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Aging as Evolution-Facilitating Program and a Biochemical Approach to Switch It Off

Conference paper
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Part of the NATO Science for Peace and Security Series B: Physics and Biophysics book series (NAPSB)

Abstract

A concept is presented considering aging of living organisms as a final step of their ontogenetic program. It is assumed that such an aging program was invented by biological evolution to facilitate the evolutionary process. Indications are summarized suggesting that controlled production of toxic forms of oxygen (so called reactive oxygen species) by respiring intracellular organelles (mitochondria) is an obligatory component of the aging program. First results of a research project devoted to an attempt to interrupt aging program by antioxidants specifically addressed to mitochondria have been described. Within the framework of the project, antioxidants of a new type (SkQ) were synthesized. SkQs are composed of (i) plastoquinone (an antioxidant moiety), (ii) a penetrating cation, and (iii) a decane or pentane linker. Using planar bilayer phospholipid membranes, we selected SkQ derivatives of the highest penetrability, namely plastoquinonyl decyl triphenylphosphonium (SkQ1), plastoquinonyl decyl rhodamine 19 (SkQR1), and methylplastoquinonyl decyl triphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in isolated mitochondria. Micromolar concentrations of cationic quinones are found to be very strong prooxidants, but in the lower (sub-micromolar) concentrations they display antioxidant activity which decreases in the series SkQ1 = SkQR1 > SkQ3 > MitoQ. Thus, the window between the anti- and prooxidant effects is the smallest for MitoQ and the largest for SkQ1 and SkQR1. SkQ1 is rapidly reduced by complex III of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Extremely low concentrations of SkQ1 and SkQR1 completely arrest the H2O2-induced apoptosis in human fibroblasts and HeLa cells (for SkQ1, C 1/2 = 8 · 10−9M). Higher concentrations of SkQ1 are required to block necrosis initiated by reactive oxygen species (ROS). In mice, SkQ1 decelerates the development of three types of accelerated aging (progeria) and also of normal aging, and this effect is especially demonstrative at early stages of aging. The same pattern is shown in invertebrates (Drosophila and Daphnia), and fungus (Podospora anserina). In mammals, the effect of SkQs on aging is accompanied by inhibition of development of such age-related diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. SkQ1 manifests a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision is recovered in 66 of 96 animals (dogs, cats and horses) who became blind because of retinopathy. SkQ1-containing drops instilled into eyes prevent the loss of sight in rabbits suffering from experimental uveitis and restore vision to animals that had already become blind due to this pathology. A favorable effect is also achieved in experimental glaucoma in rabbits. Moreover, the pretreatment of rats with 0.2 nM SkQ1 significantly decreases the H2O2-induced arrhythmia of the isolated heart. SkQ1 strongly reduces the damaged area in myocardial infarction or stroke and prevents the death of animals from kidney infarction. In p53−/− mice, SkQ1 decreases the ROS level in the spleen cells and inhibits appearance of lymphomas which are the main cause of death of such animals. As a result, the lifespan increases. SkQs look like promising drugs to treat aging and age-related diseases.

Keywords

Biological evolution aging mitochondria reactive oxygen species SkQs antioxidants 

Abbreviations

BLM

planar bilayer phospholipid membrane

C12TPP

dodecyl triphenylphosphonium

DMQ

demethoxyMitoQL, MitoQ, compound of ubiquinone and decyl triphenylphosphonium

ROS

reactive oxygen species

SkQ

compounds of plastoquinone or methylplastoquinone and decyl (or amyl) triph-enylphosphonium, methylcarninite, or tributylammonium

SkQ1

compound of plastoquinone and decyl triphenylphosphonium (other SkQ derivatives are shown in Fig. 3)

