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Cancer and ageing: rival demons?

Key Points

  • Cancer is a problem that affects organisms with renewable tissues; these have evolved tumour-suppressor mechanisms to suppress the development of cancer.

  • Tumour-suppressor genes act to prevent or repair genomic damage (caretakers), or inhibit the propagation of potential cancer cells (gatekeepers) by permanently arresting their growth (cellular senescence) or inducing cell death (apoptosis).

  • Some caretaker tumour suppressors seem to postpone the development of ageing phenotypes, and so are also longevity-assurance genes.

  • The gatekeeper tumour-suppressor mechanisms (apoptosis and cellular senescence), by contrast, might promote certain ageing phenotypes.

  • Apoptosis and cellular senescence are controlled by the p53 and RB tumour-suppressor pathways, components of which are evolutionarily conserved among multicellular organisms.

  • The evolutionary hypothesis of antagonistic pleiotropy predicts that some processes that benefit young organisms (by suppressing cancer, for example) can have detrimental effects later in life and would therefore contribute to ageing.

  • Both apoptosis and cellular senescence might be antagonistically pleiotropic, promoting ageing by exhausting progenitor or stem cells. Additionally, senescent cells secrete factors that can disrupt tissue integrity and function, and even promote the progression of late-life cancers.

  • Recent studies on p53 provide a molecular basis for how tumour suppression and ageing might be intertwined.

Abstract

Organisms with renewable tissues use a network of genetic pathways and cellular responses to prevent cancer. The main mammalian tumour-suppressor pathways evolved from ancient mechanisms that, in simple post-mitotic organisms, act predominantly to regulate embryogenesis or to protect the germline. The shift from developmental and/or germline maintenance in simple organisms to somatic maintenance in complex organisms might have evolved at a cost. Recent evidence indicates that some mammalian tumour-suppressor mechanisms contribute to ageing. How might this have happened, and what are its implications for our ability to control cancer and ageing?

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Figure 1: Cancer increases with ageing.
Figure 2: Tumour-suppressor mechanisms.
Figure 3: Evolution of ageing.
Figure 4: Effects of apoptosis and cellular senescence on stem cells and organismal fitness with age.
Figure 5: Model for how senescent cells might promote cancer.

References

  1. 1

    Miller, R. A. Gerontology as oncology: research on aging as a key to the understanding of cancer. Cancer 68, 2496–2501 (1991).

    CAS  PubMed  Google Scholar 

  2. 2

    DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).

    CAS  Google Scholar 

  3. 3

    Balducci, L. & Beghe, C. Cancer and age in the USA. Crit. Rev. Oncol. Hematol. 37, 137–145 (2001).

    CAS  PubMed  Google Scholar 

  4. 4

    Kinzler, K. W. & Vogelstein, B. Cancer susceptibility genes: gatekeepers and caretakers. Nature 386, 761–763 (1997).

    CAS  PubMed  Google Scholar 

  5. 5

    Barzilai, N. & Shuldiner, A. R. Searching for human longevity genes: the future history of gerontology in the post-genomic era. J Gerontol A Biol Sci Med Sci 56, M83–M87 (2001).

    CAS  PubMed  Google Scholar 

  6. 6

    Bookstein, R. & Lee, W. H. Molecular genetics of the retinoblastoma tumor suppressor gene. Crit Rev Oncog 2, 211–227 (1991).

    CAS  PubMed  Google Scholar 

  7. 7

    Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutation in human cancer. Science 253, 49–53 (1991).

    CAS  Google Scholar 

  8. 8

    Bishop, J. M. Cancer: the rise of the genetic paradigm. Genes Dev. 9, 1309–1315 (1995).

    CAS  PubMed  Google Scholar 

  9. 9

    Wu, X. & Pandolfi, P. Mouse models for multistep tumorigenesis. Trends Cell Biol. 11, S2–S9 (2001).

    CAS  Google Scholar 

  10. 10

    Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  Google Scholar 

  11. 11

    Compagni, A. & Christofori, G. Recent advances in research on multistage tumorigenesis. Br. J. Cancer. 83, 1–5 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Macleod, K. Tumor suppressor genes. Curr. Opin. Genet. Dev. 10, 81–93 (2000).

