Skip to main content
Log in

Telomere biology: Cancer firewall or aging clock?

  • Phenoptosis
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

It has been a decade since the first surprising discovery that longer telomeres in humans are statistically associated with longer life expectancies. Since then, it has been firmly established that telomere shortening imposes an individual fitness cost in a number of mammalian species, including humans. But telomere shortening is easily avoided by application of telomerase, an enzyme which is coded into nearly every eukaryotic genome, but whose expression is suppressed most of the time. This raises the question how the sequestration of telomerase might have evolved. The predominant assumption is that in higher organisms, shortening telomeres provide a firewall against tumor growth. A more straightforward interpretation is that telomere attrition provides an aging clock, reliably programming lifespans. The latter hypothesis is routinely rejected by most biologists because the benefit of programmed lifespan applies only to the community, and in fact the individual pays a substantial fitness cost. There is a long-standing skepticism that the concept of fitness can be applied on a communal level, and of group selection in general. But the cancer hypothesis is problematic as well. Animal studies indicate that there is a net fitness cost in sequestration of telomerase, even when cancer risk is lowered. The hypothesis of protection against cancer has never been tested in animals that actually limit telomerase expression, but only in mice, whose lifespans are not telomerase-limited. And human medical evidence suggests a net aggravation of cancer risk from the sequestration of telomerase, because cells with short telomeres are at high risk of neoplastic transformation, and they also secrete cytokines that exacerbate inflammation globally. The aging clock hypothesis fits well with what is known about ancestral origins of telomerase sequestration, and the prejudices concerning group selection are without merit. If telomeres are an aging clock, then telomerase makes an attractive target for medical technologies that seek to expand the human life- and health-spans.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mitteldorf, J. (2013) Biochemistry (Moscow), 78, 1048–1053.

    Article  Google Scholar 

  2. Melnikova, L., and Georgiev, P. (2005) Chromosome Res., 13, 431–441.

    Article  PubMed  CAS  Google Scholar 

  3. Pauliny, A., Wagner, R. H., Augustin, J., Szep, T., and Blomqvist, D. (2006) Mol. Ecol., 15, 1681–1687.

    Article  PubMed  CAS  Google Scholar 

  4. Herbig, U., Ferreira, M., Condel, L., Carey, D., and Sedivy, J. M. (2006) Science, 311, 1257.

    Article  PubMed  CAS  Google Scholar 

  5. Argyle, D., Ellsmore, V., Gault, E. A., Munro, A. F., and Nasir, L. (2003) Mech. Ageing Devel., 124, 759–764.

    Article  CAS  Google Scholar 

  6. McKevitt, T. P., Nasir, L., Devlin, P., and Argyle, D. J. (2002) J. Nutr., 132, 1604S–1606S.

    PubMed  CAS  Google Scholar 

  7. Brummendorf, T. H., Mak, J., Sabo, K. M., Baerlocher, G. M., Dietz, K., Abkowitz, J. L., and Lansdorp, P. M. (2002) Exp. Hematol., 30, 1147–1152.

    Article  PubMed  Google Scholar 

  8. Cui, W., Wylie, D., Aslam, S., Dinnyes, A., King, T., Wilmut, I., and Clark, A. J. (2003) Biol. Reprod., 69, 15–21.

    Article  PubMed  CAS  Google Scholar 

  9. Choi, D., Cho, C., and Sohn, S. (2008) J. Animal Sci. Technol., 50, 445–456.

    Article  CAS  Google Scholar 

  10. Seluanov, A., Chen, Z., Hine, C., Sasahara, T. H., Ribeiro, A. A., Catania, K. C., Presgraves, D. C., and Gorbunova, V. (2007) Aging Cell, 6, 45–52.

    Article  PubMed  CAS  Google Scholar 

  11. Wang, L., McAllan, B. M., and He, G. (2011) Biochemistry (Moscow), 76, 1017–1021.

    Article  CAS  Google Scholar 

  12. Fradiani, P., Ascenzioni, F., Lavitrano, M., and Donini, P. (2004) Biochimie, 86, 7–12.

    Article  PubMed  CAS  Google Scholar 

  13. Clark, W. R. (2004) Adv. Gerontol., 14, 7–20.

    PubMed  CAS  Google Scholar 

  14. Mitteldorf, J. (2006) Evol. Ecol. Res., 8, 561–574.

    Google Scholar 

  15. Libertini, G. J. (1988) Theor. Biol., 132, 145–162.

    Article  CAS  Google Scholar 

  16. Martins, A. C. (2011) PLOS One, 6, e24328.

    Article  PubMed  CAS  Google Scholar 

  17. West, M. D. (2003) The Immortal Cell, Doubleday, New York.

    Google Scholar 

  18. Bernardes de Jesus, B., Schneeberger, K., Vera, E., Tejera, A., Harley, C. B., and Blasco, M. A. (2011) Aging Cell, 10, 604–621.

