Biochemistry (Moscow)

, Volume 78, Issue 9, pp 1048–1053 | Cite as

How does the body know how old it is? Introducing the epigenetic clock hypothesis

Phenoptosis

Abstract

Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development, and sexual maturity. It is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks. Evolutionary reasoning first articulated by G. Williams suggests that multiple, redundant clocks might influence organismal aging. Some aging clocks that have been proposed include the suprachiasmatic nucleus, the hypothalamus, involution of the thymus, and cellular senescence. Cellular senescence, mediated by telomere attrition, is in a class by itself, having recently been validated as a primary regulator of aging. Gene expression is known to change in characteristic ways with age, and in particular DNA methylation changes in age-related ways. Herein, I propose a new candidate for an aging clock, based on epigenetics and the state of chromosome methylation, particularly in stem cells. If validated, this mechanism would present a challenging target for medical intervention.

Key words

biological clock senescence rhythm maturation aging programmed aging adaptive aging methylation epigenetics gene expression 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Mitteldorf, J. (2004) Evol. Ecol. Res., 6, 1–17.Google Scholar
  2. 2.
    Mitteldorf, J. (2010) in Approaches to the Control of Aging: Building a Pathway to Human Life Extension (Fahy, G. M., et al., eds.) Springer, New York.Google Scholar
  3. 3.
    Mitteldorf, J. (2012) Biochemistry (Moscow), 77, 716–725.CrossRefGoogle Scholar
  4. 4.
    Guarente, L., and Kenyon, C. (2000) Nature, 408, 255–262.PubMedCrossRefGoogle Scholar
  5. 5.
    Forbes, V. (2000) Funct. Ecol., 14, 12–24.CrossRefGoogle Scholar
  6. 6.
    Masoro, E. J. (2007) Interdiscipl. Top. Gerontol., 35, 1–17.Google Scholar
  7. 7.
    Leroi, A., Chippindale, A. K., and Rose, M. R. (1994) Evolution, 48, 1244–1257.CrossRefGoogle Scholar
  8. 8.
    Arantes-Oliveira, N., Berman, J. R., and Kenyon, C. (2003) Science, 302, 611.PubMedCrossRefGoogle Scholar
  9. 9.
    Fabrizio, P., Battistella, L., Vardavas, R., Gattazzo, C., Liou, L.-L., Diaspro, A., Dossen, J. W., Gralla, E. B., and Longo, V. D. (2004) J. Cell Biol., 166, 1055–1067.PubMedCrossRefGoogle Scholar
  10. 10.
    Clark, W. R. (1998) Sex and the Origins of Death, Oxford University Press, Oxford.Google Scholar
  11. 11.
    Clark, W. R. (1999) A Means to an End: the Biological Basis of Aging and Death, Oxford University Press, New York.Google Scholar
  12. 12.
    Clark, W. R. (2004) Adv. Gerontol., 14, 7–20.PubMedGoogle Scholar
  13. 13.
    Behl, C. (2000) J. Neur. Trans., 107, 1325–1344.CrossRefGoogle Scholar
  14. 14.
    Cawthon, R. M., Smith, K. R., O’Brien, E., Sivatchenko, A., and Kerber, R. A. (2003) Lancet, 361, 393–395.PubMedCrossRefGoogle Scholar
  15. 15.
    Williams, G. (1957) Evolution, 11, 398–411.CrossRefGoogle Scholar
  16. 16.
    Mitteldorf, J. (2013) Biochemistry (Moscow), 78, 1054–1060.CrossRefGoogle Scholar
  17. 17.
    Beck, S. D., and Bharadwaj, R. K. (1972) Science, 178, 1210–1211.PubMedCrossRefGoogle Scholar