    CAS  PubMed  Google Scholar 

  13. 13

    Weinberg, R. A. How cancer arises. Sci. Am. 275, 62–70 (1996).

    CAS  PubMed  Google Scholar 

  14. 14

    Ghebranious, N. & Donehower, L. A. Mouse models in tumor suppression. Oncogene 17, 3385–3400 (1998).

    PubMed  Google Scholar 

  15. 15

    Knudson, A. G. Chasing the cancer demon. Annu. Rev. Genet. 34, 1–19 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Hakem, R. & Mak, T. W. Animal models of tumor-suppressor genes. Annu. Rev. Genet. 35, 209–241 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).

    CAS  PubMed  Google Scholar 

  18. 18

    Vijg, J. & Dolle, M. E. Large genome rearrangements as a primary cause of aging. Mech. Ageing Dev. 123, 907–915 (2002).

    CAS  PubMed  Google Scholar 

  19. 19

    Rose, M. R. The Evolutionary Biology of Aging (Oxford Univ. Press, Oxford, 1991).

    Google Scholar 

  20. 20

    Kirkwood, T. B. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Umezu, K., Nakayama, K. & Nakayama, H. Escherichia coli RecQ protein is a DNA helicase. Proc. Natl Acad. Sci. USA 87, 5363–5367 (1990).

    CAS  PubMed  Google Scholar 

  22. 22

    Gangloff, S., McDonald, J. P., Bendixen, C., Arthur, L. & Rothstein, R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Mol. Cell. Biol. 14, 8391–8398 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Stewart, E., Chapman, C. R., Al-Khodairy, F., Carr, A. M. & Enoch, T. Rqh1+, a fission yeast gene related to the Bloom's and Werner's syndrome genes, is required for reversible S phase arrest. EMBO J. 16, 2682–2692 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Frei, C. & Gasser, S. M. RecQ-like helicases: the DNA replication checkpoint connection. J. Cell Sci. 113, 2641–2646 (2000).

    CAS  PubMed  Google Scholar 

  25. 25

    van Brabant, A. J., Stan, R. & Ellis, N. A. DNA helicases, genomic instability, and human genetic disease. Annu Rev Genomics Hum Genet 1, 409–459 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Chakraverty, R. K. & Hickson, I. D. Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. Bioessays 21, 286–294 (1999).

    CAS  PubMed  Google Scholar 

  27. 27

    Goto, M. Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing. Mech. Ageing Dev. 98, 239–254 (1997).

    CAS  PubMed  Google Scholar 

  28. 28

    Martin, G. M., Oshima, J., Gray, M. D. & Poot, M. What geriatricians should know about the Werner Syndrome. J. Am. Geriatr. Soc. 47, 1136–1144 (1999).

    CAS  PubMed  Google Scholar 

  29. 29

    Ellis, N. A. & German, J. Molecular genetics of Bloom's syndrome. Hum. Mol. Genet. 5, 1457–1463 (1996).

    CAS  PubMed  Google Scholar 

  30. 30

    Vennos, E. M. & James, W. D. Rothmund-Thomson syndrome. Dermatol. Clin. 13, 143–150 (1995).

    CAS  PubMed  Google Scholar 

  31. 31

    Mohaghegh, P. & Hickson, I. D. DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Mol. Genet. 10, 741–746 (2001).

    CAS  PubMed  Google Scholar 

  32. 32

    German, J. Bloom's syndrome. Dermatol. Clin. 13, 7–18 (1995).

    CAS  PubMed  Google Scholar 

  33. 33

    Oshima, J. The Werner syndrome protein: an update. Bioessays 22, 894–901 (2000).

    CAS  PubMed  Google Scholar 

  34. 34

    Hickson, I. D. RecQ helicases: caretakers of the genome. Nature Rev. Cancer 3, 169–178 (2003).

    CAS  Google Scholar 

  35. 35

    Chen, L. & Oshima, J. Werner Syndrome. J. Biomed. Biotechnol. 2, 46–54 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Fukuchi, K., Martin, G. M. & Monnat, R. J. Mutator phenotype of Werner syndrome is characterized by extensive deletions. Proc. Natl Acad. Sci. USA 86, 5893–5897 (1989).

