Biochemistry (Moscow)

, Volume 78, Issue 9, pp 1054–1060 | Cite as

Telomere biology: Cancer firewall or aging clock?

Phenoptosis

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.

Key words

telomere telomerase cancer programmed aging adaptive aging evolution 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mitteldorf, J. (2013) Biochemistry (Moscow), 78, 1048–1053.CrossRefGoogle Scholar
  2. 2.
    Melnikova, L., and Georgiev, P. (2005) Chromosome Res., 13, 431–441.PubMedCrossRefGoogle Scholar
  3. 3.
    Pauliny, A., Wagner, R. H., Augustin, J., Szep, T., and Blomqvist, D. (2006) Mol. Ecol., 15, 1681–1687.PubMedCrossRefGoogle Scholar
  4. 4.
    Herbig, U., Ferreira, M., Condel, L., Carey, D., and Sedivy, J. M. (2006) Science, 311, 1257.PubMedCrossRefGoogle Scholar
  5. 5.
    Argyle, D., Ellsmore, V., Gault, E. A., Munro, A. F., and Nasir, L. (2003) Mech. Ageing Devel., 124, 759–764.CrossRefGoogle Scholar
  6. 6.
    McKevitt, T. P., Nasir, L., Devlin, P., and Argyle, D. J. (2002) J. Nutr., 132, 1604S–1606S.PubMedGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 8.
    Cui, W., Wylie, D., Aslam, S., Dinnyes, A., King, T., Wilmut, I., and Clark, A. J. (2003) Biol. Reprod., 69, 15–21.PubMedCrossRefGoogle Scholar
  9. 9.
    Choi, D., Cho, C., and Sohn, S. (2008) J. Animal Sci. Technol., 50, 445–456.CrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang, L., McAllan, B. M., and He, G. (2011) Biochemistry (Moscow), 76, 1017–1021.CrossRefGoogle Scholar
  12. 12.
    Fradiani, P., Ascenzioni, F., Lavitrano, M., and Donini, P. (2004) Biochimie, 86, 7–12.PubMedCrossRefGoogle Scholar
  13. 13.
    Clark, W. R. (2004) Adv. Gerontol., 14, 7–20.PubMedGoogle Scholar
  14. 14.
    Mitteldorf, J. (2006) Evol. Ecol. Res., 8, 561–574.Google Scholar
  15. 15.
    Libertini, G. J. (1988) Theor. Biol., 132, 145–162.CrossRefGoogle Scholar
  16. 16.
    Martins, A. C. (2011) PLOS One, 6, e24328.PubMedCrossRefGoogle Scholar
  17. 17.
    West, M. D. (2003) The Immortal Cell, Doubleday, New York.Google Scholar
  18. 18.
    Bernardes de Jesus, B., Schneeberger, K., Vera, E., Tejera, A., Harley, C. B., and Blasco, M. A. (2011) Aging Cell, 10, 604–621.PubMedCrossRefGoogle Scholar
  19. 19.
    Cawthon, R. M., Smith, K. R., O’Brien, E., Sivatchenko, A., and Kerber, R. A. (2003) Lancet, 361, 393–395.PubMedCrossRefGoogle Scholar
  20. 20.
    Haussmann, M. F., Winkler, D. W., and Vleck, C. M. (2005) Biol. Lett., 1, 212–214.PubMedCrossRefGoogle Scholar
  21. 21.
    Bize, P., Criscuolo, F., Metcalfe, N. B., Nasir, L., and Monaghan, P. (2009) Proc. Biol. Sci., 276, 1679–1683.PubMedCrossRefGoogle Scholar
  22. 22.
    Joeng, K. S., Song, E. J., Lee, K. J., and Lee, J. (2004) Nat. Genet., 36, 607–611.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Wynford-Thomas, D., and Kipling, D. (1997) Nature, 389, 551–552.PubMedCrossRefGoogle Scholar
  25. 25.
    Chang, S. (2005) Mutat. Res., 576, 39–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Mendelsohn, A. R., and Larrick, J. W. (2012) Rejuvenation Res., 15, 435–438.PubMedCrossRefGoogle Scholar
  27. 27.
    Wright, W. E., and Shay, J. W. (2005) J. Am. Geriatr. Soc., 53, S292–S294.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 31.
    Canela, A., Martin-Caballero, J., Flores, J. M., and Blasco, M. A. (2004) Mol. Cell. Biol., 24, 4275–4293.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 33.
    Cong, Y., and Shay, J. W. (2008) Cell Res., 18, 725–732.PubMedCrossRefGoogle Scholar
  34. 34.
    Greider, C. W. (1990) Bioessays, 12, 363–369.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Campisi, J. (2005) Cell, 120, 513–522.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 41.
    Shay, J. W., and Bacchetti, S. (1997) Eur. J. Cancer, 33, 787–791.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 43.
    Shay, J. W. (2005) The Scientist, 19, 18–19.Google Scholar
  44. 44.
    Stearns, S. C. (1992) The Evolution of Life Histories, Oxford University Press, Oxford, New York.Google Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Williams, G. (1957) Evolution, 11, 398–411.CrossRefGoogle Scholar
  48. 48.
    Gonzalez-Suarez, E., Geserick, C., Flores, J. M., and Blasco, M. A. (2005) Oncogene, 24, 2256–2270.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 50.
    Rodier, F., and Campisi, J. (2011) J. Cell Biol., 192, 547–556.PubMedCrossRefGoogle Scholar
  51. 51.
    Williams, G. (1966) Adaptation and Natural Selection, Princeton University Press, Princeton.Google Scholar
  52. 52.
    Maynard Smith, J. (1976) Q. Rev. Biol., 51, 277–283.CrossRefGoogle Scholar
  53. 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. 54.
    Trubitsyn, A. (2006) Adv. Gerontol. (Russia), 19, 13–24.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  1. 1.Department of EAPSMassachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations