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The central role of DNA damage in the ageing process


Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level—for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.

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Fig. 1: DNA damage is the driver of ageing.
Fig. 2: Molecular, cellular and systemic consequences of DNA damage.


  1. 1.

    Schumacher, B. The Mystery of Human Aging: Surprising Insights from a Science That’s Still Young (Algora, 2017).

  2. 2.

    Charlesworth, B. Fisher, Medawar, Hamilton and the evolution of aging. Genetics 156, 927–931 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957).

    Google Scholar 

  4. 4.

    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 

  5. 5.

    Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709–715 (1993).

    ADS  CAS  PubMed  Google Scholar 

  6. 6.

    Niedernhofer, L. J. et al. Nuclear genomic instability and aging. Annu. Rev. Biochem. 87, 295–322 (2018).

    CAS  PubMed  Google Scholar 

  7. 7.

    Lubberts, S., Meijer, C., Demaria, M. & Gietema, J. A. Early ageing after cytotoxic treatment for testicular cancer and cellular senescence: time to act. Crit. Rev. Oncol. Hematol. 151, 102963 (2020).

    PubMed  Google Scholar 

  8. 8.

    Gonzalo, S., Kreienkamp, R. & Askjaer, P. Hutchinson–Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res. Rev. 33, 18–29 (2017).

    CAS  PubMed  Google Scholar 

  9. 9.

    Vijg, J. Aging of the Genome (Oxford Univ. Press, 2007).

  10. 10.

    Lundblad, V. & Szostak, J. W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989).

    CAS  PubMed  Google Scholar 

  11. 11.

    de Lange, T. Shelterin-mediated telomere protection. Annu. Rev. Genet. 52, 223–247 (2018).

    PubMed  Google Scholar 

  12. 12.

    Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Abdallah, P. et al. A two-step model for senescence triggered by a single critically short telomere. Nat. Cell Biol. 11, 988–993 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Martínez, P. & Blasco, M. A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 216, 875–887 (2017).

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Jaskelioff, M. et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102–106 (2011).

    ADS  CAS  PubMed  Google Scholar 

  17. 17.

    Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020).

    PubMed  Google Scholar 

  18. 18.

    Robin, J. D. et al. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 28, 2464–2476 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hauer, M. H. & Gasser, S. M. Chromatin and nucleosome dynamics in DNA damage and repair. Genes Dev. 31, 2204–2221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    O’Sullivan, R. J., Kubicek, S., Schreiber, S. L. & Karlseder, J. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat. Struct. Mol. Biol. 17, 1218–1225 (2010).

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Hu, Z. et al. Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging. Genes Dev. 28, 396–408 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Mortusewicz, O., Schermelleh, L., Walter, J., Cardoso, M. C. & Leonhardt, H. Recruitment of DNA methyltransferase I to DNA repair sites. Proc. Natl Acad. Sci. USA 102, 8905–8909 (2005).

    ADS  CAS  PubMed  Google Scholar 

  24. 24.

    Wang, S., Meyer, D. H. D. H. & Schumacher, B. H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage. Nat. Struct. Mol. Biol. 27, 1165–1177 (2020). S. Wang and colleagues revealed that, after the repair of DNA lesions, the epigenetic mark H3K4me2 is deposited to restore protein homeostasis and thus antagonize DNA damage-driven ageing.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ito, T., Teo, Y. V., Evans, S. A., Neretti, N. & Sedivy, J. M. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylation-dependent pathways. Cell Rep. 22, 3480–3492 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol. 6, 168–170 (2004).

    CAS  PubMed  Google Scholar 

  27. 27.

    Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).

    CAS  PubMed  Google Scholar 

  28. 28.

    Russo, G. et al. DNA damage and repair modify DNA methylation and chromatin domain of the targeted locus: mechanism of allele methylation polymorphism. Sci. Rep. 6, 33222 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Fang, E. F. et al. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157, 882–896 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    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 

  31. 31.

    Bahar, R. et al. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011–1014 (2006). R. Bahar and colleagues demonstrated that cell-to-cell variation in gene expression increases in aged single cardiomyocytes, suggesting that genome damage could trigger stochastic variations in transcript levels, thus compromising cellular function during ageing.