Δψ

transmembrane electric potential

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References

  1. 1.
    Skulachev, V. P. (1999) Biochemistry (Moscow), 64, 1418–1426.Google Scholar
  2. 2.
    Skulachev, V. P. (2003) in Topics in Current Genetics. Model Systems in Ageing (Nystrom, T., and Osiewacz, H. D., eds.) Vol. 3, Springer-Verlag, Berlin-Heidelberg, pp. 191–238.Google Scholar
  3. 3.
    Lewis, K. (2000) Microbiol. Mol. Biol. Rev., 64, 503–514.CrossRefGoogle Scholar
  4. 4.
    Longo, V. D., Mitteldorf, J., and Skulachev, V. P. (2005) Nature Rev. Genet., 6, 866–872.CrossRefGoogle Scholar
  5. 5.
    Skulachev, V. P. (2005) Vestn. Ros. Akad. Nauk., 75, 831–843.Google Scholar
  6. 6.
    Skulachev, V. P., and Longo, V. D. (2005) Ann. N. Y. Acad. Sci., 1057, 145–164.CrossRefADSGoogle Scholar
  7. 7.
    Darwin, Ch. (1871) The Descent of Man, Murray, London.Google Scholar
  8. 8.
    Weissmann, A. (1889) Essays upon Heredity and Kindred Biological Problems, Clarendon Press, Oxford.Google Scholar
  9. 9.
    Harman, D. (1956) J. Gerontol., 11, 298–300.Google Scholar
  10. 10.
    Skulachev, V. P. (1999) Mol. Asp. Med., 20, 139–184.CrossRefGoogle Scholar
  11. 11.
    Grivennikova, V. G., and Vinogradov, A. D. (2006) Biochim. Biophys. Acta, 1757, 553–561.CrossRefGoogle Scholar
  12. 12.
    Lambert, A. J., Boysen, H. M., Buckingham, J. A., Yang, T., Podlutsky, A., Austad, S. N., Kunz, T. H., Buffenstein, R., and Brand, M. D. (2007) Aging Cell, 6, 607–618.CrossRefGoogle Scholar
  13. 13.
    Buffenstein, R. (2005) J. Gerontol. Biol. Sci., 60, 1369–1377.Google Scholar
  14. 14.
    Andziak, B., and Buffenstein, R. (2006) Aging Cell, 5, 525–532.CrossRefGoogle Scholar
  15. 15.
    Andziak, B., O’Connor, T. P., Qi, W., DeWaal, E. M., Pierce, A., Chaudhuri, A. R., van Remmen, H., and Buffenstein, R. (2006) Aging Cell, 5, 463–471.CrossRefGoogle Scholar
  16. 16.
    Andziak, B., O’Connor, T. P., and Buffenstein, R. (2005) Mech. Ageing Dev., 126, 1206–1212.CrossRefGoogle Scholar
  17. 17.
    Labinsky, N., Csiszar, A., Orosz, Z., Smith, K., Rivera, A., Buffenstein, R., and Ungvari, Z. (2006) Am. J. Physiol. Heart Circ. Physiol., 291, H2698–H2704.CrossRefGoogle Scholar
  18. 18.
    Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Revoldi, P., Pandolfi, P. P., Lanfrancone, L., and Pelicci, P. G. (1999) Nature, 402, 309–313.CrossRefADSGoogle Scholar
  19. 19.
    Liu, X., Jiang, N., Hughes, B., Bigras, E., Shoubridge, E., and Hekimi, S. (2006) Gen. Dev., 19, 2424–2434.CrossRefGoogle Scholar
  20. 20.
    Chu, H.-P., Grigorian, I. A., Dorovkov, M. V., Nagele, R. G., Komarova, E. A., Gudkov, A. V., Harrison, D. E., and Ryazanov, A. G. (2008) Nature, in press.Google Scholar
  21. 21.
    Hagen, T. M., Liu, J., Lykkesfeldt, J., Wehr, C. M., Ingersoll, R. T., Vinarsky, V., Bartholomew, J. C., and Ames, B. N. (2002) Proc. Natl. Acad. Sci. USA, 99, 1870–1875.CrossRefADSGoogle Scholar