    CAS  PubMed  Google Scholar 

  37. 37

    Lebel, M. Increased frequency of DNA deletions in pink-eyed unstable mice carrying a mutation in the Werner syndrome gene homologue. Carcinogenesis 23, 213–216 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Oshima, J., Huang, S., Pae, C., Campisi, J. & Schiestl, R. H. Lack of WRN results in extensive deletion at nonhomologous joining ends. Cancer Res. 62, 547–551 (2002).

    CAS  PubMed  Google Scholar 

  39. 39

    Prince, P. R., Emond, M. J. & Monnat, R. J. Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev. 15, 933–938 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Martin, G. M. Somatic mutagenesis and antimutagenesis in aging research. Mutat. Res. 350, 35–41 (1996).

    PubMed  Google Scholar 

  41. 41

    Modrich, P. Mismatch repair, genetic stability, and cancer. Science 266, 1959–1960 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    de Boer, J. & Hoeijmakers, J. Cancer from the outside, aging from the inside: mouse models to study the consequences of defective nucleotide excision repair. Biochimie 81, 127–137 (1999).

    CAS  PubMed  Google Scholar 

  43. 43

    Lieber, M. R. Pathological and physiological double-strand breaks: roles in cancer, aging, and the immune system. Am. J. Pathol. 153, 1323–1332 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Modesti, M. & Kanaar, R. Homologous recombination: from model organisms to human disease. Genome Biol. 2, 1014 (2001).

    Google Scholar 

  45. 45

    Eisen, J. A. & Hanawalt, P. C. A phylogenomic study of DNA repair genes, proteins, and processes. Mutat. Res. 435, 171–213 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Burkle, A. Physiology and pathophysiology of poly(ADP-ribosyl)ation. Bioessays 23, 795–806 (2001).

    CAS  PubMed  Google Scholar 

  47. 47

    Friedberg, E. C. How nucleotide excision repair protects against cancer. Nature Rev. Cancer 1, 22–33 (2001).

    CAS  Google Scholar 

  48. 48

    Pierce, A. et al. Double-strand breaks and tumorigenesis. Trends Cell Biol. 11, S52–S59 (2001).

    CAS  PubMed  Google Scholar 

  49. 49

    Vogel, H., Lim, D. S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999). Describes the premature ageing phenotypes of mice that are deficient in a protein required for repairing double-strand breaks in DNA.

    CAS  PubMed  Google Scholar 

  50. 50

    Berneburg, M. & Lehmann, A. R. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv. Genet. 43, 71–102 (2001).

    CAS  PubMed  Google Scholar 

  51. 51

    de Boer, J. et al. Premature aging in mice deficient in DNA repair and transcription. Science 296, 1276–1279 (2002). This paper describes the premature ageing phenotypes of mice deficient in a protein required for reparing damaged nucleotides in DNA.

    CAS  PubMed  Google Scholar 

  52. 52

    Thompson, L. H. & Schild, D. Recombinational DNA repair and human disease. Mutat. Res. 509, 49–78 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Cao, L., Li, W., Kim, S., Brodie, S. G. & Deng, C. X. Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev. 17, 201–213 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Arends, M. J. & Wyllie, A. H. Apoptosis: mechanisms and roles in pathology. Int. Rev. Exp. Pathol. 32, 223–254 (1991).

    CAS  PubMed  Google Scholar 

  55. 55

    Ellis, R. E., Yuan, J. Y. & Horvitz, H. R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698 (1991).

    CAS  PubMed  Google Scholar 

  56. 56

    Vaux, D. L. & Korsmeyer, S. J. Cell death in development. Cell 96, 245–254 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Sinha Hakim, A. P. & Swerdloff, R. S. Hormonal and genetic control of germ cell apoptosis in the testis. Rev. Reprod. 4, 38–47 (1999).

    Google Scholar 

  58. 58

    Laun, P. et al. Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis. Mol. Microbiol. 39, 1166–1173 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Reed, J. C. Mechanisms of apoptosis in avoidance of cancer. Curr. Opin. Oncol. 11, 68–75 (1999).

    CAS  PubMed  Google Scholar 

  60. 60

    Green, D. R. & Evan, G. I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

    CAS  Google Scholar 

  61. 61

    Campisi, J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 11, S27–S31 (2001).

    CAS  PubMed  Google Scholar 

  62. 62

    Kim, S. H., Kaminker, P. & Campisi, J. Telomeres, aging and cancer: in search of a happy ending. Oncogene 21, 503–511 (2002).

    CAS  Google Scholar 

  63. 63

    Chiu, C. P. & Harley, C. B. Replicative senescence and cell immortality: the role of telomeres and telomerase. Proc. Soc. Exp. Biol. Med. 214, 99–106 (1997).

    CAS  PubMed  Google Scholar 

  64. 64

    Campisi, J. Cancer, aging and cellular senescence. In Vivo 14, 183–188 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001).

    CAS  PubMed  Google Scholar 

  66. 66

    Campisi, J., Dimri, G. P. & Hara, E. in Handbook of the Biology of Aging (eds Schneider, E. & Rowe, J.) 121–149 (Academic Press, New York, 1996).

    Google Scholar 

  67. 67

    Linskens, M. H. K. et al. Cataloging altered gene expression in young and senescent cells using enhanced differential display. Nucleic Acids Res 23, 3244–3251 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999). This paper uses microarrays to compare the senescent phenotype of replicatively senescent human fibroblasts with human fibroblasts that are induced to 'prematurely' senesce owing to non-telomeric events.

    CAS  PubMed  Google Scholar 

  69. 69

    Campisi, J. From cells to organisms: can we learn about aging from cells in culture? Exp. Gerontol. 36, 607–618 (2001).

    CAS  PubMed  Google Scholar 

  70. 70

    Margolis, J. & Spradling, A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121, 3797–3807 (1995).

    CAS  Google Scholar 

  71. 71

    Jazwinski, S. M. Longevity, Genes and Aging. Science 273, 54–59 (1996).

    CAS  PubMed  Google Scholar 

  72. 72

    Sager, R. Senescence as a mode of tumor suppression. Environ Health Perspect 93, 59–62 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Smith, J. R. & Pereira-Smith, O. M. Replicative senescence: implications for in vivo aging and tumor suppression. Science 273, 63–67 (1996).

    CAS  PubMed  Google Scholar 

  74. 74

    Wright, W. E. & Shay, J. W. Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr. Opin. Genet. Dev. 11, 98–103 (2001).

    CAS  PubMed  Google Scholar 

  75. 75

    Yeager, T. R. et al. Overcoming cellular senescence in human cancer pathogenesis. Genes Dev. 12, 163–174 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Serrano, M. et al. Role of the INK4A locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356, 215–221 (1992).

    CAS  Google Scholar 

  80. 80

    Hara, E. et al. Regulation of p16/CDKN2 expression and its implications for cell immortalization and senescence. Mol. Cell. Biol. 16, 859–867 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    McConnell, B. B., Starborg, M., Brookes, S. & Peters, G. Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr. Biol. 8, 351–354 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Alcorta, D. A. et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA 93, 13742–13747 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Dimri, G. P., Itahana, K., Acosta, M. & Campisi, J. Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14/ARF tumor suppressor. Mol. Cell. Biol. 20, 273–285 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Stein, G. H., Beeson, M. & Gordon, L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249, 666–669 (1990).

    CAS  PubMed  Google Scholar 

  86. 86

    Futreal, P. A. & Barrett, J. C. Failure of senescent cells to phosphorylate the RB protein. Oncogene 6, 1109–1113 (1991).

    CAS  PubMed  Google Scholar 

  87. 87

    Atadja, P., Wong, H., Garkavstev, I., Veillette, C. & Riabowol, K. Increased activity of p53 in senescing fibroblasts. Proc. Natl Acad. Sci. USA 92, 8348–8352 (1995).

    CAS  PubMed  Google Scholar 

  88. 88

    DiLeonardo, A., Linke, S. P., Clarkin, K. & Wahl, G. M. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8, 2540–2551 (1994).

    CAS  Google Scholar 

  89. 89

    Chen, Q. et al. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G(1) arrest but not cell replication. Biochem. J. 332, 43–50 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Hara, E., Tsuri, H., Shinozaki, S. & Oda, K. Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of lifespan in human diploid fibroblasts, TIG-1. Biochem. Biophys. Res. Comm. 179, 528–534 (1991).

    CAS  PubMed  Google Scholar 

  91. 91

    Shay, J. W., Pereira-Smith, O. M. & Wright, W. E. A role for both Rb and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).