  18. 18.
    Piraino, S., Boero, F., Aeschbach, B., and Schmid, V. (1996) Biol. Bull., 90, 302–312.CrossRefGoogle Scholar
  19. 19.
    Barinaga, M. (1992) Science, 258, 398–399.PubMedCrossRefGoogle Scholar
  20. 20.
    Jaskelioff, M., Muller, F. L., Paik, J.-H., Thomas, E., Jiang, S., Adams, A. C., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadicanos, J., Horner, J. W., Maratos-Flier, E., and DePinho, R. A. (2011) Nature, 469, 102–106.PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., and Rando, T. A. (2005) Nature, 433, 760–764.PubMedCrossRefGoogle Scholar
  23. 23.
    Katcher, H. (2013) Biochemistry (Moscow), 78, 1061–1070.CrossRefGoogle Scholar
  24. 24.
    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
  25. 25.
    Mair, W., Goymer, P., Pletcher, S. D., and Partridge, L. (2003) Science, 301, 1731–1733.PubMedCrossRefGoogle Scholar
  26. 26.
    Klein, D. C., Moore, R. Y., and Reppert, S. M. (1991) Suprachiasmatic Nucleus: the Mind’s Clock, Oxford University Press, New York.Google Scholar
  27. 27.
    Edgar, R. S., Green, E. W., Zhao, Y., van Ooijen, G., Olmedo, M., Qin, X., Xu, Y., Pan, M., Valekunja, U. K., Feeney, K. A., Maywood, E. S., Hastings, M. H., Baliga, N. S., Merrow, M., Millar, A. J., Johnson, C. H., Kyriacou, C. P., O’Neill, J. S., and Reddy, A. B. (2012) Nature, 485, 459–464.PubMedGoogle Scholar
  28. 28.
    Danks, H. (2005) J. Insect Physiol., 51, 609–619.PubMedCrossRefGoogle Scholar
  29. 29.
    Ebling, F. J. (2005) Reproduction, 129, 675–683.PubMedCrossRefGoogle Scholar
  30. 30.
    Kumar, S., Mohan, A., and Sharma, V. K. (2005) Chronobiol. Int., 22, 641–653.PubMedCrossRefGoogle Scholar
  31. 31.
    Dubrovsky, Y. V., Samsa, W. E., and Kondratov, R. V. (2010) Aging (Albany NY), 2, 936.Google Scholar
  32. 32.
    Dilman, V. M., and Dean, W. (1992) The Neuroendocrine Theory of Aging and Degenerative Disease, Center for Bio Gerontology.Google Scholar
  33. 33.
    Weinert, B. T., and Timiras, P. S. (2003) J. Appl. Physiol., 95, 1706–1716.PubMedGoogle Scholar
  34. 34.
    Walford, R. L. (1964) The Gerontologist, 4, 195–197.PubMedCrossRefGoogle Scholar
  35. 35.
    Walford, R. L. (1969) Immunol. Rev., 2, 171.CrossRefGoogle Scholar
  36. 36.
    West, M. D. (2003) The Immortal Cell, Doubleday, New York.Google Scholar
  37. 37.
    Johnson, A. A., Akman, K., Calimport, S. R., Wuttke, D., Stolzing, A., and de Magalhres, J. P. (2012) Rejuvenation Res., 15, 483–494.PubMedCrossRefGoogle Scholar
  38. 38.
    Cooney, C., and Lawren, B. (1999) Methyl Magic: Maximum Health through Methylation, Andrews McNeel Pub.Google Scholar
  39. 39.
    Jablonka, E., and Raz, G. (2009) The Quart. Rev. Biol., 84, 131–176.CrossRefGoogle Scholar
  40. 40.
    Bellizzi, D., D’Aquila, P., Montesanto, A., Corsonello, A., Mari, V., Mazzei, B., Lattanzio, F., and Passarino, G. (2012) Age, 34, 169–179.PubMedCrossRefGoogle Scholar
  41. 41.
    Lin, M.-J., Tang, L. Y., Reddy, M. N., and Shen, C. K. (2005) J. Biol. Chem., 280, 861–864.PubMedCrossRefGoogle Scholar
  42. 42.
