Burhans, W. C. & Curcio, M. J. Retrotransposition is associated with genome instability during chronological aging. Proc. Natl Acad. Sci. USA 108, 20376–20381 (2011).

    CAS  PubMed  Google Scholar 

  173. 173.

    de Koning, A. P. J., Gu, W., Castoe, T. A., Batzer, M. A. & Pollock, D. D. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 7, e1002384 (2011).

    PubMed  PubMed Central  Google Scholar 

  174. 174.

    Van Meter, M. et al. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat. Commun. 5, 5011 (2014).

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Gorbunova, V., Boeke, J. D., Helfand, S. L. & Sedivy, J. M. Sleeping dogs of the genome. Science 346, 1187–1188 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    De Cecco, M. et al. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging 5, 867–883 (2013).

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    Chandra, T. & Kirschner, K. Chromosome organisation during ageing and senescence. Curr. Opin. Cell Biol. 40, 161–167 (2016).

    CAS  PubMed  Google Scholar 

  178. 178.

    Green, C. D. et al. Impact of dietary interventions on noncoding RNA networks and mRNAs encoding chromatin-related factors. Cell Rep. 18, 2957–2968 (2017).

    CAS  PubMed  Google Scholar 

  179. 179.

    Guo, C. et al. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 23, 2874–2880 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Kubben, N. & Misteli, T. Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat. Rev. Mol. Cell Biol. 18, 595 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Pegoraro, G. et al. Ageing-related chromatin defects through loss of the NURD complex. Nat. Cell Biol. 11, 1261–1267 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Deng, L. et al. Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Nat. Commun. 10, 3329 (2019).

    PubMed  PubMed Central  Google Scholar 

  183. 183.

    Wu, Z. et al. Differential stem cell aging kinetics in hutchinson-gilford progeria syndrome and Werner syndrome. Protein Cell 9, 333–350 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Kreienkamp, R. et al. A cell-Intrinsic Interferon-like response links replication stress to cellular aging caused by progerin. Cell Rep. 22, 2006–2015 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). De Cecco et al. demonstrate that activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing.

    PubMed  PubMed Central  Google Scholar 

  186. 186.

    Sousa-Victor, P. et al. Piwi Is required to limit exhaustion of aging somatic stem cells. Cell Rep. 20, 2527–2537 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 (2019).

    CAS  PubMed  Google Scholar 

  188. 188.

    Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Talluri, S. & Dick, F. A. Regulation of transcription and chromatin structure by pRB: here, there and everywhere. Cell Cycle 11, 3189–3198 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Blaudin de Thé, F. X. et al. Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression. EMBO J. 37, e97374 (2018).

    PubMed  PubMed Central  Google Scholar 

  191. 191.

    Liu, N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228 (2017).

    PubMed  PubMed Central  Google Scholar 

  192. 192.

    Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl Acad. Sci. USA 113, 11277 (2016).

    CAS  PubMed  Google Scholar 

  193. 193.

    Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69, S4–S9 (2014).

    PubMed  Google Scholar 

  194. 194.

    Gowers, I. R. et al. Age-related loss of CpG methylation in the tumour necrosis factor promoter. Cytokine 56, 792–797 (2011).

    CAS  PubMed  Google Scholar 

  195. 195.

    Schäfer, A. et al. Impaired DNA demethylation of C/EBP sites causes premature aging. Genes. Dev. 32, 742–762 (2018).

    PubMed  PubMed Central  Google Scholar 

  196. 196.

    Bradburn, S. et al. Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance. Neurobiol. Aging 63, 54–64 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Bacos, K. et al. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes. Nat. Commun. 7, 11089 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Glück, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. 200.

    Ablasser, A. & Chen, Z. J. cGAS in action: expanding roles in immunity and inflammation. Science 363, eaat8657 (2019).

    CAS  PubMed  Google Scholar 

  201. 201.

    Kerur, N. et al. cGAS drives noncanonical-inflammasome activation in age-related macular degeneration. Nat. Med. 24, 50 (2017).