    ADS  CAS  PubMed  Google Scholar 

  32. 32.

    Takada, K. & Becker, L. E. Cockayne’s syndrome: report of two autopsy cases associated with neurofibrillary tangles. Clin. Neuropathol. 5, 64–68 (1986).

    CAS  PubMed  Google Scholar 

  33. 33.

    Lopes, A. F. C. et al. A C. elegans model for neurodegeneration in Cockayne syndrome. Nucleic Acids Res. 48, 10973–10985 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bucholtz, N. & Demuth, I. DNA-repair in mild cognitive impairment and Alzheimer’s disease. DNA Repair 12, 811–816 (2013).

    CAS  PubMed  Google Scholar 

  35. 35.

    Weissman, L. et al. Defective DNA base excision repair in brain from individuals with Alzheimer’s disease and amnestic mild cognitive impairment. Nucleic Acids Res. 35, 5545–5555 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Leandro, G. S., Lobo, R. R., Oliveira, D. V. N. P., Moriguti, J. C. & Sakamoto-Hojo, E. T. Lymphocytes of patients with Alzheimer’s disease display different DNA damage repair kinetics and expression profiles of DNA repair and stress response genes. Int. J. Mol. Sci. 14, 12380–12400 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Sepe, S., Payan-Gomez, C., Milanese, C., Hoeijmakers, J. H. & Mastroberardino, P. G. Nucleotide excision repair in chronic neurodegenerative diseases. DNA Repair 12, 568–577 (2013).

    CAS  PubMed  Google Scholar 

  38. 38.

    Obulesu, M. & Rao, D. M. DNA damage and impairment of DNA repair in Alzheimer’s disease. Int. J. Neurosci. 120, 397–403 (2010).

    CAS  PubMed  Google Scholar 

  39. 39.

    Sepe, S. et al. Inefficient DNA repair is an aging-related modifier of Parkinson’s disease. Cell Rep. 15, 1866–1875 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Jones, L., Houlden, H. & Tabrizi, S. J. DNA repair in the trinucleotide repeat disorders. Lancet Neurol. 16, 88–96 (2017).

    CAS  PubMed  Google Scholar 

  41. 41.

    Gao, R. et al. Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription. eLife 8, e42988 (2019).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018). Using single-cell sequencing, this study revealed increasing somatic mutations in neurons during human ageing, indicating that even post-mitotic cell types accrue mutations that might trigger age-associated functional decline and degeneration.

    ADS  CAS  PubMed  Google Scholar 

  43. 43.

    Vermeij, W. P. et al. Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice. Nature 537, 427–431 (2016). W. P. Vermeij and colleagues showed that premature ageing in DNA repair-deficient mice could be alleviated by dietary restriction, suggesting that DNA repair is capable of reducing DNA damage infliction and promoting genome stability.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Wei, Y. N. et al. Transcript and protein expression decoupling reveals RNA binding proteins and miRNAs as potential modulators of human aging. Genome Biol. 16, 41 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kelmer Sacramento, E. et al. Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation. Mol. Syst. Biol. 16, e9596 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Edifizi, D. et al. Multilayered reprogramming in response to persistent DNA damage in C. elegans. Cell Rep. 20, 2026–2043 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). This study established that senescent cells release cytokines and thus elicit non-cell-autonomous effects such as inflammatory responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Williams, A. B. et al. Restoration of proteostasis in the endoplasmic reticulum reverses an inflammation-like response to cytoplasmic DNA in Caenorhabditis elegans. Genetics 212, 1259–1278 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    CAS  PubMed  Google Scholar 

  50. 50.

    Kauppila, T. E. S., Kauppila, J. H. K. & Larsson, N. G. Mammalian mitochondria and aging: an update. Cell Metab. 25, 57–71 (2017).

    CAS  PubMed  Google Scholar 

  51. 51.

    Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    ADS  CAS  PubMed  Google Scholar 

  52. 52.

    Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    ADS  CAS  PubMed  Google Scholar 

  53. 53.