    Yung, R., Ray, D., Eisenbraun, J. K., Deng, C., Attwood, J., Eisenbraun, M. D., Johnson, K., Miller, R. A., Hanash, S., and Richardson, B. (2001) J. Gerontol. Ser. A: Biol. Sci. Med. Sci., 56, B268–B276.CrossRefGoogle Scholar
  43. 43.
    Ray, D., Wu, A., Wilkinson, J. E., Murphy, H. S., Lu, Q., Kluve-Beckerman, B., Liepnieks, J. J., Benson, M., Yung, R., and Richardson, B. (2006) J. Gerontol. Ser. A: Biol. Sci. Med. Sci., 61, 115–124.CrossRefGoogle Scholar
  44. 44.
    Liu, L., van Groen, T., Kadish, I., Li, Y., Wang, D., James, S. R., Karpf, A. R., and Tollefsbol, T. O. (2011) Clin. Epigenetics, 2, 349–360.PubMedCrossRefGoogle Scholar
  45. 45.
    Fraga, M. F., Ballestar, E., Paz, M. F., Ropero, S., Setien, F., Ballestar, M. L., Heine-Sucer, D., Cigudosa, J. C., Urioste, M., Benitez, J., Boix-Chornet, M., Sanchez-Aguilera, A., Ling, C., Carlsson, E., Poulsen, P., Vaag, A., Stephan, Z., Spector, T. D., Wu, Y. Z., Plass, C., and Esteller, M. (2005) Proc. Natl. Acad. Sci. USA, 102, 10604–10609.PubMedCrossRefGoogle Scholar
  46. 46.
    Wilson, V. L., and Jones, P. A. (1983) Science (NY), 220, 1055.CrossRefGoogle Scholar
  47. 47.
    Heyn, H., Li, N., Ferreira, H. J., Moran, S., Pisano, D. G., Gomez, A., Diez, J., Sanchez-Mut, J. V., Setien, F., Carmona, F. J., Puca, A. A., Sayols, S., Pujana, M. A., Serra-Musach, J., Iglesias-Platas, I., Formiga, F., Fernandez, A. F., Fraga, M. F., Heath, S. C., Valencia, A., Gut, I. G., Wang, J., and Esteller, M. (2012) Proc. Natl. Acad. Sci. USA, 109, 10522–10527.PubMedCrossRefGoogle Scholar
  48. 48.
    Bowles, J. T. (1998) Med. Hypotheses, 51, 179–221.PubMedCrossRefGoogle Scholar
  49. 49.
    Vanyushin, B., Nemirovsky, L. E., Klimenko, V. V., Vasiliev, V. K., and Belozersky, A. N. (1973) Gerontology, 19, 138–152.CrossRefGoogle Scholar
  50. 50.
    Wilson, V. L., Smith, R. A., Ma, S., and Culter, R. G. (1987) J. Biol. Chem., 262, 9948–9951.PubMedGoogle Scholar
  51. 51.
    Mazin, A. (1993) Mol. Biol. (Moscow), 27, 160.Google Scholar
  52. 52.
    Mazin, A. (1993) Mol. Biol. (Moscow), 27, 895.Google Scholar
  53. 53.
    Skulachev, V. P. (2004) in Model Systems in Aging (Nystrom, T., and Osiewacz, H. D., eds.) Springer, Berlin, pp. 191–238.Google Scholar
  54. 54.
    Weitzman, S. A., Turk, P. W., Milkowski, D. H., and Kozlowski, K. (1994) Proc. Natl. Acad. Sci. USA, 91, 1261–1264.PubMedCrossRefGoogle Scholar
  55. 55.
    Romanenko, E. B., Alessenko, A. V., and Vanyushin, B. F. (1995) Biochem. Mol. Biol. Int., 35, 87.PubMedGoogle Scholar
  56. 56.
    Panning, B., and Jaenisch, R. (1996) Genes Devel., 10, 1991–2002.PubMedCrossRefGoogle Scholar
  57. 57.
    Kelly, G. (2010) Altern. Med. Rev., 15, 245–263.PubMedGoogle Scholar
  58. 58.
    Zimmerman, J. A., Malloy, V., Krajcik, R., and Orentreich, N. (2003) Exp. Gerontol., 38, 47.PubMedCrossRefGoogle Scholar
  59. 59.
    Baldessarini, R. J. (1987) Am. J. Med., 83 (Suppl. 1), 95–103.PubMedCrossRefGoogle Scholar
  60. 60.
    Batra, V., Sridhar, S., and Devasagayam, T. P. A. (2010) Chem.-Biol. Interact., 183, 425–433.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2013

Authors and Affiliations

  1. 1.Department of EAPSMassachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations