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Annual Review of Biochemistry

Volume 87, 2018

Nuclear Genomic Instability and Aging

Abstract

The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.

Keyword(s): aging, DNA damage, DNA damage response, DNA repair, mutations, senescence
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/content/journals/10.1146/annurev-biochem-062917-012239
2018-06-20
2024-04-25
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Literature Cited

  1. 1.  Lindahl T. 1993. Instability and decay of the primary structure of DNA. Nature 362:709–15An excellent review from a Nobel Prize winner thoroughly elaborating spontaneous, endogenous DNA damage.
     [Google Scholar]
  2. 2.  Sugimoto M. 2014. A cascade leading to premature aging phenotypes including abnormal tumor profiles in Werner syndrome (review). Int. J. Mol. Med. 33:247–53
     [Google Scholar]
  3. 3.  Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR et al. 2006. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444:1038–43
     [Google Scholar]
  4. 4.  Kraemer KH, DiGiovanna JJ 2014. Forty years of research on xeroderma pigmentosum at the US National Institutes of Health. Photochem. Photobiol. 91:452–59
     [Google Scholar]
  5. 5.  Nance MA, Berry SA 1992. Cockayne syndrome: review of 140 cases. Am. J. Med. Genet. 42:68–84
     [Google Scholar]
  6. 6.  Armstrong GT, Kawashima T, Leisenring W, Stratton K, Stovall M et al. 2014. Aging and risk of severe, disabling, life-threatening, and fatal events in the childhood cancer survivor study. J. Clin. Oncol. 32:1218–27
     [Google Scholar]
  7. 7.  Armstrong GT, Liu Q, Yasui Y, Huang S, Ness KK et al. 2009. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J. Natl. Cancer Inst. 101:946–58
     [Google Scholar]
  8. 8.  Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y et al. 2013. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J. Clin. Oncol. 31:3673–80
     [Google Scholar]
  9. 9.  Baker KS, Chow EJ, Goodman PJ, Leisenring WM, Dietz AC et al. 2013. Impact of treatment exposures on cardiovascular risk and insulin resistance in childhood cancer survivors. Cancer Epidemiol. Biomarkers Prev. 22:1954–63
     [Google Scholar]
  10. 10.  Ness KK, Krull KR, Jones KE, Mulrooney DA, Armstrong GT et al. 2013. Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J. Clin. Oncol. 31:4496–503
     [Google Scholar]
  11. 11.  Henderson TO, Ness KK, Cohen HJ 2014. Accelerated aging among cancer survivors: from pediatrics to geriatrics. ASCO Educational Book DS Dizon e423–30 Alexandria, VA: Am. Soc. Clin. Oncol
     [Google Scholar]
  12. 12.  Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U et al. 2013. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 368:987–98
     [Google Scholar]
  13. 13.  Harman D. 1956. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11:298–300The original proposal that reactive oxygen species produced endogenously might drive aging.
     [Google Scholar]
  14. 14.  Orr WC, Sohal RS 1994. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 263:1128–30
     [Google Scholar]
  15. 15.  Jang YC, Van Remmen H 2009. The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp. Gerontol. 44:256–60A review of murine genetic studies that obfuscates the free radical theory of aging.
     [Google Scholar]
  16. 16.  Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE et al. 2005. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–11
     [Google Scholar]
  17. 17.  Strong R, Miller RA, Antebi A, Astle CM, Bogue M et al. 2016. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872–84
     [Google Scholar]
  18. 18.  Moller P, Cooke MS, Collins A, Olinski R, Rozalski R, Loft S 2012. Harmonising measurements of 8-oxo-7,8-dihydro-2′-deoxyguanosine in cellular DNA and urine. Free Radic. Res. 46:541–53A cautionary note on the challenges of measuring spontaneous DNA damage.