    Article  PubMed  CAS  Google Scholar 

  19. Cawthon, R. M., Smith, K. R., O’Brien, E., Sivatchenko, A., and Kerber, R. A. (2003) Lancet, 361, 393–395.

    Article  PubMed  CAS  Google Scholar 

  20. Haussmann, M. F., Winkler, D. W., and Vleck, C. M. (2005) Biol. Lett., 1, 212–214.

    Article  PubMed  CAS  Google Scholar 

  21. Bize, P., Criscuolo, F., Metcalfe, N. B., Nasir, L., and Monaghan, P. (2009) Proc. Biol. Sci., 276, 1679–1683.

    Article  PubMed  CAS  Google Scholar 

  22. Joeng, K. S., Song, E. J., Lee, K. J., and Lee, J. (2004) Nat. Genet., 36, 607–611.

    Article  PubMed  CAS  Google Scholar 

  23. Tomas-Loba, A., Flores, I., Fernandez-Marcos, P. J., Cayuela, M. L., Maraver, A., Tejera, A., Borras, C., Matheu, A., Klatt, P., Flores, J. M., Vina, J., Serrano, M., and Blasco, M. A. (2008) Cell, 135, 609–622.

    Article  PubMed  CAS  Google Scholar 

  24. Wynford-Thomas, D., and Kipling, D. (1997) Nature, 389, 551–552.

    Article  PubMed  Google Scholar 

  25. Chang, S. (2005) Mutat. Res., 576, 39–53.

    Article  PubMed  CAS  Google Scholar 

  26. Mendelsohn, A. R., and Larrick, J. W. (2012) Rejuvenation Res., 15, 435–438.

    Article  PubMed  CAS  Google Scholar 

  27. Wright, W. E., and Shay, J. W. (2005) J. Am. Geriatr. Soc., 53, S292–S294.

    Article  PubMed  Google Scholar 

  28. Wu, X., Amos, C. I., Zhu, Y., Zhao, H., Grossman, B. H., Shay, J. W., Luo, S., Hong, W. K., and Spitz, M. R. (2003) J. Natl. Cancer Inst., 95, 1211–1218.

    Article  PubMed  CAS  Google Scholar 

  29. Ma, H., Zhou, Z., Wei, S., Liu, Z., Pooley, K. A., Dunning, A. M., Svenson, U., Roos, G., Hosgood, H. D., 3rd., Shen, M., and Wei, Q. (2011) PLoS ONE, 6, e20466.

    Article  PubMed  CAS  Google Scholar 

  30. Artandi, S. E., Alson, S., Tietze, M. K., Sharpless, N. E., Ye, S., Greenberg, R. A., Castrillon, D. H., Horner, J. W., Wieler, S. R., Carrasco, R. D., and DePinho, R. A. (2002) Proc. Natl. Acad. Sci. USA, 99, 8191–8196.

    Article  PubMed  CAS  Google Scholar 

  31. Canela, A., Martin-Caballero, J., Flores, J. M., and Blasco, M. A. (2004) Mol. Cell. Biol., 24, 4275–4293.

    Article  PubMed  CAS  Google Scholar 

  32. Gonzalez-Suarez, E., Samper, E., Ramirez, A., Flores, J. M., Martin-Caballero, J., Jorcano, J. L., and Blasco, M. A. (2001) EMBO J., 20, 2619–2630.

    Article  PubMed  CAS  Google Scholar 

  33. Cong, Y., and Shay, J. W. (2008) Cell Res., 18, 725–732.

    Article  PubMed  CAS  Google Scholar 

  34. Greider, C. W. (1990) Bioessays, 12, 363–369.

    Article  PubMed  CAS  Google Scholar 

  35. Schoeftner, S., Blanco, R., Lopez de Silanes, I., Munoz, P., Gomez-Lopez, G., Flores, J. M., and Blasco, M. A. (2009) Proc. Natl. Acad. Sci. USA, 106, 19393–19398.

