Cancer Res Treat.  2009 Dec;41(4):187-195.

Significance of Cellular Senescence in Aging and Cancer

• Grimes A
• Chandra SB

Abstract

Cellular senescence is a mechanism that induces an irreversible growth arrest in all somatic cells. Senescent cells are metabolically active but lack the capacity to replicate. Evolutionary theories suggest that cellular senescence is related to the organismal decline occurring in aging organisms. Also, such theories describe senescence as an antagonistically pleiotropic process that can have beneficial or detrimental effect on the organism. Cellular senescence is believed to be involved in the cellular changes observed as aging progresses. Accumulation of senescent cells appears to occur widely as the organism ages. Furthermore, senescence is a key element of the tumor suppressor pathways. Therefore, it is part of the natural barrier against the uncontrolled proliferation observed in cellular development of malignancies in multicellular organisms. Activation of the senescence process guarantees a limited number of cellular replications. The genetic network led by p53 is responsible for activation of senescence in response to DNA damage and genomic instability that could lead to cancer. A better comprehension of the genetic networks that control the cell cycle and induce senescence is important to analyze the association of senescence to longevity and diseases related to aging. For these reasons, experimental research both in vitro and in vivo aims to develop anticancer therapies based on senescence activation. The last decade of research on role and function of senescence in aging and cancer are discussed in this paper.

Keyword

Aging; Neoplasms; Pleiotropy; Telomere; Genetic pathways

MeSH Terms

Aging
Cell Aging
Cell Cycle
Comprehension
DNA Damage
Genomic Instability
Longevity
Telomere

Reference

1. Smith JR, Pereira-Smith OM. Replicative senescence: implications for in vivo aging and tumor suppression. Science. 1996; 273:63–67. PMID: 8658197.

2. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A. 2001; 98:12072–12077. PMID: 11593017.

3. Cotter MA, Florell SR, Leachman SA, Grossman D. Absence of senescence-associated β,-galactosidase activity in human melanocytic nevi in vivo. J Invest Dermatol. 2007; 127:2469–2471. PMID: 17522702.

4. Ben-Porath I, Weinberg RA. When cells get stressed: an integrative view of cellular senescence. J Clin Invest. 2004; 113:8–13. PMID: 14702100.

5. de Magalhaes JP. From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. Exp Cell Res. 2004; 300:1–10. PMID: 15383309.

6. Sandhu AK, Hubbard K, Kaur OP, Jha KK, Ozer HL, Athwal RS. Senescence of immortal human fibroblasts by the introduction of normal human chromosome 6. Proc Natl Acad Sci U S A. 1994; 91:5498–5502. PMID: 8202516.

7. Itahana K, Campisi J, Dimri GP. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004; 5:1–10. PMID: 15138376.

8. Mooi WJ, Peeper DS. Oncogene-induced cell senescence-halting on the road to cancer. N Engl J Med. 2006; 355:1037–1046. PMID: 16957149.

9. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005; 436:660–665. PMID: 16079837.

10. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005; 436:720–724. PMID: 16079850.

11. Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 2007; 35:7417–7428. PMID: 17913751.

12. Berube NG, Smith JR, Pereira-Smith OM. The genetics of cellular senescence. Am J Hum Genet. 1998; 62:1015–1019. PMID: 9545418.

13. Sitte N, Merker K, von Zglinicki T, Grune T, Davies KJ. Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part I--effects of proliferative senescence. FASEB J. 2000; 14:2495–2502. PMID: 11099467.

14. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001; 11:S27–S31. PMID: 11684439.

15. Spencer CC, Howell CE, Wright AR, Promislow DE. Testing an 'aging gene' in long-lived drosophila strains: increased longevity depends on sex and genetic Background. Aging Cell. 2003; 2:123–130. PMID: 12882325.

16. Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer. 2003; 3:339–349. PMID: 12724732.