     [Google Scholar]
  19. 19.  Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM et al. 2001. Does oxidative damage to DNA increase with age?. PNAS 98:10469–74
     [Google Scholar]
  20. 20.  Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA et al. 1998. DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. PNAS 95:288–93
     [Google Scholar]
  21. 21.  Wong YT, Gruber J, Jenner AM, Ng MP, Ruan R, Tay FE 2009. Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: protection by chronic oral intake of resveratrol. Free Radic. Biol. Med. 46:799–809
     [Google Scholar]
  22. 22.  Nie B, Gan W, Shi F, Hu GX, Chen LG et al. 2013. Age-dependent accumulation of 8-oxoguanine in the DNA and RNA in various rat tissues. Oxid. Med. Cell Longev. 2013:303181
     [Google Scholar]
  23. 23.  Gan W, Nie B, Shi F, Xu XM, Qian JC et al. 2012. Age-dependent increases in the oxidative damage of DNA, RNA, and their metabolites in normal and senescence-accelerated mice analyzed by LC-MS/MS: urinary 8-oxoguanosine as a novel biomarker of aging. Free Radic. Biol. Med. 52:1700–7
     [Google Scholar]
  24. 24.  Takabayashi F, Tahara S, Kaneko T, Miyoshi Y, Harada N 2004. Accumulation of 8-oxo-2′-deoxyguanosine (as a biomarker of oxidative DNA damage) in the tissues of aged hamsters and change in antioxidant enzyme activities after single administration of N-nitrosobis(2-oxopropyl) amine. Gerontology 50:57–63
     [Google Scholar]
  25. 25.  Sasaki T, Tahara S, Shinkai T, Kuramoto K, Matsumoto S et al. 2013. Lifespan extension in the spontaneous dwarf rat and enhanced resistance to hyperoxia-induced mortality. Exp. Gerontol. 48:457–63
     [Google Scholar]
  26. 26.  Ning YC, Cai GY, Zhuo L, Gao JJ, Dong D et al. 2013. Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage. Mech. Ageing Dev. 134:570–79
     [Google Scholar]
  27. 27.  Aydin S, Yanar K, Atukeren P, Dalo E, Sitar ME et al. 2012. Comparison of oxidative stress biomarkers in renal tissues of d-galactose induced, naturally aged and young rats. Biogerontology 13:251–60
     [Google Scholar]
  28. 28.  Jacob KD, Noren Hooten N, Trzeciak AR, Evans MK 2013. Markers of oxidant stress that are clinically relevant in aging and age-related disease. Mech. Ageing Dev. 134:139–57
     [Google Scholar]
  29. 29.  Jaruga P, Dizdaroglu M 2008. 8,5′-Cyclopurine-2′-deoxynucleosides in DNA: mechanisms of formation, measurement, repair and biological effects. DNA Repair 7:1413–25A review of spontaneous oxidative DNA lesions that are detected in mice and in humans.
     [Google Scholar]
  30. 30.  Wang J, Clauson CL, Robbins PD, Niedernhofer LJ, Wang Y 2012. The oxidative DNA lesions 8,5′-cyclopurines accumulate with aging in a tissue-specific manner. Aging Cell 11:714–16
     [Google Scholar]
  31. 31.  Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ 2014. Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15:37–50
     [Google Scholar]
  32. 32.  Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC 2004. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat. Cell Biol. 6:168–70
     [Google Scholar]
  33. 33.  Heuser VD, de Andrade VM, Peres A, Gomes de Macedo Braga LM, Bogo Chies JA 2008. Influence of age and sex on the spontaneous DNA damage detected by micronucleus test and comet assay in mice peripheral blood cells. Cell Biol. Int. 32:1223–29
     [Google Scholar]
  34. 34.  Rube CE, Fricke A, Widmann TA, Furst T, Madry H et al. 2011. Accumulation of DNA damage in hematopoietic stem and progenitor cells during human aging. PLOS ONE 6:e17487
     [Google Scholar]
  35. 35.  Sedelnikova OA, Horikawa I, Redon C, Nakamura A, Zimonjic DB et al. 2008. Delayed kinetics of DNA double-strand break processing in normal and pathological aging. Aging Cell 7:89–100
     [Google Scholar]
  36. 36.  Li Z, Zhang W, Chen Y, Guo W, Zhang J et al. 2016. Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans. Cell Death Differ 23:1765–77
     [Google Scholar]
  37. 37.  Soares JP, Cortinhas A, Bento T, Leitao JC, Collins AR et al. 2014. Aging and DNA damage in humans: a meta-analysis study. Aging 6:432–39
     [Google Scholar]
  38. 38.  Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B 2008. Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans. Nucleic Acids Res 36:1380–89
     [Google Scholar]
  39. 39.  Moriwaki S-I, Ray S, Tarone RE, Kraemer KH, Grossman L 1996. The effect of donor age on the processing of UV-damaged DNA by cultured human cells: reduced DNA repair capacity and increased DNA mutability. Mutat. Res. 364:117–23A rare epidemiologic study suggesting that nucleotide excision repair capacity declines with human age.