    Article  PubMed  CAS  Google Scholar 

  36. Campisi, J. (2005) Cell, 120, 513–522.

    Article  PubMed  CAS  Google Scholar 

  37. Rodier, F., Coppe, J. P., Patil, C. K., Hoeijmakers, W. A., Munoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., and Campisi, J. (2009) Nat. Cell Biol., 11, 973–979.

    Article  PubMed  CAS  Google Scholar 

  38. Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Slius, B., Kirkland, J. L., and van Deursen, J. M. (2011) Nature, 479, 232–236.

    Article  PubMed  CAS  Google Scholar 

  39. Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., Foerster, F., Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M., Martin, E. S., Heffernan, T. P., Protopopov, A., Ivanova, I., Mahoney, J. E., Kost-Alimova, M., Perry, S. R., Bronson, R., Liao, R., Mulligan, R., Shirihai, O. S., Chin, L., and DePinho, R. A. (2011) Nature, 470, 359–365.

    Article  PubMed  CAS  Google Scholar 

  40. Masutomi, K., Yu, E. Y., Khurts, S., Ben-Porath, I., Currier, J. L., Metz, G. B., Brooks, M. W., Kaneko, S., Murakami, S., DeCaprio, J. A., Weinberg, R. A., Stewart, S. A., and Hahn, W. C. (2003) Cell, 114, 241–253.

    Article  PubMed  CAS  Google Scholar 

  41. Shay, J. W., and Bacchetti, S. (1997) Eur. J. Cancer, 33, 787–791.

    Article  PubMed  CAS  Google Scholar 

  42. Blasco, M. A., Lee, H. W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., and Greider, C. W. (1997) Cell, 91, 25–34.

    Article  PubMed  CAS  Google Scholar 

  43. Shay, J. W. (2005) The Scientist, 19, 18–19.

    Google Scholar 

  44. Stearns, S. C. (1992) The Evolution of Life Histories, Oxford University Press, Oxford, New York.

    Google Scholar 

  45. Kimura, M., Hjelmborg, J. V., Gardner, J. P., Bathum, L., Brimacombe, M., Lu, X., Christiansen, L., Vaupel, J. W., Aviv, A., and Chistensen, K. (2008) Am. J. Epidemiol., 167, 799–806.

    Article  PubMed  Google Scholar 

  46. Bernardes de Jesus, B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., and Blasco, M. A. (2012) EMBO Mol. Med., 4, 691–704.

    Article  PubMed  CAS  Google Scholar 

  47. Williams, G. (1957) Evolution, 11, 398–411.

    Article  Google Scholar 

  48. Gonzalez-Suarez, E., Geserick, C., Flores, J. M., and Blasco, M. A. (2005) Oncogene, 24, 2256–2270.

    Article  PubMed  CAS  Google Scholar 

  49. Gomes, N. M. V., Ryder, O. A., Houck, M. L., Charter, S. J., Walker, W., Forsyth, N. R., Austad, S. N., Venditti, C., Pagel, M., Shay, J. W., and Wright, W. E. (2011) Aging Cell, 10, 761–768.

    Article  PubMed  CAS  Google Scholar 

  50. Rodier, F., and Campisi, J. (2011) J. Cell Biol., 192, 547–556.

    Article  PubMed  CAS  Google Scholar 

  51. Williams, G. (1966) Adaptation and Natural Selection, Princeton University Press, Princeton.

    Google Scholar 

  52. Maynard Smith, J. (1976) Q. Rev. Biol., 51, 277–283.

    Article  Google Scholar 

  53. Sober, E., and Wilson, D. S. (1998) Unto Others: The Evolution and Psychology of Unselfish Behavior, Harvard University Press, Cambridge, MA.

    Google Scholar 

  54. Trubitsyn, A. (2006) Adv. Gerontol. (Russia), 19, 13–24.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J. J. Mitteldorf.

Additional information

Published in Russian in Biokhimiya, 2013, Vol. 78, No. 9, pp. 1345–1353.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitteldorf, J.J. Telomere biology: Cancer firewall or aging clock?. Biochemistry Moscow 78, 1054–1060 (2013). https://doi.org/10.1134/S0006297913090125

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297913090125

Key words

Navigation