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Cellular senescence: when bad things happen to good cells

Key Points

  • Cellular senescence is a multifaceted process that arrests the proliferation of cells that are at risk of neoplastic transformation.

  • Many stimuli elicit a senescence response. These include dysfunctional telomeres, DNA damage, the expression of certain oncogenes, perturbations to chromatin organization and strong mitogenic signals.

  • Two powerful tumour suppressor pathways, controlled by the p53 and retinoblastoma (pRB) proteins, are important for establishing and maintaining the senescence growth arrest. These pathways respond to somewhat different stimuli but interact and cooperate to control the senescence response.

  • There is now substantial evidence that cellular senescence is a barrier to malignant tumorigenesis in vivo.

  • In mammalian organisms, cells that express markers of senescence have been shown to accumulate with age and at sites of certain age-related pathologies. There is also mounting evidence that cellular senescence contributes to ageing. Although this evidence is still mainly circumstantial, it suggests that the senescence response might be an example of evolutionary antagonistic pleiotropy.

Abstract

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

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Figure 1: The senescent phenotype induced by multiple stimuli.
Figure 2: Telomere-dependent senescence.
Figure 3: The DNA-damage response.
Figure 4: Senescence controlled by the p53 and p16–pRB pathways.
Figure 5: Potential deleterious effects of senescent cells.

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References

  1. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965). A classic paper that describes the limited replicative lifespan of normal human cells.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Bishop, J. M. Cancer: the rise of the genetic paradigm. Genes Dev. 9, 1309–1315 (1995). References 2 and 3 describe the characteristics of cancer cells and the importance of mutations in cancer development.

    CAS  PubMed  Google Scholar 

  4. Busuttil, R. A., Rubio, M., Dolle, M. E., Campisi, J. & Vijg, J. Mutant frequencies and spectra depend on growth state and passage number in cells cultured from transgenic lacZ-plasmid reporter mice. DNA Repair 5, 52–60 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Campisi, J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 11, 27–31 (2001).

    Google Scholar 

  7. Braig, M. & Schmitt, C. A. Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res. 66, 2881–2884 (2006).

    CAS  PubMed  Google Scholar 

  8. Campisi, J. Cancer and ageing: rival demons? Nature Rev. Cancer 3, 339–349 (2003).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  10. Dimri, G. P. What has senescence got to do with cancer? Cancer Cell 7, 505–512 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Campisi, J. Senescent cells, tumor suppression and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    CAS  PubMed  Google Scholar 

  13. Hornsby, P. J. Cellular senescence and tissue aging in vivo. J. Gerontol. 57, 251–256 (2002). References 5–13 describe the historic and current evidence that cellular senescence suppresses the development of cancer. In addition, references 8 and 9 explain the concept of antagonistic pleiotropy.

    Google Scholar 

  14. Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).

    CAS  PubMed  Google Scholar 

  15. 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 

  16. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513 (2004).

    CAS  PubMed  Google Scholar 

  17. Ogryzko, V. V., Hirai, T. H., Russanova, V. R., Barbie, D. A. & Howard, B. H. Human fibroblast commitment to a senescence-like state in response to histone deacetylase inhibitors is cell cycle dependent. Mol. Cell. Biol. 16, 5210–5218 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Wada, T. et al. MKK7 couples stress signaling to G2/M cell-cycle progression and cellular senescence. Nature Cell Biol. 6, 215–226 (2004).

    CAS  PubMed  Google Scholar 

  20. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    CAS  PubMed  Google Scholar 

  21. Olsen, C. L., Gardie, B., Yaswen, P. & Stampfer, M. R. Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion. Oncogene 21, 6328–6339 (2002).

    CAS  PubMed  Google Scholar 

  22. Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic raf. Genes Dev. 12, 2997–3007 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Shay, J. W. & Roninson, I. B. Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23, 2919–2933 (2004). References 15–23 show that many potentially oncogenic stimuli can induce a senescence response.

    CAS  PubMed  Google Scholar 

  24. Itahana, K., Campisi, J. & Dimri, G. P. Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5, 1–10 (2004).

    CAS  PubMed  Google Scholar 

  25. 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 

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

    CAS  PubMed  Google Scholar 

  27. Hampel, B., Malisan, F., Niederegger, H., Testi, R. & Jansen-Durr, P. Differential regulation of apoptotic cell death in senescent human cells. Exp. Gerontol. 39, 1713–1721 (2004).

