Advertisement

Moscow University Biological Sciences Bulletin

, Volume 73, Issue 4, pp 185–190 | Cite as

Cell Kinetic Approaches to the Search for Anti-Aging Drugs: Thirty Years After

  • A. N. KhokhlovEmail author
Editorial

Abstract

This is a brief overview of the ideas of the possibility of using the cell kinetic model developed by the author in the 1980s to test, in experiments on cell cultures, potential geroprotectors and geropromoters that slow down or accelerate, respectively, the aging process in animals and humans. The history of the evolution of this model—from estimation of only the cell reproduction rate and saturation density in a non-subcultured cell culture to constructing survival curves in the stationary phase of growth and to a further analysis of the possible interrelation between all parts of the curve of cells’ growth and subsequent dying out—is considered. Possible approaches to mathematical and statistical analysis of the data obtained within the framework of this model system are analyzed. It is emphasized that such studies can be carried out on cells of a very different nature (normal and transformed human and animal cells, plant cells, yeast, mycoplasmas, bacteria, etc.), which makes possible an evolutionary approach to the interpretation of the results obtained. At the same time, in the author’s opinion, the most promising experiments are those carried out on immortalized cells of humans and animals, since they are not cancerous on the one hand and have an unlimited mitotic potential on the other hand and, therefore, do not “age” in the process of numerous divisions, as, for example, normal human diploid fibroblasts do. It is assumed that the appropriate mathematical analysis of the entire growth and dying out curve of a non-subcultured cell culture (from seeding into a culture flask to the complete death of all cells) may allow the clarification of certain relationships between the development and aging of a multicellular organism and to increase the reliability of identifying promising geroprotectors.

Keywords

aging cell cultures geroprotectors geropromoters cell proliferation stationary phase aging kinetics test systems review 