  22. 22.
    Atamna, H., Robinson, C., Ingersoll, R., Elliott, H., and Ames, B. N. (2001) FASEB J., 15, 196–204.CrossRefGoogle Scholar
  23. 23.
    Howes, R. M. (2006) Ann. N. Y. Acad. Sci., 1067, 22–26.CrossRefADSGoogle Scholar
  24. 24.
    Goldstein, N. (2002) Biochemistry (Moscow), 67, 161–170.CrossRefGoogle Scholar
  25. 25.
    Liberman, E. A., Topali, V. P., Tsofina, L. M., Jasaitis, A. A., and Skulachev, V. P. (1969) Nature, 222, 1076–1078.CrossRefADSGoogle Scholar
  26. 26.
    Grinius, L. L., Jasaitis, A. A., Kadziauskas, Yu. L., Liberman, E. A., Skulachev, V. P., Topali, V. P., Tsofina, L. M., and Vladimirova, M. A. (1970) Biochim. Biophys. Acta, 216, 1–12.CrossRefGoogle Scholar
  27. 27.
    Bakeeva, L. E., Grinius, L. L., Jasaitis, A. A., Kuliene, V. V., Levitsky, D. O., Liberman, E. A., Severina, I. I., and Skulachev, V. P. (1970) Biochim. Biophys. Acta, 216, 12–21.Google Scholar
  28. 28.
    Liberman, E. A., and Skulachev, V. P. (1970) Biochim. Biophys. Acta, 216, 30–42.CrossRefGoogle Scholar
  29. 29.
    Skulachev, V. P. (1988) Memb. Bioenerg., Springer-Verlag, Berlin.Google Scholar
  30. 30.
    Severin, S. E., Skulachev, V. P., and Yaguzinsky, L. S. (1970) Biokhimiya, 35, 1250–1257.Google Scholar
  31. 31.
    Smith, R. A., Porteous, C. M., Coulter, C. V., and Murphy, M. P. (1999) Eur. J. Biochem., 263, 709–716.CrossRefGoogle Scholar
  32. 32.
    Kelso, G. F., Porteous, C. M., Coulter, C. V., Hughes, G., Porteous, W. K., Ledgerwood, E. C., Smith, R. A., and Murphy, M. P. (2001) J. Biol. Chem., 276, 4588–4596.CrossRefGoogle Scholar
  33. 33.
    Murphy, M. P., and Smith, R. A. (2007) Annu. Rev. Pharmacol. Toxicol., 47, 629–656.CrossRefGoogle Scholar
  34. 34.
    James, A. M., Cocheme, H. M., Smith, R. A., and Murphy, M. P. (2005) J. Biol. Chem., 280, 21295–21312.CrossRefGoogle Scholar
  35. 35.
    Kelso, G. F., Porteous, C. M., Hughes, G., Ledgerwood, E. C., Gane, A. M., Smith, R. A., and Murphy, M. P. (2002) Ann. N. Y. Acad. Sci., 959, 263–274.CrossRefADSGoogle Scholar
  36. 36.
    Saretzki, G., Murphy, M. P., and von Zglinicki, T. (2003) Aging Cell, 2, 141–143.CrossRefGoogle Scholar
  37. 37.
    Jauslin, M. L., Meier, T., Smith, R. A., and Murphy, M. P. (2003) FASEB J., 17, 1972–1974.Google Scholar
  38. 38.
    Antonenko, Yu. N., Archipova, L. T., Archipova, M. M., Bakeeva, L. E., Chernyak, B. F., Domnina, L. V., Fursova, A. Zh., Grigorian, E. N., Ivanova, O. Yu., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Kolosova, N. G., Kopenkin, E. P., Korshunov, S. S., Korshunova, G. A., Kovaleva, N. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Philippov, P. P., Pletjushkina, O. Yu., Pustovidko, A. V., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Senin, I. I., Severina, I. I., Simonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sotnikova, L. F., Sumbatyan, N. V., Tashlitsky, V. N., Trofimova, N. A., Vassiliev, Yu. M., Vyssokikh, M. Yu., Yaguzhinsky, L. S., and Skulachev, V. P. (2008), in press.Google Scholar