    CAS  PubMed  Google Scholar 

  28. Chen, Q. M., Liu, J. & Merrett, J. B. Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. Biochem. J. 347, 543–551 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Tepper, C. G., Seldin, M. F. & Mudryj, M. Fas-mediated apoptosis of proliferating, transiently growth-arrested, and senescent normal human fibroblasts. Exp. Cell Res. 260, 9–19 (2000).

    CAS  PubMed  Google Scholar 

  30. Rebbaa, A., Zheng, X., Chou, P. M. & Mirkin, B. L. Caspase inhibition switches doxorubicin-induced apoptosis to senescence. Oncogene 22, 2805–2811 (2003).

    CAS  PubMed  Google Scholar 

  31. Seluanov, A. et al. Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol. Cell. Biol. 21, 1552–1564 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Crescenzi, E., Palumbo, G. & Brady, H. J. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem. J. 375, 263–274 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Marcotte, R., Lacelle, C. & Wang, E. Senescent fibroblasts resist apoptosis by downregulating caspase-3. Mech. Ageing Dev. 125, 777–783 (2004).

    CAS  PubMed  Google Scholar 

  34. Murata, Y. et al. Death-associated protein 3 regulates cellular senescence through oxidative stress response. FEBS Lett. 580, 6093–6099 (2006).

    CAS  PubMed  Google Scholar 

  35. Jackson, J. G. & Pereira-Smith, O. M. p53 is preferentially recruited to the promoters of growth arrest genes p21 and GADD45 during replicative senescence of normal human fibroblasts. Cancer Res. 66, 8356–8360 (2006).

    CAS  PubMed  Google Scholar 

  36. Chang, B. D. et al. Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc. Natl Acad. Sci. USA 99, 389–394 (2002).

    CAS  PubMed  Google Scholar 

  37. Mason, D. X., Jackson, T. J. & Lin, A. W. Molecular signature of oncogenic ras-induced senescence. Oncogene 23, 9238–9246 (2004).

    CAS  PubMed  Google Scholar 

  38. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999).

    CAS  PubMed  Google Scholar 

  39. Trougakos, I. P., Saridaki, A., Panayotou, G. & Gonos, E. S. Identification of differentially expressed proteins in senescent human embryonic fibroblasts. Mech. Ageing Dev. 127, 88–92 (2006).

    CAS  PubMed  Google Scholar 

  40. Yoon, I. K. et al. Exploration of replicative senescence-associated genes in human dermal fibroblasts by cDNA microarray technology. Exp. Gerontol. 39, 1369–1378 (2004).

    CAS  PubMed  Google Scholar 

  41. Zhang, H., Pan, K. H. & Cohen, S. N. Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc. Natl Acad. Sci. USA 100, 3251–3256 (2003). References 36–41 describe the many changes in gene expression that are linked to the senescence response.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).

    CAS  PubMed  Google Scholar 

  43. Espinosa, J. M., Verdun, R. E. & Emerson, B. M. p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage. Mol. Cell 12, 1015–1027 (2003).

    CAS  PubMed  Google Scholar 

  44. Gil, J. & Peters, G. Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all. Nature Rev. Mol. Cell Biol. 7, 667–677 (2006).

    CAS  Google Scholar 

  45. Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003). The first description of senescence-associated heterochromatin foci.

    CAS  PubMed  Google Scholar 

  46. Pang, J. H. & Chen, K. Y. Global change of gene expression at late G1/S boundary may occur in human IMR-90 diploid fibroblasts during senescence. J. Cell Physiol. 160, 531–538 (1994).

    CAS  PubMed  Google Scholar 

  47. Seshadri, T. & Campisi, J. Repression of c-fos transcription and an altered genetic program in senescent human fibroblasts. Science 247, 205–209 (1990).

    CAS  PubMed  Google Scholar 

  48. Stein, G. H., Drullinger, L. F., Robetorye, R. S., Pereira-Smith, O. M. & Smith, J. R. Senescent cells fail to express CDC2, CYCA, and CYCB in response to mitogen stimulation. Proc. Natl Acad. Sci USA 88, 11012–11016 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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). First description of a senescence-associated marker that allowed the identification of senescent cells in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Lee, B. Y. et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Aging Cell 5, 187–195 (2006).