    Bua, E. et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79, 469–480 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Wanagat, J., Cao, Z., Pathare, P. & Aiken, J. M. Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J. 15, 322–332 (2001).

    CAS  PubMed  Google Scholar 

  55. 55.

    Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518–520 (2006).

    CAS  PubMed  Google Scholar 

  56. 56.

    Taylor, R. W. et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J. Clin. Invest. 112, 1351–1360 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Vermulst, M. et al. Mitochondrial point mutations do not limit the natural lifespan of mice. Nat. Genet. 39, 540–543 (2007).

    CAS  PubMed  Google Scholar 

  58. 58.

    O’Hara, R. et al. Quantitative mitochondrial DNA copy number determination using droplet digital PCR with single-cell resolution. Genome Res. 29, 1878–1888 (2019).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Hoch, N. C. et al. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541, 87–91 (2017).

    ADS  CAS  PubMed  Google Scholar 

  61. 61.

    Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    CAS  PubMed  Google Scholar 

  62. 62.

    Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).

    ADS  CAS  PubMed  Google Scholar 

  63. 63.

    Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    ADS  CAS  PubMed  Google Scholar 

  65. 65.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). D. J. Baker and colleagues revealed that the elimination of senescent cells could delay ageing and provided the conceptual framework for eliminating senescence cells for therapeutic interventions aimed at extending healthspan.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Kotsantis, P., Petermann, E. & Boulton, S. J. Mechanisms of oncogene-induced replication stress: jigsaw falling into place. Cancer Discov. 8, 537–555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    CAS  PubMed  Google Scholar 

  70. 70.

    Andriani, G. A. et al. Whole chromosome instability induces senescence and promotes SASP. Sci. Rep. 6, 35218 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).

    CAS  PubMed  Google Scholar 

  72. 72.

    McNeely, T., Leone, M., Yanai, H. & Beerman, I. DNA damage in aging, the stem cell perspective. Hum. Genet. 139, 309–331 (2020).

    PubMed  Google Scholar 

  73. 73.

    Matsumura, H. et al Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    PubMed  Google Scholar 

  74. 74.

    Alyodawi, K. et al. Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling. J. Cachexia Sarcopenia Muscle 10, 662–686 (2019).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Geiger, H., de Haan, G. & Florian, M. C. The ageing haematopoietic stem cell compartment. Nat. Rev. Immunol. 13, 376–389 (2013).

    CAS  PubMed  Google Scholar 

  76. 76.

    Beerman, I., Seita, J., Inlay, M. A., Weissman, I. L. & Rossi, D. J. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37–50 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Flach, J. et al. Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 512, 198–202 (2014). This study established that increasing DNA replication stress in ageing haematopoietic stem cells leads to their functional decline.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Mohrin, M. et al. Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis. Cell Stem Cell 7, 174–185 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007).

    ADS  CAS  PubMed  Google Scholar 

  80. 80.

    Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zink, F. et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 130, 742–752 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Zhang, L. & Vijg, J. Somatic mutagenesis in mammals and its implications for human disease and aging. Annu. Rev. Genet. 52, 397–419 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Franco, I. et al. Somatic mutagenesis in satellite cells associates with human skeletal muscle aging. Nat. Commun. 9, 800 (2018).

    ADS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Ju, Z. et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat. Med. 13, 742–747 (2007).

    CAS  PubMed  Google Scholar 

  85. 85.

    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 

  86. 86.

    Liu, L. et al. Impaired Notch signaling leads to a decrease in p53 activity and mitotic catastrophe in aged muscle stem cells. Cell Stem Cell 23, 544–556.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Ou, H.-L., Kim, C. S., Uszkoreit, S., Wickström, S. A. & Schumacher, B. Somatic niche cells regulate the CEP-1/p53-mediated DNA damage response in primordial germ cells. Dev. Cell 50, 167–183.e8 (2019).

    CAS  PubMed  Google Scholar 

  88. 88.

    Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    ADS  CAS  PubMed  Google Scholar 

  89. 89.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Prasad, R. & Katiyar, S. K. Crosstalk among UV-induced inflammatory mediators, DNA damage and epigenetic regulators facilitates suppression of the immune system. Photochem. Photobiol. 93, 930–936 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Ermolaeva, M. A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Schumacher, B. et al. Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet. 4, e1000161 (2008).