    CAS  PubMed  Google Scholar 

  92. 92

    Gire, V. & Wynford-Thomas, D. Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol. Cell. Biol. 18, 1611–1621 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Lundberg, A. S., Hahn, W. C., Gupta, P. & Weinberg, R. A. Genes involved in senescence and immortalization. Curr. Opin. Cell Biol. 12, 705–709 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Bringold, F. & Serrano, M. Tumor suppressors and oncogenes in cellular senescence. Exp. Gerontol. 35, 317–329 (2000).

    CAS  PubMed  Google Scholar 

  95. 95

    Itahana, K., Dimri, G. & Campisi, J. Regulation of cellular senescence by p53. Eur. J. Biochem. 268, 2784–2791 (2001).

    CAS  PubMed  Google Scholar 

  96. 96

    Sharpless, N. E. & DePinho, R. A. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9, 22–30 (1999).

    CAS  PubMed  Google Scholar 

  97. 97

    Dai, C. Y. & Enders, G. H. p16 INK4a can initiate an autonomous senescence program. Oncogene 19, 1613–1622 (2000).

    CAS  PubMed  Google Scholar 

  98. 98

    Sugrue, M. M., Shin, D. Y., Lee, S. W. & Aaronson, S. A. Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc. Natl Acad. Sci. USA 94, 9648–9653 (1997).

    CAS  PubMed  Google Scholar 

  99. 99

    Xu, H. J. et al. Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition. Oncogene 15, 2589–2596 (1997).

    CAS  PubMed  Google Scholar 

  100. 100

    Amundson, S. A., Myers, T. G. & Fornace, A. J. Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene 17, 3287–3299 (1998).

    PubMed  Google Scholar 

  101. 101

    Prives, C. & Hall, P. A. The p53 pathway. J. Pathol. 187, 112–126 (1999).

    CAS  PubMed  Google Scholar 

  102. 102

    Bargonetti, J. & Manfredi, J. J. Multiple roles of the tumor suppressor p53. Curr. Opin. Oncol. 14, 86–91 (2002).

    CAS  PubMed  Google Scholar 

  103. 103

    Wahl, G. M. & Carr, A. M. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biol. 3, E277–E286 (2001).

    CAS  Google Scholar 

  104. 104

    Lu, X. & Horvitz, H. R. lin-35 and lin–53, two genes that antagonize a C. elegans Ras pathway, encode proteins similar to Rb and its binding protein RbbAp48. Cell 95, 981–991 (1998).

    CAS  PubMed  Google Scholar 

  105. 105

    Du, W., Vidal, M., Xie, J. E. & Dyson, N. RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev. 10, 1206–1218 (1996).

    CAS  PubMed  Google Scholar 

  106. 106

    Derry, W. B., Putzke, A. P. & Rothman, J. H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591–595 (2001).

    CAS  Google Scholar 

  107. 107

    Schumacher, B., Hoffman, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11, 1722–1727 (2001).

    CAS  Google Scholar 

  108. 108

    Brodsky, M. H. et al. Drosophila p53 binds a damage response element at the reaper locus. Cell 101, 103–113 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Ollmann, M. et al. Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101, 91–101 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Jin, S. et al. Identification and characterization of a p53 homologue in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 97, 7301–7306 (2000). References 106–110 describe the conserved sequence and functions of invertebrate ( C. elegans and D. melanogaster ) p53.

    CAS  PubMed  Google Scholar 

  111. 111

    Finch, C. R. Longevity, Senescence and the Genome (Univ. Chicago Press, Chicago, 1991).

    Google Scholar 

  112. 112

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

    Google Scholar 

  113. 113

    Thompson, C. B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995).

    CAS  Google Scholar 

  114. 114

    Fadeel, B., Orrenius, S. & Zhivotovsky, B. Apoptosis in human disease: a new skin for an old ceremony? Biochem. Biophys. Res. Comm. 266, 699–717 (1999).

    CAS  PubMed  Google Scholar 

  115. 115

    Martin, L. J. Neuronal cell death in nervous system development, disease, and injury. Int. J. Mol. Med. 7, 455–478 (2001).