    CAS  PubMed  Google Scholar 

  51. Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Beausejour, C. M. et al. Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22, 4212–4222 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Itahana, K. et al. Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol. Cell. Biol. 23, 389–401 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472–476 (2006).

    CAS  Google Scholar 

  55. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    CAS  PubMed  Google Scholar 

  56. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003). References 55 and 56, along with reference 16, provide the first direct evidence that dysfunctional telomeres trigger a DNA-damage response.

    CAS  PubMed  Google Scholar 

  57. Bartholdi, M. F. Nuclear distribution of centromeres during the cell cycle of human diploid fibroblasts. J. Cell Sci. 99, 255–263 (1991).

    PubMed  Google Scholar 

  58. Cerda, M. C., Berrios, S., Fernandez-Donoso, R., Garagna, S. & Redi, C. Organisation of complex nuclear domains in somatic mouse cells. Biol. Cell 91, 55–65 (1999).

    CAS  PubMed  Google Scholar 

  59. d'Adda di Fagagna, F., Teo, S. H. & Jackson, S. P. Functional links between telomeres and proteins of the DNA-damage response. Genes Dev. 18, 1781–1799 (2004).

    PubMed  Google Scholar 

  60. Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).

    CAS  PubMed  Google Scholar 

  61. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during aging of human fibroblasts. Nature 345, 458–460 (1990). First evidence linking telomere shortening to replicative senescence.

    CAS  PubMed  Google Scholar 

  62. Hemann, M. T., Strong, M.A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

    CAS  PubMed  Google Scholar 

  63. Martens, U. M., Chavez, E. A., Poon, S. S., Schmoor, C. & Lansdorp, P. M. Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp. Cell Res. 256, 291–299 (2000).

    CAS  PubMed  Google Scholar 

  64. Gire, V., Roux, P., Wynford-Thomas, D., Brondello, J. M. & Dulic, V. DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J. 23, 2554–2563 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Collins, K. & Mitchell, J. R. Telomerase in the human organism. Oncogene 21, 564–579 (2002).

    CAS  PubMed  Google Scholar 

  66. Effros, R. B., Dagarag, M. & Valenzuela, H. F. In vitro senescence of immune cells. Exp. Gerontol. 38, 1243–1249 (2003).

    CAS  PubMed  Google Scholar 

  67. Masutomi, K. et al. Telomerase maintains telomere structure in normal human cells. Cell 114, 241–253 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  69. Chen, Q. M., Prowse, K. R., Tu, V. C., Purdom, S. & Linskens, M. H. Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Exp. Cell Res. 265, 294–303 (2001).

    CAS  PubMed  Google Scholar 

  70. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative life span of murine cells. Nature Cell Biol. 5, 741–747 (2003).

    CAS  PubMed  Google Scholar 

  71. Jacobs, J. J. & de Lange, T. Significant role for p16(INK4a) in p53-independent telomere-directed senescence. Curr. Biol. 14, 2302–2308 (2004).

    CAS  PubMed  Google Scholar 

  72. Stein, G. H., Drullinger, L. F., Soulard, A. & Dulic, V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell. Biol. 19, 2109–2117 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Roninson, I. B. Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705–2715 (2003).

    CAS  PubMed  Google Scholar 

  74. Roberson, R. S., Kussick, S. J., Vallieres, E., Chen, S. Y. & Wu, D. Y. Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res. 65, 2795–2803 (2005).

    CAS  PubMed  Google Scholar 

  75. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002).

    CAS  PubMed  Google Scholar 

  76. te Poele, R. H., Okorokov, A. L., Jardine, L., Cummings, J. & Joel, S. P. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 62, 1876–1883 (2002). References 73–76 describe evidence that tumour cells can undergo senescence in response to DNA-damaging chemotherapy.

    CAS  PubMed  Google Scholar 

  77. Munro, J., Barr, N. I., Ireland, H., Morrison, V. & Parkinson, E. K. Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp. Cell Res. 295, 525–538 (2004).

    CAS  PubMed  Google Scholar 

  78. Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003).

    CAS  PubMed  Google Scholar 

  79. Bandyopadhyay, D. et al. Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res. 62, 6231–6239 (2002).

    CAS  PubMed  Google Scholar 

  80. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38–51 (2006).

    CAS  Google Scholar 

  81. 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 

  82. Lin, A. W. et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 12, 3008–3019 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human nevi. Nature 436, 720–724 (2005).