  39. 39.
    Lakowski, B., and Hekimi, S. (1996) Science, 272, 1010–1013.CrossRefADSGoogle Scholar
  40. 40.
    Kruk, J., Jemiola-Rzeminska, M., and Strzalka, K. (1997) Chem. Phys. Lipids, 87, 73–80.CrossRefGoogle Scholar
  41. 41.
    Roginsky, V., Barsukova, T., Loshadkin, D., and Pliss, E. (2003) Chem. Phys. Lipids, 125, 49–58.CrossRefGoogle Scholar
  42. 42.
    Skulachev, V. P., Bakeeva, L. E., Chernyak, B. V., Domnina, L. V., Minin, A. A., Pletjushkina, O. Yu., Saprunova, V. B., Skulachev, I. V., Tsyplenkova, V. G., Vasiliev, J. M., Yaguzhinsky, L. S., and Zorov, D. B. (2004) Mol. Cell. Biochem., 256/257, 341–358.CrossRefGoogle Scholar
  43. 43.
    Skulachev, V. P., et al., in preparation.Google Scholar
  44. 44.
    Trifunovic, A., Wreeenberg, A., Falkenberg, M., Spelbrink, J. N., Rovio, A. T., Bruder, C. E., Bohlooly, Y. M., Gidlof, S., Oldfors, A., Wilbom, R., Tornell, J., Jacobs, H. T., and Larsson, N.-G. (2004) Nature, 429, 417–423.CrossRefADSGoogle Scholar
  45. 45.
    Solov’eva, N. A., Morozkova, T. S., and Salganik, R. I. (1975) Genetika, 11, 63–71.Google Scholar
  46. 46.
    Kolosova, N. G., Lebedev, P. A., Aidagulova, S. V., and Morozkova, T. S. (2003) Bull. Exp. Biol. Med., 136, 415–419.CrossRefGoogle Scholar
  47. 47.
    Sergeeva, S., Bagryanskaya, E., Korbolina, E., and Kolosova, N. (2006) Exp. Gerontol., 41, 141–150.CrossRefGoogle Scholar
  48. 48.
    Kolosova, N. G., Shcheglova, T. V., Sergeeva, S. V., and Loskutova, L. V. (2006) Neurobiol. Aging, 27, 1289–1297.CrossRefGoogle Scholar
  49. 49.
    Vlachantoni, D., Tulloch, B., Taylor, R. W., Turnbull, D. M., Murphy, M. P., and Wright, A. F. (2006) Invest. Ophthalmol. Vis. Sci., E-5773.Google Scholar
  50. 50.
    Rajendram, R., Saraswathy, S., and Rao, N. A. (2007) Br. J. Ophthalmol., 91, 531–537.CrossRefGoogle Scholar
  51. 51.
    Moreno, M. C., Campanelli, J., Sande, P., Sanez, D. A., Keller Sarmiento, M. I., and Rosenstein, R. E. (2004) Free Rad. Biol. Med., 37, 803–812.CrossRefGoogle Scholar
  52. 52.
    Madeo, F., Frohlich, E., Ligr, M., Grey, M., Sigrist, S. J., Wolf, D. H., and Frohlich, K.-U. (1999) J. Cell Biol., 145, 757–767.CrossRefGoogle Scholar
  53. 53.
    Anisimov, V. N., Semenchenko, A. V., and Yashin, A. I. (2003) Biogerontology, 4, 297–307.CrossRefGoogle Scholar
  54. 54.
    Hamilton, W. D. (1964) J. Theor. Biol., 7, 1–16, 17–52.CrossRefGoogle Scholar
  55. 55.
    Dowkins, R. (1976) The Selfish Gene, Oxford University Publishers, Oxford.Google Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  1. 1.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia
  2. 2.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia

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