     [Google Scholar]
  40. 40.  Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA 2000. Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB J 14:1325–34
     [Google Scholar]
  41. 41.  Yamada M, Udono MU, Hori M, Hirose R, Sato S et al. 2006. Aged human skin removes UVB-induced pyrimidine dimers from the epidermis more slowly than younger adult skin in vivo. Arch. Dermatol. Res. 297:294–302
     [Google Scholar]
  42. 42.  Guo Z, Heydari A, Richardson A 1998. Nucleotide excision repair of actively transcribed versus nontranscribed DNA in rat hepatocytes: effect of age and dietary restriction. Exp. Cell Res. 245:228–38
     [Google Scholar]
  43. 43.  Intano GW, Cho EJ, McMahan CA, Walter CA 2003. Age-related base excision repair activity in mouse brain and liver nuclear extracts. J. Gerontol. A 58:205–11
     [Google Scholar]
  44. 44.  Imam SZ, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA 2006. Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol. Aging 27:1129–36
     [Google Scholar]
  45. 45.  Chen D, Cao G, Hastings T, Feng Y, Pei W et al. 2002. Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria. J. Neurochem. 81:1273–84
     [Google Scholar]
  46. 46.  Donati A, Cavallini G, Bergamini E 2013. Effects of aging, antiaging calorie restriction and in vivo stimulation of autophagy on the urinary excretion of 8OHdG in male Sprague–Dawley rats. Age 35:261–70
     [Google Scholar]
  47. 47.  Atamna H, Cheung I, Ames BN 2000. A method for detecting abasic sites in living cells: age-dependent changes in base excision repair. PNAS 97:686–91
     [Google Scholar]
  48. 48.  Ren K, Pena de Ortiz S 2002. Non-homologous DNA end joining in the mature rat brain. J. Neurochem. 80:949–59
     [Google Scholar]
  49. 49.  Guedj A, Geiger-Maor A, Galun E, Benyamini H, Nevo Y et al. 2016. Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression. Aging 8:3131–46
     [Google Scholar]
  50. 50.  Vaidya A, Mao Z, Tian X, Spencer B, Seluanov A, Gorbunova V 2014. Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age. PLOS Genet 10:e1004511
     [Google Scholar]
  51. 51.  Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U 2007. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128:36–44
     [Google Scholar]
  52. 52.  Boyle J, Kill IR, Parris CN 2005. Heterogeneity of dimer excision in young and senescent human dermal fibroblasts. Aging Cell 4:247–55
     [Google Scholar]
  53. 53.  Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V 2004. DNA end joining becomes less efficient and more error-prone during cellular senescence. PNAS 101:7624–29
     [Google Scholar]
  54. 54.  Ferguson-Smith MA. 2015. History and evolution of cytogenetics. Mol. Cytogenet. 8:19
     [Google Scholar]
  55. 55.  Ramsey MJ, Moore DH 2nd, Briner JF, Lee DA, Olsen L et al. 1995. The effects of age and lifestyle factors on the accumulation of cytogenetic damage as measured by chromosome painting. Mutat. Res. 338:95–106
     [Google Scholar]
  56. 56.  Jones IM, Thomas CB, Tucker B, Thompson CL, Pleshanov P et al. 1995. Impact of age and environment on somatic mutation at the hprt gene of T lymphocytes in humans. Mutat. Res. 338:129–39
     [Google Scholar]
  57. 57.  Dempsey JL, Pfeiffer M, Morley AA 1993. Effect of dietary restriction on in vivo somatic mutation in mice. Mutat. Res. 291:141–45
     [Google Scholar]
  58. 58.  Odagiri Y, Uchida H, Hosokawa M, Takemoto K, Morley AA, Takeda T 1998. Accelerated accumulation of somatic mutations in the senescence-accelerated mouse. Nat. Genet. 19:116–17
     [Google Scholar]
  59. 59.  Dollé MET, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E et al. 2006. Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat. Res. 596:22–35
     [Google Scholar]
  60. 60.  Garcia AM, Busuttil RA, Calder RB, Dolle ME, Diaz V et al. 2008. Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. Mech. Ageing Dev. 129:528–33
     [Google Scholar]
  61. 61.  Dolle ME, Snyder WK, Dunson DB, Vijg J 2002. Mutational fingerprints of aging. Nucleic Acids Res 30:545–49A review of the mutation spectra that spontaneously arise in mouse tissues with aging.
     [Google Scholar]