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Niedernhofer, L. J. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006). This study linked unrepaired DNA damage to genetic regulators of longevity by showing that ILS is attenuated in progeroid mice deficient in DNA repair.

    ADS  CAS  PubMed  Google Scholar 

  94. 94.

    Garinis, G. A. et al. Persistent transcription-blocking DNA lesions trigger somatic growth attenuation associated with longevity. Nat. Cell Biol. 11, 604–615 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Mueller, M. M. et al. DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat. Cell Biol. 16, 1168–1179 (2014). Using C. elegans, M. M. Mueller and colleagues demonstrated that the longevity regulator DAF-16 responds to DNA damage and elevates the tolerance of the organism tolerance to persistent DNA lesions.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    McCay, C. M., Maynard, L. A., Sperling, G. & Barnes, L. L. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. J. Nutr. 18, 1–13 (1939).

    CAS  Google Scholar 

  97. 97.

    López-Otín, C., Galluzzi, L., Freije, J. M. P., Madeo, F. & Kroemer, G. Metabolic control of longevity. Cell 166, 802–821 (2016).

    PubMed  Google Scholar 

  98. 98.

    Matsuoka, S. et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160–1166 (2007).

    ADS  CAS  PubMed  Google Scholar 

  99. 99.

    Dominick, G., Bowman, J., Li, X., Miller, R. A. & Garcia, G. G. mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice. Aging Cell 16, 52–60 (2017).

    CAS  PubMed  Google Scholar 

  100. 100.

    Alves-Fernandes, D. K. & Jasiulionis, M. G. The role of SIRT1 on DNA damage response and epigenetic alterations in cancer. Int. J. Mol. Sci. 20, 1–13 (2019).

    Google Scholar 

  101. 101.

    Wu, C. L. et al. Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 32, 2682–2689 (2013).

    CAS  PubMed  Google Scholar 

  102. 102.

    Ma, Y., Vassetzky, Y. & Dokudovskaya, S. mTORC1 pathway in DNA damage response. Biochim. Biophys. Acta 1865, 1293–1311 (2018).

    CAS  Google Scholar 

  103. 103.

    Adamowicz, M., Vermezovic, J. & d’Adda di Fagagna, F. NOTCH1 inhibits activation of ATM by impairing the formation of an ATM-FOXO3a-KAT5/Tip60 complex. Cell Rep. 16, 2068–2076 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Tian, X. et al. SIRT6 is responsible for more efficient DNA double-strand break repair in long-lived species. Cell 177, 622–638.e22 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012). This study established that in male mice transgenic expression of SIRT6 leads to reduced IGF-1 signalling and lifespan extension.

    ADS  CAS  PubMed  Google Scholar 

  106. 106.

    Shaposhnikov, M., Proshkina, E., Shilova, L., Zhavoronkov, A. & Moskalev, A. Lifespan and stress resistance in Drosophila with overexpressed DNA repair genes. Sci. Rep. 5, 15299 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019). Using single cell sequencing,  L. Zhang and colleagues show increased somatic mutations during normal human ageing occurring in genes and regulatory regions indicating their role in the age-dependent functional decline.

    CAS  PubMed  Google Scholar 

  108. 108.

    Brazhnik, K. et al. Single-cell analysis reveals different age-related somatic mutation profiles between stem and differentiated cells in human liver. Sci. Adv. 6, eaax2659 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Franco, I. et al. Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type. Genome Biol. 20, 285 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726 (2019). This study used RNA sequencing to reveal the clonal expansion of somatic mutations in different human tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Johnson, S. C., Dong, X., Vijg, J. & Suh, Y. Genetic evidence for common pathways in human age-related diseases. Aging Cell 14, 809–817 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Day, F. R. et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat. Genet. 47, 1294–1303 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Laven, J. S. E., Visser, J. A., Uitterlinden, A. G., Vermeij, W. P. & Hoeijmakers, J. H. J. Menopause: Genome stability as new paradigm. Maturitas 92, 15–23 (2016).