    CAS  PubMed  Google Scholar 

  84. Woo, R. A. & Poon, R. Y. Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation. Genes Dev. 18 (2004).

  85. Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L. & Lloyd, A. C. Lack of replicative senescence in normal rodent glia. Science 291, 872–875 (2001).

    CAS  PubMed  Google Scholar 

  86. Tang, D. G., Tokumoto, Y. M., Apperly, J. A., Lloyd, A. C. & Raff, M. C. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science 291, 868–871 (2001).

    CAS  PubMed  Google Scholar 

  87. Ohtani, N. et al. Opposing effects of Ets and Id proteins on p16/INK4a expression during cellular senescence. Nature 409, 1067–1070 (2001).

    CAS  PubMed  Google Scholar 

  88. Zhang, R. et al. Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–31 (2005).

    CAS  PubMed  Google Scholar 

  89. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    CAS  PubMed  Google Scholar 

  90. Benanti, J. A. & Galloway, D. A. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24, 2842–2852 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Skinner, J. et al. Opposing effects of mutant ras oncoprotein on human fibroblast and epithelial cell proliferation: implications for models of human tumorigenesis. Oncogene 23, 5994–5999 (2004).

    CAS  PubMed  Google Scholar 

  92. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    CAS  PubMed  Google Scholar 

  93. Chen, Z. et al. Critical role of p53-dependent cellular senescence in suppression of PTEN-deficient tumorigenesis. Nature 436, 725–730 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Collado, M. et al. Identification of senescent cells in premalignant tumours. Nature 436, 642 (2005).

    CAS  PubMed  Google Scholar 

  95. Lazzerini Denchi, E., Attwooll, C., Pasini, D. & Helin, K. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol. Cell. Biol. 25, 2660–2672 (2005). Together with references 83 and 89, references 92–95 provide evidence that cellular senescence suppresses tumorigenesis in vivo.

    PubMed  Google Scholar 

  96. Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A. & Ferbeyre, G. DNA damage signaling and p53-dependent senescence after prolonged β-interferon stimulation. Mol. Biol. Cell 17, 1583–1592 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Vijayachandra, K., Lee, J. & Glick, A. B. Smad3 regulates senescence and malignant conversion in a mouse multistage skin carcinogenesis model. Cancer Res. 63, 3447–3452 (2003).

    CAS  PubMed  Google Scholar 

  98. Zhang, H. & Cohen, S. N. Smurf2 up-regulation activates telomere-dependent senescence. Genes Dev. 18, 3028–3040 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15, 398–403 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Brenner, A. J., Stampfer, M. R. & Aldaz, C. M. Increased p16 expression with first senescence arrest in human mammary epithelial cells and extended growth capacity with p16 inactivation. Oncogene 17, 199–205 (1998).

    CAS  PubMed  Google Scholar 

  101. Huschtscha, L. I. et al. Loss of p16INK4 expression by methylation is associated with lifespan extension of human mammary epithelial cells. Cancer Res. 58, 3508–3512 (1998).

    CAS  PubMed  Google Scholar 

  102. Forsyth, N. R., Evans, A. P., Shay, J. W. & Wright, W. E. Developmental differences in the immortalization of lung fibroblasts by telomerase. Aging Cell 2, 235–243 (2003).

    CAS  PubMed  Google Scholar 

  103. Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene BMI-1 regulates cell proliferation and senescence through the INK4a locus. Nature 397, 164–168 (1999).

    CAS  PubMed  Google Scholar 

  104. Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211 (1997). First report that p16 expression increases during ageing.

    CAS  PubMed  Google Scholar 

  105. Janzen, V. et al. Stem cell aging modified by the cyclin-dependent kinase inhibitor, p16INK4a. Nature 443, 421–426 (2006).

    CAS  PubMed  Google Scholar 

  106. Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006).

    CAS  PubMed  Google Scholar 

  107. Molofsky, A. V. et al. Declines in forebrain progenitor function and neurogenesis during aging are partially caused by increasing Ink4a expression. Nature 443, 448–452 (2006). References 105–107 describe evidence that p16 limits stem-cell or progenitor-cell proliferation, which drives ageing phenotypes.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Holst, C. R. et al. Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 63, 1596–1601 (2003).