  62. 62.  Butler MG, Tilburt J, DeVries A, Muralidhar B, Aue G et al. 1998. Comparison of chromosome telomere integrity in multiple tissues from subjects at different ages. Cancer Genet. Cytogenet. 105:138–44
     [Google Scholar]
  63. 63.  Coolbaugh-Murphy MI, Xu J, Ramagli LS, Brown BW, Siciliano MJ 2005. Microsatellite instability (MSI) increases with age in normal somatic cells. Mech. Ageing Dev. 126:1051–59
     [Google Scholar]
  64. 64.  De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA 2013. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging 5:867–83
     [Google Scholar]
  65. 65.  Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z et al. 2012. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44:651–58
     [Google Scholar]
  66. 66.  Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR et al. 2012. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44:642–50
     [Google Scholar]
  67. 67.  Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S et al. 2016. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538:260–64
     [Google Scholar]
  68. 68.  Behjati S, Huch M, van Boxtel R, Karthaus W, Wedge DC et al. 2014. Genome sequencing of normal cells reveals developmental lineages and mutational processes. Nature 513:422–25
     [Google Scholar]
  69. 69.  Johnson TE, Henderson S, Murakami S, de Castro E, de Castro SH et al. 2002. Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. J. Inherit. Metab. Dis. 25:197–206
     [Google Scholar]
  70. 70.  Hart RW, Setlow RB 1974. Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. PNAS 71:2169–73
     [Google Scholar]
  71. 71.  Austad SN. 2010. Methusaleh's zoo: How nature provides us with clues for extending human health span. J. Comp. Pathol. 142:Suppl. 1S10–21
     [Google Scholar]
  72. 72.  Cortopassi GA, Wang E 1996. There is substantial agreement among interspecies estimates of DNA repair activity. Mech. Ageing Dev. 91:211–18
     [Google Scholar]
  73. 73.  Chevanne M, Caldini R, Tombaccini D, Mocali A, Gori G, Paoletti F 2003. Comparative levels of DNA breaks and sensitivity to oxidative stress in aged and senescent human fibroblasts: a distinctive pattern for centenarians. Biogerontology 4:97–104
     [Google Scholar]
  74. 74.  Franzke B, Neubauer O, Wagner KH 2015. Super DNAging—new insights into DNA integrity, genome stability and telomeres in the oldest old. Mutat. Res. Rev. Mutat. Res. 766:48–57
     [Google Scholar]
  75. 75.  Cho M, Suh Y 2014. Genome maintenance and human longevity. Curr. Opin. Genet. Dev. 26:105–15
     [Google Scholar]
  76. 76.  Laven JS, Visser JA, Uitterlinden AG, Vermeij WP, Hoeijmakers JH 2016. Menopause: genome stability as new paradigm. Maturitas 92:15–23
     [Google Scholar]
  77. 77.  Keane M, Semeiks J, Webb AE, Li YI, Quesada V et al. 2015. Insights into the evolution of longevity from the bowhead whale genome. Cell Rep 10:112–22
     [Google Scholar]
  78. 78.  Matt K, Burger K, Gebhard D, Bergemann J 2016. Influence of calorie reduction on DNA repair capacity of human peripheral blood mononuclear cells. Mech. Ageing Dev. 154:24–29
     [Google Scholar]
  79. 79.  Hayflick L. 1965. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37:614–36
     [Google Scholar]
  80. 80.  Hayflick L, Moorhead PS 1961. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25:585–621
     [Google Scholar]
  81. 81.  Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW et al. 2003. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–22
     [Google Scholar]
  82. 82.  White RR, Milholland B, de Bruin A, Curran S, Laberge RM et al. 2015. Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. Nat. Commun. 6:6790
     [Google Scholar]
  83. 83.  Dorr JR, Yu Y, Milanovic M, Beuster G, Zasada C et al. 2013. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501:421–25
     [Google Scholar]
  84. 84.  Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP et al. 2008. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol 6:2853–68
     [Google Scholar]
  85. 85.  Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ et al. 2016. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–89Proof that senescent cells, arising spontaneously in mammals, cause age-related loss of tissue homeostasis.
     [Google Scholar]