    CAS  PubMed  Google Scholar 

  114. 114.

    Henshaw, P. S., Riley, E. F. & Stapleton, G. E. The biologic effects of pile radiations. Radiology 49, 349–360 (1947).

    CAS  PubMed  Google Scholar 

  115. 115.

    Alexander, P. The role of DNA lesions in the processes leading to aging in mice. Symp. Soc. Exp. Biol. 21, 29–50 (1967).

    CAS  PubMed  Google Scholar 

  116. 116.

    Jans, J. et al. Powerful skin cancer protection by a CPD-photolyase transgene. Curr. Biol. 15, 105–115 (2005).

    CAS  PubMed  Google Scholar 

  117. 117.

    Hart, R. W. & Setlow, R. B. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. Proc. Natl Acad. Sci. USA 71, 2169–2173 (1974).

    ADS  CAS  PubMed  Google Scholar 

  118. 118.

    Gensler, H. L. & Bernstein, H. DNA damage as the primary cause of aging. Q. Rev. Biol. 56, 279–303 (1981).

    CAS  PubMed  Google Scholar 

  119. 119.

    de Boer, J. et al. Premature aging in mice deficient in DNA repair and transcription. Science 296, 1276–1279 (2002). J. de Boer and colleagues established that genetic defects in DNA repair accelerate the mammalian ageing process.

    ADS  PubMed  Google Scholar 

  120. 120.

    Barzilai, A., Schumacher, B. & Shiloh, Y. Genome instability: linking ageing and brain degeneration. Mech. Ageing Dev. 161 (Pt A), 4–18 (2017).

    CAS  PubMed  Google Scholar 

  121. 121.

    Traube, F. R. et al. Isotope-dilution mass spectrometry for exact quantification of noncanonical DNA nucleosides. Nat. Protoc. 14, 283–312 (2019).

    CAS  PubMed  Google Scholar 

  122. 122.

    Mori, T. et al. High levels of oxidatively generated DNA damage 8,5′-cyclo-2′-deoxyadenosine accumulate in the brain tissues of xeroderma pigmentosum group A gene-knockout mice. DNA Repair 80, 52–58 (2019).

    CAS  PubMed  Google Scholar 

  123. 123.

    Van Houten, B., Cheng, S. & Chen, Y. Measuring gene-specific nucleotide excision repair in human cells using quantitative amplification of long targets from nanogram quantities of DNA. Mutat. Res. 460, 81–94 (2000).

    PubMed  Google Scholar 

  124. 124.

    Nakazawa, Y. et al. Ubiquitination of DNA damage-stalled RNAPII promotes transcription-coupled repair. Cell 180, 1228–1244.e24 (2020).

    CAS  PubMed  Google Scholar 

  125. 125.

    Mingard, C., Wu, J., McKeague, M. & Sturla, S. J. Next-generation DNA damage sequencing. Chem. Soc. Rev. 49, 7354–7377 (2020).

    CAS  PubMed  Google Scholar 

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The research was supported by the Deutsche Forschungsgemeinschaft (SCHU 2494/3-1, SCHU 2494/7-1, SCHU 2494/10-1, SCHU 2494/11-1, KFO 286, KFO 329, GRK 2407 to B.S., and CECAD EXC 2030–390661388, SFB 829 to B.S. and J.H.J.H.), Deutsche Krebshilfe (70112899), H2020-MSCA-ITN-2018 (Healthage and ADDRESS ITNs) and John Templeton Foundation Grant (61734) to B.S., NIH grants (PO1 AG017242 to J.V. and J.H., and U19 AG056278, U01 ES029519, P01AG047200, U01HL145560, P30AG038072 to J.V.), European Research Council Advanced Grants DamAge and Dam2Age, ONCODE (Dutch Cancer Society), Memorabel and Chembridge (ZonMW) and BBoL (NWO-ENW) to J.P. and J.H.

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Correspondence to Björn Schumacher.

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J.V. is a co-founder of SingulOmics Corp. The other authors declare no competing interests.

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Peer review information Nature thanks Jan van Deursen, John Sedivy and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Schumacher, B., Pothof, J., Vijg, J. et al. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021).

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