    PubMed  PubMed Central  Google Scholar 

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Due to limitations of space, the authors apologize for not being able to cite all important studies in this Review. The authors thank Y. Wang, S. Wang, X. He, X. Liu and J. Li for their assistance in preparing the manuscript. This work was supported by the National Key Research and Development Program of China (2018YFC2000100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2017YFA0102802, 2017YFA0103304, 2018YFA0107203, 2018YFC2000400, 2015CB964800), the National Natural Science Foundation of China (81625009, 81330008, 91749202, 81861168034, 81921006, 91749123, 31671429, 81671377, 81771515, 31601158, 81701388, 81601233, 31601109, 81822018, 81870228, 81801399, 31801010, 81801370, 81861168034), the Key Research Program of the Chinese Academy of Sciences (KJZDEWTZ-L05), the Beijing Natural Science Foundation (Z190019), the Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), the Advanced Innovation Center for Human Brain Protection (3500-1192012) and the State Key Laboratory of Membrane Biology. J.C.I.B. was supported by the Glenn Foundation, the Moxie Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, Fundación Dr. Pedro Guillen, Fundación Teléfonica, Fundación MAPFRE and Universidad Católica San Antonio de Murcia.

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Correspondence to Guang-Hui Liu or Juan Carlos Izpisua Belmonte.

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Ten–eleven translocation enzymes

TET enzymes. A family of dioxygenases, including TET1, TET2, and TET3, involved in DNA demethylation. They function by converting 5-methylcytosine into 5-hydroxymethylcytosine.

Constitutive heterochromatin

Constitutive heterochromatin encompasses highly repetitive DNA sequences, is enriched around the pericentromeric and telomeric regions of chromosomes and is consistently stable in many cell types of most eukaryotes.

Epigenetic drifts

Age-associated heterogeneity of the epigenome which will lead to increased noise of gene expression during ageing.


A macrolide compound approved by the US Food and Drug Administration to prevent organ transplant rejection and also thought to be able to extend lifespan in diverse species.

Senescent cell

Aged cells characterized by irreversible cell cycle arrest, along with acquisition of a proinflammatory secretome and activation of the cyclin-dependent kinase inhibitor p16.

Senescence-associated heterochromatin foci

In some types of senescent cells, such as oncogene-induced senescent cells, domains of facultative heterochromatin are formed to silence the expression of proliferation-promoting genes.

Phenotypic discordance

Phenotypic variability can be caused by accumulation of environmental effects on the epigenetic state of cells and tissues during ageing.

Satellite cells

Adult stem cells of muscle tissue, quiescent under normal physiological conditions and activated on injury.

Pioneer factor

Bookmarking transcription factor that can directly bind and recruit other chromatin remodellers to condensed chromatin, allowing initiation of new molecular programmes and cell fate transition.

Stem cell exhaustion

The number or function of stem cells declines with age, which dampens tissue homeostasis.


Selective elimination of damaged mitochondria through autophagy.

Mitochondrial unfolded protein response

Imbalance between mitochondrion-encoding and nucleus-encoding protein and accumulation of misfolded protein in mitochondria cause mitochondrial unfolded protein response, a conserved transcriptional response that activates genes involved in antioxidant response, mitophagy and protein homeostasis and promotes lifespan extension in animal models.

Senescence-associated secretory phenotype

Senescent cells in vivo and in vitro secrete numerous inflammatory cytokines, proteases and growth factors in an autocrine or a paracrine manner, which leads to chronic inflammation.

Innate immune activity

As the first line of immune defence, innate immunity is an evolutionarily conserved defence system that recognize ‘foreign’ components, such as DNA, RNA and protein, and triggers non-specific inflammatory responses.

cGAS−STING pathway

A major DNA-sensing mechanism in mammalian cells that starts from cyclic GMP–AMP synthase (cGAS), which senses cytosolic DNA, produces cyclic GMP–AMP, activates STING and triggers innate immune response that plays a critical role in senescence.

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Zhang, W., Qu, J., Liu, GH. et al. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 21, 137–150 (2020).

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