  86. 86.  Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H et al. 2015. The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–58
     [Google Scholar]
  87. 87.  Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P et al. 2013. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15:978–90
     [Google Scholar]
  88. 88.  Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R et al. 2008. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–31
     [Google Scholar]
  89. 89.  Lyng FM, Seymour CB, Mothersill C 2002. Initiation of apoptosis in cells exposed to medium from the progeny of irradiated cells: a possible mechanism for bystander-induced genomic instability?. Radiat. Res. 157:365–70
     [Google Scholar]
  90. 90.  Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP et al. 2009. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11:973–79
     [Google Scholar]
  91. 91.  Rodier F, Munoz DP, Teachenor R, Chu V, Le O et al. 2011. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124:68–81
     [Google Scholar]
  92. 92.  Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J 2009. Cell surface-bound IL-1α is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. PNAS 106:17031–36
     [Google Scholar]
  93. 93.  Chien Y, Scuoppo C, Wang X, Fang X, Balgley B et al. 2011. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–36
     [Google Scholar]
  94. 94.  Gilbert LA, Hemann MT 2010. DNA damage-mediated induction of a chemoresistant niche. Cell 143:355–66
     [Google Scholar]
  95. 95.  Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H 2011. Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur. J. Neurosci. 34:3–11
     [Google Scholar]
  96. 96.  Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC et al. 2013. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–30
     [Google Scholar]
  97. 97.  Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J et al. 2008. Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–67
     [Google Scholar]
  98. 98.  Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W et al. 2014. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31:722–33
     [Google Scholar]
  99. 99.  Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T et al. 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–51
     [Google Scholar]
  100. 100.  d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P et al. 2003. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–98
     [Google Scholar]
  101. 101.  Wu CS, Ouyang J, Mori E, Nguyen HD, Marechal A et al. 2014. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes Dev 28:1472–84
     [Google Scholar]
  102. 102.  Mallette FA, Gaumont-Leclerc MF, Ferbeyre G 2007. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev 21:43–48
     [Google Scholar]
  103. 103.  Kang C, Xu Q, Martin TD, Li MZ, Demaria M et al. 2015. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349:aaa5612
     [Google Scholar]
  104. 104.  Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N et al. 2002. p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53
     [Google Scholar]
  105. 105.  Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I et al. 2007. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–79
     [Google Scholar]
  106. 106.  Brown JP, Wei W, Sedivy JM 1997. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277:831–34
     [Google Scholar]
  107. 107.  Yosef R, Pilpel N, Papismadov N, Gal H, Ovadya Y et al. 2017. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. EMBO J 36:2280–95
     [Google Scholar]
  108. 108.  Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K et al. 2004. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114:1299–307
     [Google Scholar]
  109. 109.  Stein GH, Drullinger LF, Soulard A, Dulic V 1999. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19:2109–17
     [Google Scholar]
  110. 110.  Narita M, Nunez S, Heard E, Narita M, Lin AW et al. 2003. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–16
     [Google Scholar]
  111. 111.  Burd CE, Sorrentino JA, Clark KS, Darr DB, Krishnamurthy J et al. 2013. Monitoring tumorigenesis and senescence in vivo with a p16INK4a-luciferase model. Cell 152:340–51The first demonstration that senescent cells accumulate exponentially in mice as they age.