17. Hardy K, Mansfield L, Mackay A, Benvenuti S, Ismail S, Arora P, et al. Transcriptional networks and cellular senescence in human mammary fibroblasts. Mol Biol Cell. 2005; 16:943–953. PMID: 15574883.

18. Wright WE, Shay JW. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet Dev. 2001; 11:98–103. PMID: 11163158.

19. Patil CK, Mian IS, Campisi J. The thorny path linking cellular senescence to organismal aging. Mech Ageing Dev. 2005; 126:1040–1045. PMID: 16153470.

20. Martinez DE. Mortality patterns suggest lack of senescence in hydra. Exp Gerontol. 1998; 33:217–225. PMID: 9615920.

21. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120:513–522. PMID: 15734683.

22. Narita M. Cellular senescence and chromatin organization. Br J Cancer. 2007; 96:686–691. PMID: 17311013.

23. Parrinello S, Coppe JP, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci. 2005; 118:485–496. PMID: 15657080.

24. Itahana K, Dimri G, Campisi J. Regulation of cellular senescence by p53. Eur J Biochem. 2001; 268:2784–2791. PMID: 11358493.

25. Jackson JG, Pereira-Smith OM. p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res. 2006; 66:8356–8360. PMID: 16951143.

26. Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. DNA end joining becomes less efficient and more error-prone during cellular senescence. Proc Natl Acad Sci U S A. 2004; 101:7624–7629. PMID: 15123826.

27. Sedelnikova OA, Horikawa I, Zimonjic DB, Popescu NC, Bonner WM, Barrett JC. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol. 2004; 6:168–170. PMID: 14755273.

28. Shay JW, Roninson IB. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene. 2004; 23:2919–2933. PMID: 15077154.

29. Vieira C, Pasyukova EG, Zeng ZB, Hackett JB, Lyman RF, Mackay TF. Genotype-environment interaction for quantitative trait loci affecting life span in Drosophila melanogaster. Genetics. 2000; 154:213–227. PMID: 10628982.

30. Hughes KA, Alipaz JA, Drnevich JM, Reynolds RM. A test of evolutionary theories of aging. Proc Natl Acad Sci U S A. 2002; 99:14286–14291. PMID: 12386342.

31. Hendry AP, Morbey YE, Berg OK, Wenburg JK. Adaptive variation in senescence: reproductive lifespan in a wild salmon population. Proc Biol Sci. 2004; 271:259–266. PMID: 15058436.

32. Leroi AM, Bartke A, De Benedictis G, Franceschi C, Gartner A, Gonos ES, et al. What evidence is there for the existence of individual genes with antagonistic pleiotropic effects? Mech Ageing Dev. 2005; 126:421–429. PMID: 15664630.

33. Charmantier A, Perrins C, McCleery RH, Sheldon BC. Age-dependent genetic variance in a life-history trait in the mute swan. Proc Biol Sci. 2006; 273:225–232. PMID: 16555791.

34. Silbermann R, Tatar M. Reproductive costs of heat shock protein in transgenic Drosophila melanogaster. Evolution. 2000; 54:2038–2045. PMID: 11209780.

35. Nuzhdin SV, Pasyukova EG, Dilda C, Zeng ZB, Mackay TF. Sex-specific quantitative trait loci affecting longevity in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1997; 94:9734–9739. PMID: 9275193.

36. Charlesworth B, Hughes KA. Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence. Proc Natl Acad Sci U S A. 1996; 93:6140–6145. PMID: 8650233.

37. Swindell WR, Bouzat JL. Inbreeding depression and male survivorship in Drosophila: Implications for senescence theory. Genetics. 2006; 172:317–327. PMID: 16204222.

38. Borash DJ, Rose MR, Mueller LD. Mutation accumulation affects male virility in Drosophila selected for later reproduction. Physiol Biochem Zool. 2007; 80:461–472. PMID: 17717809.

39. Nussey DH, Kruuk LE, Donald A, Fowlie M, Clutton-Brock TH. The rate of senescence in maternal performance increases with early-life fecundity in red deer. Ecol Lett. 2006; 9:1342–1350. PMID: 17118008.