    CAS  PubMed  Google Scholar 

  116. 116

    Almeida-Porada, G., Porada, C. & Zanjani, E. D. Adult stem cell plasticity and methods of detection. Rev. Clin. Exp. Hematol. 5, 26–41 (2001).

    CAS  PubMed  Google Scholar 

  117. 117

    Weissman, I. L., Anderson, D. J. & Gage, F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Weinstein, B. S. & Ciszek, D. The reserve capacity hypothesis: evolutionary origins and modern implications between tumor suppression and tissue repair. Exp. Gerontol. 37, 615–627 (2002).

    CAS  PubMed  Google Scholar 

  119. 119

    Donehower, L. A. Does p53 affect organismal aging? J. Cell Physiol. 192, 23–33 (2002).

    CAS  PubMed  Google Scholar 

  120. 120

    Krtolica, A. & Campisi, J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int. J. Biochem. Cell Biol. 34, 1401–1414 (2002).

    CAS  PubMed  Google Scholar 

  121. 121

    Dimri, G. P. et al. A novel biomarker identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Choi, J. et al. Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia. Urology 56, 160–166 (2000).

    CAS  PubMed  Google Scholar 

  123. 123

    Paradis, V. et al. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Hum. Pathol. 32, 327–332 (2001).

    CAS  PubMed  Google Scholar 

  124. 124

    Vasile, E., Tomita, Y., Brown, L. F., Kocher, O. & Dvorak, H. F. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 15, 458–466 (2001). References 121–124 describe some of the evidence that senescent cells exist, accumulate with age and contribute to age-related pathology in vivo.

    CAS  PubMed  Google Scholar 

  125. 125

    Fusenig, N. E. & Boukamp, P. Multiple stages and genetic alterations in immortalization, malignant transformation, and tumor progression of human skin keratinocytes. Mol. Carcinog. 23, 144–158 (1998).

    CAS  PubMed  Google Scholar 

  126. 126

    Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999). Shows that fibroblasts, if appropriately stimulated, can facilitate the neoplastic progression of epithelial cells.

    CAS  PubMed  Google Scholar 

  127. 127

    Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. & 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). Shows that senescent human fibroblasts can promote the neoplastic progression of preneoplastic epithelial cells.

    CAS  PubMed  Google Scholar 

  128. 128

    Tyner, S. D. et al. p53 mutant mice that display early aging-associated phenotypes. Nature 415, 45–53 (2002). Shows that increased p53 activity suppresses the development of cancer in mice, but also promotes the premature development of ageing phenotypes.

    CAS  PubMed  Google Scholar 

  129. 129

    Garcia-Cao, I. et al. 'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Davenport, J. Tumor-free but not in the clear. Science, SAGE–KE, 2002.

    Google Scholar 

  131. 131

    Gray, J. W. & Collins, C. Genome changes and gene expression in human solid tumors. Carcinogenesis 21, 443–452 (2000).

    CAS  Google Scholar 

  132. 132

    Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 93, 14025–14029 (1996). Shows that potentially oncogenic cells — in this case, harbouring TP53 mutations — are present in apparently normal young human tissue.

    CAS  PubMed  Google Scholar 

  133. 133

    Aubele, M. et al. Extensive ductal carcinoma in situ with small foci of invasive ductal carcinoma: evidence of genetic resemblance by CGH. Int. J. Cancer 85, 82–86 (2000).

    CAS  PubMed  Google Scholar 

  134. 134

    Deng, G., Lu, Y., Zlotnikov, G., Thor, A. D. & Smith, H. S. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274, 2057–2059 (1996). Shows that apparently normal human tissue harbours potentially oncogenic mutations.

    CAS  PubMed  Google Scholar 

  135. 135

    Umayahara, K. et al. Comparative genomic hybridization detects genetic alterations during early stages of cervical cancer progression. Genes Chromosom. Cancer 33, 98–102 (2002).

    CAS  PubMed  Google Scholar 

  136. 136

    Ilmensee, K. Reversion of malignancy and normalized differentiation of teratocarcinoma cells in chimeric mice. Basic Life Sci. 12, 3–25 (1978). Shows that potentially malignant cells can fail to express their neoplastic properties when placed in a normal tissue microenvironment.

    Google Scholar 

  137. 137

    Liotta, L. A. & Kohn, E. C. The microenvironment of the tumour-host interface. Nature 411, 375–379 (2001).

    CAS  Google Scholar 

  138. 138

    Park, C. C., Bissell, M. J. & Barcellos-Hoff, M. H. The influence of the microenvironment on the malignant phenotype. Mol Med Today 6, 324–329 (2000).

    CAS  PubMed  Google Scholar 

  139. 139

    Yap, D. B., Hsieh, J. K., Chan, F. S. & Lu, X. Mdm2: a bridge over the two tumour suppressors, p53 and Rb. Oncogene 18, 7681–7689 (1999).

    CAS  PubMed  Google Scholar 

  140. 140

    Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).

    CAS  Google Scholar 

  141. 141

    Dyson, N. The regulation of E2F by pRB-family proteins. Genes Dev. 12, 2245–2262 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Affiliations

Authors

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DATABASES

FlyBase

dp53

LocusLink

BLM

Brca1

CDKN2A

collagen

cyclin A

cyclin B

elastin

FOS

interleukin-1

Ku80

MDM2

p53

RB

RECQ1

RECQ5

RTS

Trp53

WAF1

WRN

XPA

XPB

XPC

XPD

XPE

XPF

XPG

OMIM

Bloom syndrome

Rothmund–Thomson syndrome

trichothiodystrophy

type II diabetes

Werner syndrome

Saccharomyces Genome Database

SGS1

WormBase

CEP-1

Glossary

COMPLEX ORGANISMS

Multicellular organisms that are composed of both post-mitotic and renewable (mitotic) somatic tissues.

SIMPLE ORGANISMS

Multicellular organisms that are composed entirely or largely of post-mitotic somatic cells.

CARETAKERS

Tumour-suppressor genes or proteins that act to protect the genome from damage or mutations. Many caretaker genes encode proteins that recognize or repair DNA damage.

GATEKEEPERS

Tumour-suppressor genes or proteins that regulate cellular responses that prevent the survival or proliferation of potential cancer cells. These responses are known as apoptosis and cellular senescence, respectively.

NUCLEOTIDE EXCISION REPAIR

A DNA-repair pathway that removes and replaces damaged nucleotides, particularly those that distort the DNA helix.

TELOMERES

The DNA–protein structure that stabilizes the ends of linear chromosomes and protects them from degradation or fusion. In vertebrates, telomeres are composed of several-kilobase pairs of the sequence TTTAGGG and several associated proteins.

APOPTOSIS

Ordered, genetically programmed cell death triggered by both physiological stimuli and cellular damage. Apoptosis avoids cell lysis and subsequent inflammation.

CELLULAR SENESCENCE

The essentially irreversible loss of cell division potential and the associated functional changes that are triggered by damage and other potential cancer-causing stimuli.

LONGEVITY

Average or maximum lifespan of a cohort of organisms.

AGEING

The decline in organismal fitness that occurs with increasing age.

AGEING PHENOTYPES

The specific physiological manifestations of ageing.

ANTAGONISTIC PLEIOTROPY

The hypothesis that genes or processes that were selected to benefit the health and fitness of young organisms can have unselected deleterious effects that are manifest in older organisms and thereby contribute to ageing.

MISMATCH REPAIR

A DNA-repair pathway that removes and replaces nucleotides that have been misrepaired by DNA polymerases during DNA replication.

BASE EXCISION REPAIR

A DNA-repair pathway that excises and replaces damaged DNA bases.

NON-HOMOLOGOUS END-JOINING REPAIR

A relatively error-prone pathway that repairs double-strand breaks by ligating non-homologous DNA ends.

HOMOLOGOUS RECOMBINATIONAL REPAIR

A relatively error-free pathway that repairs DNA double-strand breaks using an undamaged sister chromatid or homologous chromosome as a template.

XERODERMA PIGMENTOSUM

A group of cancer-prone syndromes in humans that are caused by defects in the nucleotide excision repair genes.

NECROSIS

Passive or unregulated cell death, in which cells lyse and deposit degradative and antigenic cell constituents into the surrounding tissue. Necrotic cell death, in contrast to apoptosis, often provokes an inflammation reaction.

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Campisi, J. Cancer and ageing: rival demons?. Nat Rev Cancer 3, 339–349 (2003). https://doi.org/10.1038/nrc1073

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