     [Google Scholar]
  112. 112.  Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN 1999. Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab. Invest. 79:1137–43
     [Google Scholar]
  113. 113.  Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G 1997. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–46
     [Google Scholar]
  114. 114.  Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M 2004. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562–66
     [Google Scholar]
  115. 115.  Suh Y, Atzmon G, Cho MO, Hwang D, Liu B et al. 2008. Functionally significant insulin-like growth factor I receptor mutations in centenarians. PNAS 105:3438–42
     [Google Scholar]
  116. 116.  Ock S, Lee WS, Ahn J, Kim HM, Kang H et al. 2016. Deletion of IGF-1 receptors in cardiomyocytes attenuates cardiac aging in male mice. Endocrinology 157:336–45
     [Google Scholar]
  117. 117.  Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T et al. 1997. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51
     [Google Scholar]
  118. 118.  Eren M, Boe AE, Murphy SB, Place AT, Nagpal V et al. 2014. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. PNAS 111:7090–95
     [Google Scholar]
  119. 119.  Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A et al. 2005. Suppression of aging in mice by the hormone Klotho. Science 309:1829–33
     [Google Scholar]
  120. 120.  Murakami S. 2006. Stress resistance in long-lived mouse models. Exp. Gerontol. 41:1014–19
     [Google Scholar]
  121. 121.  Osorio FG, Barcena C, Soria-Valles C, Ramsay AJ, de Carlos F et al. 2012. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response. Genes Dev 26:2311–24
     [Google Scholar]
  122. 122.  Sabatel H, Di Valentin E, Gloire G, Dequiedt F, Piette J, Habraken Y 2012. Phosphorylation of p65(RelA) on Ser547 by ATM represses NF-κB-dependent transcription of specific genes after genotoxic stress. PLOS ONE 7:e38246
     [Google Scholar]
  123. 123.  Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY 2007. Motif module map reveals enforcement of aging by continual NF-κB activity. Genes Dev 21:3244–57
     [Google Scholar]
  124. 124.  Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL et al. 2012. NF-κB inhibition delays DNA damage-induced senescence and aging in mice. J. Clin. Invest. 122:2601–12
     [Google Scholar]
  125. 125.  Salminen A, Kauppinen A, Kaarniranta K 2012. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell. Signal 24:835–45
     [Google Scholar]
  126. 126.  Kaeberlein M, McVey M, Guarente L 1999. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–80
     [Google Scholar]
  127. 127.  Lin SJ, Defossez PA, Guarente L 2000. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289:2126–28
     [Google Scholar]
  128. 128.  Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B et al. 2010. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat. Commun. 1:3
     [Google Scholar]
  129. 129.  Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G et al. 2012. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:218–21
     [Google Scholar]
  130. 130.  Rose G, Dato S, Altomare K, Bellizzi D, Garasto S et al. 2003. Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp. Gerontol. 38:1065–70
     [Google Scholar]
  131. 131.  Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA et al. 2001. hSIR2SIRT1 functions as an NAD-dependent p53 deacetylase. Cell 107:149–59
     [Google Scholar]
  132. 132.  Langley E, Pearson M, Faretta M, Bauer UM, Frye RA et al. 2002. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21:2383–96
     [Google Scholar]
  133. 133.  Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL 2007. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447:725–29A clear demonstration that time-dependent accrual of endogenous DNA damage affects stem cell function.
