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).

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

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

4. Li, E. & Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a019133 (2014).

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).

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

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

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

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).

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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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).

26. Sidler, C., Kovalchuk, O. & Kovalchuk, I. Epigenetic regulation of cellular senescence and aging. Front. Genet. https://doi.org/10.3389/fgene.2017.00138 (2017).

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).

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).

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. 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.

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.

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

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).

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).

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).

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

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

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

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).

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

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

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

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

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

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

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

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

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).

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

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).

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).

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).

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

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).

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

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

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

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).

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).

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

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

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).

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).

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).

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

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).

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

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).

69. Sae-Lee, C. et al. Dietary intervention modifies DNA methylation age assessed by the epigenetic clock. Mol. Nutr. Food Res. https://doi.org/10.1002/mnfr.201800092 (2018).

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

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

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).

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).

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

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.

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).

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

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

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

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

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

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).

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

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

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

86. Cao, T. et al. Histone deacetylase inhibitor alleviates the neurodegenerative phenotypes and histone dysregulation in presenilins-deficient mice. Front. Aging Neurosci. https://doi.org/10.3389/fnagi.2018.00137 (2018).

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

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

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

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).

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

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

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

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).

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

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

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

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

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

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.

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

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

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

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

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).

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).

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).

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

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

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

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

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).

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

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

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

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

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).

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

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

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).

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).

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).

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

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

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).

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).

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

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

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).

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

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).

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

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

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

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

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

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

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.

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

140. Jeon, O. H. et al. Senescence cell–associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight https://doi.org/10.1172/jci.insight.125019 (2019).

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

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

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

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).

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

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.

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).

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

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

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

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

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

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

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

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).

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

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).

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).

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).

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

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

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

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).

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

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

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).

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

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

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).

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

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

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).

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).

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).

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

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).

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

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).

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

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).

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

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

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

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).

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.

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

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

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

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

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).

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

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).

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).

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

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

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).

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).

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

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

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