40. Moorad JA, Promislow DE. A theory of age-dependent mutation and senescence. Genetics. 2008; 179:2061–2073. PMID: 18660535.

41. Lendvay TS, Morris DK, Sah J, Balasubramanian B, Lundblad V. Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics. 1996; 144:1399–1412. PMID: 8978029.

42. Rheinwald JG, Hahn WC, Ramsey MR, Wu JY, Guo Z, Tsao H, et al. A two-stage, p16 (INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status. Mol Cell Biol. 2002; 22:5157–5172. PMID: 12077343.

43. Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998; 58:4168–4172. PMID: 9751630.

44. Ning Y, Xu JF, Li Y, Chavez L, Riethman HC, Lansdorp PM, et al. Telomere length and the expression of natural telomeric genes in human fibroblasts. Hum Mol Genet. 2003; 12:1329–1336. PMID: 12761048.

45. Gorbunova V, Seluanov A, Pereira-Smith OM. Expression of human telomerase (hTERT) does not prevent stress-induced senescence in normal human fibroblasts but protects the cells from stress-induced apoptosis and necrosis. J Biol Chem. 2002; 277:38540–38549. PMID: 12140282.

46. Ohmura H, Tahara H, Suzuki M, Ide T, Shimizu M, Yoshida MA, et al. Restoration of the cellular senescence program and repression of telomerase by human chromosome 3. Jpn J Cancer Res. 1995; 86:899–904. PMID: 7493906.

47. Cosme-Blanco W, Shen MF, Lazar AJ, Pathak S, Lozano G, Multani AS, et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 2007; 8:497–503. PMID: 17396137.

48. Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science. 2002; 295:2446–2449. PMID: 11923537.

49. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426:194–198. PMID: 14608368.

50. Goytisolo FA, Blasco MA. Many ways to telomere dysfunction: in vivo studies using mouse models. Oncogene. 2002; 21:584–591. PMID: 11850783.

51. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet. 2007; 39:99–105. PMID: 17143283.

52. Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001; 107:67–77. PMID: 11595186.

53. Wei S, Sedivy JM. Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts. Cancer Res. 1999; 59:1539–1543. PMID: 10197626.

54. Farwell DG, Shera KA, Koop JI, Bonnet GA, Matthews CP, Reuther GW, et al. Genetic and epigenetic changes in human epithelial cells immortalized by telomerase. Am J Pathol. 2000; 156:1537–1547. PMID: 10793065.

55. Li S, Rosenberg JE, Donjacour AA, Botchkina IL, Hom YK, Cunha GR, et al. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutanttemplate telomerase RNA and anti-telomerase short-interfering RNA. Cancer Res. 2004; 64:4833–4840. PMID: 15256453.

56. Dickson MA, Hahn WC, Ino Y, Ronfard V, Wu JY, Weinberg RA, et al. Human keratinocytes that express hTERT and also bypass a p16 (INK4a)-enforced mechanism that limits life span become immortal yet retain normal growth and differentiation characteristics. Mol Cell Biol. 2000; 20:1436–1447. PMID: 10648628.

57. Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell. 2007; 11:461–469. PMID: 17433785.

58. Deng Q, Liao R, Wu BL, Sun P. High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J Biol Chem. 2004; 279:1050–1059. PMID: 14593117.

59. Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007; 27:2343–2358. PMID: 17242207.

60. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113:703–716. PMID: 12809602.

61. Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 2007; 5:e110. PMID: 17472436.

62. Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci U S A. 2005; 102:17993–17998. PMID: 16332961.

63. de Haan JB, Cristiano F, Iannello RC, Bladier C, Kelner MJ, Kola I. Elevation in the ratio of Cu/Zn-superoxide dismutase to glutathione peroxidase activity induces features of cellular senescence and this effect is mediated by hydrogen peroxide. Hum Mol Genet. 1996; 5:283–292. PMID: 8824885.

64. Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem. 1999; 274:7936–7940. PMID: 10075689.

65. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88:593–602. PMID: 9054499.

66. Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998; 12:3008–3019. PMID: 9765203.

67. Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature. 2000; 406:207–210. PMID: 10910364.

68. Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444:638–642. PMID: 17136094.

69. Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol. 2007; 9:493–505. PMID: 17450133.

70. Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998; 12:2997–3007. PMID: 9765202.

71. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92:9363–9367. PMID: 7568133.

72. Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006; 444:633–637. PMID: 17136093.

73. Sherr CJ. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 1998; 12:2984–2991. PMID: 9765200.

74. Lavin MF, Gueven N. The complexity of p53 stabilization and activation. Cell Death Differ. 2006; 13:941–950. PMID: 16601750.

75. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445:656–660. PMID: 17251933.

76. Marusyk A, Wheeler LJ, Mathews CK, Degregori J. p53 mediates senescence-like arrest induced by chronic replicational stress. Mol Cell Biol. 2007; 27:5336–5351. PMID: 17515610.

77. Feng L, Hollstein M, Xu Y. Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence. Cell Cycle. 2006; 5:2812–2819. PMID: 17172844.

78. Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, et al. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002; 22:3497–3508. PMID: 11971980.

79. Sionov RV, Haupt Y. The cellular response to p53: the decision between life and death. Oncogene. 1999; 8:6145–6157. PMID: 10557106.

80. He X, He L, Hannon GJ. The guardian's little helper: microRNAs in the p53 tumor suppressor network. Cancer Res. 2007; 67:11099–11101. PMID: 18056431.

81. Bandyopadhyay D, Curry JL, Lin Q, Richards HW, Chen D, Hornsby PJ, et al. Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi. Aging Cell. 2007; 6:577–591. PMID: 17578512.

82. Lal A, Kim HH, Abdelmohsen K, Kuwano Y, Pullmann R Jr, Srikantan S, et al. p16(INK4a) translation suppressed by miR-24. PLoS One. 2008; 3:e1864. PMID: 18365017.

83. Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 2003; 22:4212–4222. PMID: 12912919.

84. Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ, Tainsky MA. Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene. 2003; 22:4118–4127. PMID: 12821946.

85. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol. 1996; 16:859–867. PMID: 8622687.

86. Crescenzi E, Palumbo G, Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J. 2003; 375:263–274. PMID: 12871207.

87. Lopez-Diazguerrero NE, Lopez-Araiza H, Conde-Perezprina JC, Bucio L, Cardenas-Aguayo MC, Ventura JL, et al. Bcl-2 protects against oxidative stress while inducing premature senescence. Free Radic Biol Med. 2006; 40:1161–1169. PMID: 16545683.

88. Keyes WM, Mills AA. p63: a new link between senescence and aging. Cell Cycle. 2006; 5:260–265. PMID: 16434880.

89. Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV, et al. Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A. 2000; 97:4291–4296. PMID: 10760295.

90. Mallette FA, Goumard S, Gaumont-Leclerc MF, Moiseeva O, Ferbeyre G. Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene. 2004; 23:91–99. PMID: 14712214.

91. Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, et al. "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 2002; 21:6225–6235. PMID: 12426394.

92. Matheu A, Pantoja C, Efeyan A, Criado LM, Martin-Caballero J, Flores JM, et al. Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev. 2004; 18:2736–2746. PMID: 15520276.

93. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell. 2002; 109:335–346. PMID: 12015983.

94. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002; 62:1876–1883. PMID: 11912168.

95. Kahlem P, Dorken B, Schmitt CA. Cellular senescence in cancer treatment: friend or foe? J Clin Invest. 2004; 113:169–174. PMID: 14722606.

96. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, et al. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445:661–665. PMID: 17251932.

97. Joerger AC, Fersht AR. Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene. 2007; 26:2226–2242. PMID: 17401432.