     [Google Scholar]
  134. 134.  Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T et al. 2007. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447:686–90
     [Google Scholar]
  135. 135.  Cho JS, Kook SH, Robinson AR, Niedernhofer LJ, Lee BC 2013. Cell autonomous and nonautonomous mechanisms drive hematopoietic stem/progenitor cell loss in the absence of DNA repair. Stem Cells 31:511–25
     [Google Scholar]
  136. 136.  Reese JS, Liu L, Gerson SL 2003. Repopulating defect of mismatch repair-deficient hematopoietic stem cells. Blood 102:1626–33
     [Google Scholar]
  137. 137.  Chen Q, Liu K, Robinson AR, Clauson CL, Blair HC et al. 2013. DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism. J. Bone Miner. Res. 28:1214–28
     [Google Scholar]
  138. 138.  Lavasani M, Robinson AR, Lu A, Song M, Feduska JM et al. 2012. Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat. Commun. 3:608
     [Google Scholar]
  139. 139.  Ciaffardini F, Nicolai S, Caputo M, Canu G, Paccosi E et al. 2014. The Cockayne syndrome B protein is essential for neuronal differentiation and neuritogenesis. Cell. Death. Dis. 5:e1268
     [Google Scholar]
  140. 140.  Kim J, Wong PK 2009. Loss of ATM impairs proliferation of neural stem cells through oxidative stress-mediated p38 MAPK signaling. Stem Cells 27:1987–98
     [Google Scholar]
  141. 141.  Scheibye-Knudsen M, Ramamoorthy M, Sykora P, Maynard S, Lin PC et al. 2012. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J. Exp. Med. 209:855–69
     [Google Scholar]
  142. 142.  Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M et al. 2012. Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119:1490–500
     [Google Scholar]
  143. 143.  Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T et al. 2014. Defective mitophagy in XPA via PARP-1 hyperactivation and NAD+/SIRT1 reduction. Cell 157:882–96
     [Google Scholar]
  144. 144.  Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K et al. 2016. NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24:566–81
     [Google Scholar]
  145. 145.  Feng Z, Zhang H, Levine AJ, Jin S 2005. The coordinate regulation of the p53 and mTOR pathways in cells. PNAS 102:8204–9
     [Google Scholar]
  146. 146.  Hoshino A, Mita Y, Okawa Y, Ariyoshi M, Iwai-Kanai E et al. 2013. Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat. Commun. 4:2308
     [Google Scholar]
  147. 147.  Park C, Suh Y, Cuervo AM 2015. Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nat. Commun. 6:6823
     [Google Scholar]
  148. 148.  Illuzzi J, Yerkes S, Parekh-Olmedo H, Kmiec EB 2009. DNA breakage and induction of DNA damage response proteins precede the appearance of visible mutant huntingtin aggregates. J. Neurosci. Res. 87:733–47
     [Google Scholar]
  149. 149.  Kim D, Frank CL, Dobbin MM, Tsunemoto RK, Tu W et al. 2008. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60:803–17
     [Google Scholar]
  150. 150.  Cardinale A, Racaniello M, Saladini S, De Chiara G Mollinari C et al. 2012. Sublethal doses of β-amyloid peptide abrogate DNA-dependent protein kinase activity. J. Biol. Chem. 287:2618–31
     [Google Scholar]
  151. 151.  Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM et al. 2014. Geroscience: linking aging to chronic disease. Cell 159:709–13
     [Google Scholar]
  152. 152.  Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV et al. 2016. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet. Med. 18:483–93
     [Google Scholar]
  153. 153.  de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB et al. 2002. Premature aging in mice deficient in DNA repair and transcription. Science 296:1276–79
     [Google Scholar]
  154. 154.  Faghri S, Tamura D, Kraemer KH, Digiovanna JJ 2008. Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J. Med. Genet. 45:609–21
