Journal of Bioenergetics and Biomembranes

, Volume 37, Issue 2, pp 83–90 | Cite as

Dietary Restriction at Old Age Lowers Mitochondrial Oxygen Radical Production and Leak at Complex I and Oxidative DNA Damage in Rat Brain

  • Alberto Sanz
  • Pilar Caro
  • Jorge Ibañez
  • José Gómez
  • Ricardo Gredilla
  • Gustavo Barja
Article

Abstract

Previous studies in mammalian models indicate that the rate of mitochondrial reactive oxygen species ROS production and the ensuing modification of mitochondrial DNA (mtDNA) link oxidative stress to aging rate. However, there is scarce information concerning this in relation to caloric restriction (CR) in the brain, an organ of maximum relevance for ageing. Furthermore, it has never been studied if CR started late in life can improve those oxidative stress-related parameters. In this investigation, rats were subjected during 1 year to 40% CR starting at 24 months of age. This protocol of CR significantly decreased the rate of mitochondrial H2O2 production (by 24%) and oxidative damage to mtDNA (by 23%) in the brain below the level of both old and young ad libitum-fed animals. In agreement with the progressive character of aging, the rate of H2O2 production of brain mitochondria stayed constant with age. Oxidative damage to nuclear DNA increased with age and this increase was fully reversed by CR to the level of the young controls. The decrease in ROS production induced by CR was localized at Complex I and occurred without changes in oxygen consumption. Instead, the efficiency of brain mitochondria to avoid electron leak to oxygen at Complex I was increased by CR. The mechanism involved in that increase in efficiency was related to the degree of electronic reduction of the Complex I generator. The results agree with the idea that CR decreases aging rate in part by lowering the rate of free radical generation of mitochondria in the brain.

Keywords

Caloric restriction brain mitochondria free radical generation aging old age oxygen radicals Complex I oxidative DNA damage 8-hydroxydeoxyguanosine mitochondrial DNA 

Abbreviations:

dG

deoxyguanosine

mtDNA

mitochondrial DNA

nDNA

nuclear DNA

8-oxodG

8-oxo,7,8-dihydro-2′-deoxyguanosine

ROS

reactive oxygen species

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asunción, J. G., Millan, A., Pla, R., Bruseghini, I., Esteras, A., Pallardo, F. V., Sastre, J., and Viña, J. (1996). FASEB J. 10, 333–338.PubMedGoogle Scholar
  2. Baek, B. S., Kwon, H. J., Lee, K. H., Yoo, M. A., Kim, K. W., Ikeno, Y., Yu, B. P., and Chung, H. Y. (1999). Arch. Pharm. Res. 22, 361–366.PubMedGoogle Scholar
  3. Barja, G. (1999). J. Bioenerg. Biomembr. 31, 347–366.PubMedGoogle Scholar
  4. Barja, G. (2000). Aging Clin. Exp. Res. 12, 342–355.Google Scholar
  5. Barja, G. (2002). J. Bioenerg. Biomembr. 34, 227–233.PubMedGoogle Scholar
  6. Barja, G. (2004a). Trends Neurosci. 27, 595–600.Google Scholar
  7. Barja, G. (2004b). Biol. Rev. 79, 235–251.Google Scholar
  8. Beal, M. F. (2003). Ann. N.Y. Acad. Sci. 991, 120–131.PubMedGoogle Scholar
  9. Beckman, K. B., and Ames, B. (1998). Physiol. Rev. 78, 547–581.PubMedGoogle Scholar
  10. Cao, S. X., Dhabi, J. M., Mote, P. L., and Spindler, S. R. (2001). PNAS. 98, 10630–10635.PubMedGoogle Scholar
  11. Edwards, M. G., Sarkar, D., Klopp, R., Morrow, J. D., Weindruch, R. D., and Prolla, T. A. (2003). Physiol. Genomics. 13, 119–127.PubMedGoogle Scholar
  12. Forster, M. J., Morris, P., and Sohal, R. S. (2003). FASEB J. 17, 690–692.PubMedGoogle Scholar
  13. Gredilla, R., Sanz, A., López-Torres, M., and Barja, G. (2001). FASEB J. 15, 1589–1591.PubMedGoogle Scholar
  14. Greenberg, J. A., Wei, H., Ward, K., and Boozer, C. N. (2000). Mech. Ageing Dev. 115, 107–117.PubMedGoogle Scholar
  15. Hamilton, M. L., Van Remmen, H. V., Drake, J. A., Yang, H., Guo, Z. M., Kewitt, K., Walter, C. A., and Richardson, A. (2001). PNAS 98, 10469–10474.PubMedGoogle Scholar
  16. Herrero, A., and Barja, G. (2001). J. Am. Aging Assoc. 24, 45–50.Google Scholar
  17. Hoglinger, G. U., Carrad, G., Michel, P. P., Medja, F., Lombes, A., Ruberg, M., Friguet, B., and Hirsch, E. C. (2003). J. Neurochem. 86, 1297–1307.PubMedGoogle Scholar
  18. Honda, K. (2004). Ann. N.Y. Acad. Sci. 1012, 179–182.PubMedGoogle Scholar
  19. Ingram, D. K., Weindruch, R., Spangler, E. L., Freeman, J. R., and Walford, R. L. (1987). J. Gerontol. 42, 78–81.PubMedGoogle Scholar
  20. Kanda, K. (2002). Micros Res. Tech. 59, 301–305.Google Scholar
  21. Kaneko, T., Tahara, S., and Matsuo, M. (1997). Free Radical. Biol. Med. 23, 76–81.Google Scholar
  22. Khrapko, K., Nekhaeva, E., Kraytsberg, Y., and Kunz, W. (2003). Mutat. Res. 522, 13–19.PubMedGoogle Scholar
  23. Lai, C. K., and Clark, J. B. (1979). Methods Enzymol. 55, 51–60.PubMedGoogle Scholar
  24. Latorre, A., Moya, A., and Ayala, A. (1986). PNAS USA 83, 8649–8653.Google Scholar
  25. Lee, C. K., Allison, D. B., Brand, J., Weindruch, R., and Prolla, T. A. (2002). PNAS 99, 14988–14993.PubMedGoogle Scholar
  26. López-Torres, M., Gredilla, R., Sanz, A., and Barja, G. (2002). Free Radical. Biol. Med. 32, 882–889.Google Scholar
  27. Loft, S., and Poulsen, H. E. (1999). Methods Enzymol. 300, 166–184.PubMedGoogle Scholar
  28. Mattson, M. P., Chan, S. L., and Duan, W. (2002). Physiol. Rev. 82, 637–672.PubMedGoogle Scholar
  29. Mattson, M. P. (2003). Neurology 60, 690–695.PubMedGoogle Scholar
  30. Meccoci, P., MacGarvey, U., Kaufman, A. E., Koontz, D., Shoffner, J. M., Wallace, D. C., and Beal, F. (1993). Ann. Neurol. 34, 609–616.PubMedGoogle Scholar
  31. Moroi-Fetters, S. E. (1989). Neurobiol. Aging 10, 317–322.PubMedGoogle Scholar
  32. Sanz, A., Gredilla, R., Pamplona, R., Portero-Otín, M., Vara, E., Tresguerres, J. A. F., and Barja, G. (2005). Biogerontol. 6, 15–26.Google Scholar
  33. Sohal, R. S., Ku, H. H., Agarwal, S., Forster, M. J., and Lal, H. (1994a). Mech. Ageing Dev. 74, 121–133.Google Scholar
  34. Sohal, R. S., Agarwal, S., Candas, M., Forster, M. J., and Lal, H. (1994b). Mech. Ageing Dev. 76, 215–224.Google Scholar
  35. Starkov, A. A., and Fiskum, G. (2003). J. Neurochem. 86, 1101–1107.PubMedGoogle Scholar
  36. Stuart, J. A., Karahalil, B., Hogue, B. A., Souza-Pinto, N. C., and Bohr, V. A. (2004). FASEB J. 18, 595–597.PubMedGoogle Scholar
  37. Takahashi, R., and Goto, S. (2002). Micros Res. Tech. 59, 278–281.Google Scholar
  38. Tyler, D. D. (1992). The Mitochondria in Health and Disease, VCH Publishers, New York.Google Scholar
  39. Wanagat, J., Allison, D. B., and Weindruch, R. (1999). Toxicol. Sci. 52S, 35–40.Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Alberto Sanz
    • 1
  • Pilar Caro
    • 1
  • Jorge Ibañez
    • 1
  • José Gómez
    • 1
  • Ricardo Gredilla
    • 1
  • Gustavo Barja
    • 1
    • 2
  1. 1.Department of Animal Physiology-II, Faculty of Biological SciencesComplutense UniversityMadridSpain
  2. 2.Departamento de Fisiología Animal-II, Facultad de Ciencias BiológicasUniversidad ComplutenseMadridSpain

Personalised recommendations