    CAS  PubMed  Google Scholar 

  109. Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    CAS  PubMed  Google Scholar 

  110. Won, J. et al. Small molecule-based reversible reprogramming of cellular lifespan. Nature Chem. Biol. 2, 369–374 (2006).

    CAS  Google Scholar 

  111. Shay, J. W. & Wright, W. E. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26, 867–874 (2005).

    CAS  PubMed  Google Scholar 

  112. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  113. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    CAS  PubMed  Google Scholar 

  114. Smogorzewska, A. & de Lange, T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21, 4338–4348 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hara, E. et al. Id related genes encoding helix loop helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J. Biol. Chem. 269, 2139–2145 (1994).

    CAS  PubMed  Google Scholar 

  116. Bracken, A. P. et al. The Polycomb group proteins bind throughout the INK4A–ARF locus and are disassociated in senescent cells. Genes Dev. 21, 525–530 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Gil, J., Bernard, D., Martinez, D. & Beach, D. Polycomb CBX7 has a unifying role in cellular lifespan. Nature Cell Biol. 6, 62–67 (2004).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  119. Bates, S. et al. p14ARF links the tumor suppressors RB and p53. Nature 395, 125–125 (1998).

    Google Scholar 

  120. Zhang, J., Pickering, C. R., Holst, C. R., Gauthier, M. L. & Tlsty, T. D. p16INK4a modulates p53 in primary human mammary epithelial cells. Cancer Res. 66, 10325–10331 (2006).

    CAS  PubMed  Google Scholar 

  121. Funayama, R., Saito, M., Tanobe, H. & Ishikawa, F. Loss of linker histone H1 in cellular senescence. J. Cell Biol. 175, 869–880 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2343–2358 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Macaluso, M., Montanari, M. & Giordano, A. Rb family proteins as modulators of gene expression and new aspects regarding the interaction with chromatin remodeling enzymes. Oncogene 25, 5263–5267 (2006).

    CAS  PubMed  Google Scholar 

  124. Jeyapalan, J. C., Ferreira, M., Sedivy, J. M. & Herbig, U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36–44 (2007).

    CAS  PubMed  Google Scholar 

  125. Chang, E. & Harley, C. B. Telomere length and replicative aging in human vascular tissues. Proc. Natl Acad. Sci. USA 92, 11190–11194 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Price, J. S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002).

    CAS  PubMed  Google Scholar 

  127. Vasile, E., Tomita, Y., Brown, L. F., Kocher, O. & Dvorak, H. F. Differential expression of thymosin β-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).

    CAS  PubMed  Google Scholar 

  128. Castro, P., Giri, D., Lamb, D. & Ittmann, M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate 55, 30–38 (2003).

    CAS  PubMed  Google Scholar 

  129. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    CAS  PubMed  Google Scholar 

  130. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–650 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Cosme-Blanco, W. et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 8, 497–503 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006).

    CAS  PubMed  Google Scholar 

  133. Feldser, D. M. & Greider, C. W. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11, 461–469 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  135. Iwakuma, T., Lozano, G. & Flores, E. R. Li-Fraumeni syndrome: a p53 family affair. Cell Cycle 4, 865–867 (2005).

    CAS  PubMed  Google Scholar 

  136. Lee, S. B. et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Res. 61, 8062–8067 (2001).

    CAS  PubMed  Google Scholar 

  137. Shay, J. W., Tomlinson, G., Piatyszek, M. A. & Gollahon, L. S. Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. Mol. Cell Biol. 15, 425–432 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Morales, C. P. et al. Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nature Genet. 21, 115–118 (1999).

    CAS  PubMed  Google Scholar 

  139. Shay, J. W., Van Der Haegen, B. A., Ying, Y. & Wright, W. E. The frequency of immortalization of human fibroblasts and mammary epithelial cells transfected with SV40 large T-antigen. Exp. Cell Res. 209, 45–52 (1993).

    CAS  PubMed  Google Scholar 

  140. Hahn, W. C. et al. Creation of human tumor cells with defined genetic elements. Nature 400, 464–468 (1999).

    CAS  PubMed  Google Scholar 

  141. Tyner, S. D. et al. p53 mutant mice that display early aging-associated phenotypes. Nature 415, 45–53 (2002).

    CAS  PubMed  Google Scholar 

  142. Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004). References 141 and 142 show that constitutive p53 activity can suppress the development of cancer at the cost of accelerating ageing phenotypes.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Funk, W. D. et al. Telomerase expression restores dermal integrity to in vitro aged fibroblasts in a reconstituted skin model. Exp. Cell Res. 258, 270–278 (2000).