     [Google Scholar]
  155. 155.  Kudlow BA, Kennedy BK, Monnat RJ Jr 2007. Werner and Hutchinson-Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nat. Rev. Mol. Cell Biol. 8:394–404
     [Google Scholar]
  156. 156.  Ahmed MS, Ikram S, Bibi N, Mir A 2017. Hutchinson-Gilford Progeria Syndrome: a premature aging disease. Mol. Neurobiol. 55:54417–27
     [Google Scholar]
  157. 157.  Liu B, Wang J, Chan KM, Tjia WM, Deng W et al. 2005. Genomic instability in laminopathy-based premature aging. Nat. Med. 11:780–85
     [Google Scholar]
  158. 158.  Ceccaldi R, Sarangi P, D'Andrea AD 2016. The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol. 17:337–49
     [Google Scholar]
  159. 159.  Ying S, Hickson ID 2011. Fanconi anaemia proteins are associated with sister chromatid bridging in mitosis. Int. J. Hematol. 93:440–45
     [Google Scholar]
  160. 160.  Carfi A, Antocicco M, Brandi V, Cipriani C, Fiore F et al. 2014. Characteristics of adults with Down syndrome: prevalence of age-related conditions. Front. Med. 1:51
     [Google Scholar]
  161. 161.  Necchi D, Pinto A, Tillhon M, Dutto I, Serafini MM et al. 2015. Defective DNA repair and increased chromatin binding of DNA repair factors in Down syndrome fibroblasts. Mutat. Res. 780:15–23
     [Google Scholar]
  162. 162.  Patterson D, Cabelof DC 2012. Down syndrome as a model of DNA polymerase beta haploinsufficiency and accelerated aging. Mech. Ageing Dev. 133:133–37
     [Google Scholar]
  163. 163.  Tiano L, Littarru GP, Principi F, Orlandi M, Santoro L et al. 2005. Assessment of DNA damage in Down syndrome patients by means of a new, optimised single cell gel electrophoresis technique. BioFactors 25:187–95
     [Google Scholar]
  164. 164.  Cabanillas R, Cadinanos J, Villameytide JA, Perez M, Longo J et al. 2011. Nestor-Guillermo Progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am. J. Med. Genet. A 155:2617–25
     [Google Scholar]
  165. 165.  Loi M, Cenni V, Duchi S, Squarzoni S, Lopez-Otin C et al. 2016. Barrier-to-autointegration factor (BAF) involvement in prelamin A–related chromatin organization changes. Oncotarget 7:15662–77
     [Google Scholar]
  166. 166.  Hanada K, Hickson ID 2007. Molecular genetics of RecQ helicase disorders. Cell Mol. Life Sci. 64:2306–22
     [Google Scholar]
  167. 167.  Nguyen GH, Tang W, Robles AI, Beyer RP, Gray LT et al. 2014. Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs. PNAS 111:9905–10
     [Google Scholar]
  168. 168.  Croteau DL, Singh DK, Hoh Ferrarelli L, Lu H, Bohr VA 2012. RECQL4 in genomic instability and aging. Trends Genet 28:624–31
     [Google Scholar]
  169. 169.  Ghosh AK, Rossi ML, Singh DK, Dunn C, Ramamoorthy M et al. 2012. RECQL4, the protein mutated in Rothmund-Thomson syndrome, functions in telomere maintenance. J. Biol. Chem. 287:196–209
     [Google Scholar]
  170. 170.  Weedon MN, Ellard S, Prindle MJ, Caswell R, Lango Allen H et al. 2013. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat. Genet. 45:947–50
     [Google Scholar]
  171. 171.  Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I et al. 2014. Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat. Genet. 46:1239–44
     [Google Scholar]
  172. 172.  Stingele J, Habermann B, Jentsch S 2015. DNA-protein crosslink repair: proteases as DNA repair enzymes. Trends Biochem. Sci. 40:67–71
     [Google Scholar]
/content/journals/10.1146/annurev-biochem-062917-012239
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Nuclear Genomic Instability and Aging
Annual Review of Biochemistry 87, 295 (2018); https://doi.org/10.1146/annurev-biochem-062917-012239
/content/journals/10.1146/annurev-biochem-062917-012239
/content/journals/10.1146/annurev-biochem-062917-012239
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