    CAS  PubMed  Google Scholar 

  144. Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118, 485–496 (2005).

    CAS  PubMed  Google Scholar 

  145. Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802 (2006).

    CAS  PubMed  Google Scholar 

  146. Coppe, J. P., Kauser, K., Campisi, J. & Beausejour, C. M. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J. Biol. Chem. 281, 29568–29574 (2006).

    CAS  PubMed  Google Scholar 

  147. Dilley, T. K., Bowden, G. T. & Chen, Q. M. Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity. Exp. Cell Res. 290, 38–48 (2003).

    CAS  PubMed  Google Scholar 

  148. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Martens, J. W. et al. Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. Thromb. Haemost. 89, 393–404 (2003).

    CAS  PubMed  Google Scholar 

  150. 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 

  151. Matheu, A. et al. Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging. Genes Dev. 18, 2736–2746 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Mendrysa, S. M. et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev. 20, 16–21 (2006). References 150–152 show that resistance to cancer need not accelerate ageing.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta Rev. Cancer 1071, 1–7 (1991).

    Google Scholar 

  154. Romanov, S. R. et al. Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature 409, 633–637 (2001).

    CAS  PubMed  Google Scholar 

  155. Emsley, J. G., Mitchell, B. D., Kempermann, G. & Macklis, J. D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 75, 321–341 (2005).

    CAS  PubMed  Google Scholar 

  156. Shi, X. & Garry, D. J. Muscle stem cells in development, regeneration, and disease. Genes Dev. 20, 1692–1708 (2006).

    CAS  PubMed  Google Scholar 

  157. Srivastava, D. & Ivey, K. N. Potential of stem-cell-based therapies for heart disease. Nature 441, 1097–1099 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank colleagues and the members of their laboratories for stimulating discussions. The F.d'A.d.F. group is supported by the Associazione Italiana per la Ricerca sul Cancro, the Association for International Cancer Research and the Human Frontier Science Program. The J.C. group is supported by the US National Institute of Aging, the National Cancer Institute and the Department of Energy.

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DATABASES

OMIM

Li-Fraumeni syndrome

type II diabetes

FURTHER INFORMATION

Judith Campisi's homepage (Buck Institute for Age Research)

Judith Campisi's homepage (Lawrence Berkeley National Laboratory)

Fabrizio d'Adda di Fagagna's homepage

Glossary

Renewable tissue

A tissue in which cell proliferation is important for tissue repair or regeneration. Renewable tissues typically contain, but sometimes recruit, mitotic cells upon injury or cell loss.

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 manifest in older organisms and thereby contribute to ageing.

Mitotic cell

A cell that has the ability to proliferate. In vivo, mitotic cells often exist in a reversible growth-arrested state that is termed quiescence or G0 phase, but such cells can be stimulated to proliferate in response to appropriate physiological signals.

Post-mitotic cell

A cell that has permanently lost the ability to proliferate, usually due to differentiation.

Quiescence

A reversible non-dividing state from which cells can be stimulated to proliferate in response to physiological signals.

Senescent phenotype

The combination of changes in cell behaviour, structure and function that occur upon cellular senescence. For most cell types, these changes include an essentially irreversible growth arrest, resistance to apoptosis and many alterations in gene expression.

Oncogene

A gene that contributes to the malignant transformation of cells. Oncogenes can be cellular or viral in origin. Cellular oncogenes are usually mutant or overexpressed forms of normal cellular genes. Viral oncogenes can also originate from cellular genes, acquiring mutations during viral capture, but they can also be distinctly viral in origin.

Chromatin

The DNA and complex of associated proteins that determine the accessibility of large DNA regions to the transcription machinery and other large protein complexes.

Euchromatin

Chromatin that is in an open conformation and hence accessible. Also termed active chromatin.

Heterochromatin

Chromatin that is in a closed conformation and hence inaccessible. Also termed silent or inactive chromatin. Chromatin probably exists in many forms between the extremes of euchromatin and heterochromatin.

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Campisi, J., d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8, 729–740 (2007). https://doi.org/10.1038/nrm2233

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