References

  1. 1.
    Schneider, E.L. and Smith, J.R., The relationship of in vitro studies to in vivo human aging, Int. Rev. Cytol., 1981, vol. 69, pp. 261–270.CrossRefGoogle Scholar
  2. 2.
    Gazzola, G.C., Bussolati, O., Longo, N., Dall’Asta, V., Franchi-Gazzola, R., and Guidotti, G.G., Effect of in vitro ageing on the transport of neutral amino acids in human fibroblasts, in Cellular Ageing. Monographs in Developmental Biology, Sauer, H.W., Ed., Basel–New York: S. Karger, 1984, vol. 17, pp. 234–244.Google Scholar
  3. 3.
    Macieira-Coelho, A., Loria, E., and Berumen, L., Relationship between cell kinetic changes and metabolic events during cell senescence in vitro, in Cell Impairment in Aging and Development, Cristofalo, V.J. and Holeckova, E., Eds., New York–London: Plenum Press, 1975, pp. 51–65.CrossRefGoogle Scholar
  4. 4.
    Macieira-Coelho, A., Kinetics of the proliferation of human fibroblasts during their lifespan in vitro, Mech. Ageing Dev., 1977, vol. 6, no. 5, pp. 341–343.CrossRefGoogle Scholar
  5. 5.
    Ohashi, M., Aizawa, S., Ooka, H., Ohsawa, T., Kaji, K., Kondo, H., Kobayashi, T., Noumura, T., Matsuo, M., Mitsui, Y., Murota, S., Yamamoto, K., Ito, H., Shimada, H., and Utakoji, T., A new human diploid cell strain, TIG-1, for the research on cellular aging, Exp. Gerontol., 1980, vol. 15, no. 2, pp. 121–133.CrossRefGoogle Scholar
  6. 6.
    Wasko, B.M., Carr, D.T., Tung, H., et al., Buffering the pH of the culture medium does not extend yeast replicative lifespan, F1000Research, 2013, vol. 2:216.CrossRefGoogle Scholar
  7. 7.
    Morgunova, G.V., Klebanov, A.A., Marotta, F., and Khokhlov, A.N., Culture medium pH and stationary phase/chronological aging of different cells, Moscow Univ. Biol. Sci. Bull., 2017, vol. 72, no. 2, pp. 47–51.CrossRefGoogle Scholar
  8. 8.
    Chirkova, E.Iu., Golovina, M.E., Nadzharian, T.L., and Khokhlov, A.N., Cellular kinetic model for studying geroprotectors and geropromotors, Dokl. Akad. Nauk SSSR, 1984, vol. 278, no. 6, pp. 1474–1476.Google Scholar
  9. 9.
    Khokhlov, A.N., Golovina, M.E., Chirkova, E.Iu., and Nadzharian, T.L., Analysis of the kinetic growth patterns of cultured cells. I. The model, Tsitologiia, 1985, vol. 27, no. 8, pp. 960–965.Google Scholar
  10. 10.
    Khokhlov, A.N., The cell kinetics model for determination of organism biological age and for geroprotectors or geropromoters studies, in Biomarkers of Aging: Expression and Regulation. Proceeding, Licastro, F. and Caldarera, C.M., Eds., Bologna: CLUEB, 1992, pp. 209–216.Google Scholar
  11. 11.
    Konev, S.V. and Mazhul’, V.M., Mezhkletochnye kontakty (Intercellular Contacts), Minsk: Nauka i Tekhnika, 1977.Google Scholar
  12. 12.
    Kondo, H., Kasuga, H., and Noumura, T., Effects of various steroids on in vitro lifespan and cell growth of human fetal lung fibroblasts (WI-38), Mech. Ageing Dev., 1983, vol. 21, no. 3–4, pp. 335–344.CrossRefGoogle Scholar
  13. 13.
    Macieira-Coelho, A., Action of cortisone on human fibroblasts in vitro, Experientia, 1966, vol. 22, no. 6, pp. 390–391.CrossRefGoogle Scholar
  14. 14.
    Grünwald, J., Mey, J., Schönleben, W., Hauss, J., and Hauss, W.H., Cultivated human arterial smooth muscle cells. The effect of donor age, blood pressure, diabetes and smoking on in vitro cell growth, Pathol. Biol. (Paris), 1983, vol. 31, no. 10, pp. 819–823.Google Scholar
  15. 15.
    Khokhlov, A.N., Cell Proliferation and Aging, in Itogi nauki i tekhniki VINITI AN SSSR, seriya “Obshchie problemy fiziko-khimicheskoi biologii” (Advances in Science and Technology, VINITI Akad. Sci. USSR, Ser. General Problems of Physicochemical Biology), Moscow: VINITI, 1988, vol. 9.Google Scholar
  16. 16.
    Khokhlov, A.N., Cytogerontology at the beginning of the third millennium: from “correlative” to “gist” models, Russ. J. Dev. Biol., 2003, vol. 34, no. 5, pp. 321–326.CrossRefGoogle Scholar
  17. 17.
    Morgunova, G.V., Kolesnikov, A.V., Klebanov, A.A., and Khokhlov, A.N., Senescence-aßsociated ß-galactosidase—a biomarker of aging, DNA damage, or cell proliferation restriction?, Moscow Univ. Biol. Sci. Bull., 2015, vol. 70, no. 4, pp. 165–167.CrossRefGoogle Scholar
  18. 18.
    Khokhlov, A.N., Stationary cell cultures as a tool for gerontological studies, Ann. N. Y. Acad. Sci., 1992, vol. 663, pp. 475–476.CrossRefGoogle Scholar
  19. 19.
    Khokhlov, A.N., Cell proliferation restriction: is it the primary cause of aging?, Ann. N. Y. Acad. Sci., 1998, vol. 854, p. 519.CrossRefGoogle Scholar
  20. 20.
    Khokhlov, A.N., From Carrel to Hayflick and back, or what we got from the 100-year cytogerontological studies, Biophysics, 2010, vol. 55, no. 5, pp. 859–864.CrossRefGoogle Scholar
  21. 21.
    Khokhlov, A.N., Does aging need its own program, or is the program of development quite sufficient for it? Stationary cell cultures as a tool to search for anti-aging factors, Curr. Aging Sci., 2013, vol. 6, no. 1, pp. 14–20.CrossRefGoogle Scholar
  22. 22.
    Khokhlov, A.N., Impairment of regeneration in aging: appropriateness or stochastics?, Biogerontology, 2013, vol. 14, no. 6, pp. 703–708.CrossRefGoogle Scholar
  23. 23.
    Khokhlov, A.N., Klebanov, A.A., and Morgunova, G.V., Does aging have a purpose?, Moscow Univ. Biol. Sci. Bull., 2017, vol. 72, no. 4, pp. 222–224.CrossRefGoogle Scholar
  24. 24.
    Shilovsky, G.A., Shram, S.I., Morgunova, G.V., and Khokhlov, A.N., Protein poly(ADP-ribosyl)ation system: Changes in development and aging as well as due to restriction of cell proliferation, Biochemistry (Moscow), 2017, vol. 82, no. 11, pp. 1391–1401.CrossRefGoogle Scholar
  25. 25.
    Fabrizio, P. and Longo, V.D., The chronological life span of Saccharomyces cerevisiae, Aging Cell, 2003, vol. 2, no. 2, pp. 73–81.CrossRefGoogle Scholar
  26. 26.
    Nyström, T., Stationary-phase physiology, Annu. Rev. Microbiol., 2004, vol. 58, pp. 161–181.CrossRefGoogle Scholar
  27. 27.
    Khokhlov, A.N., Which aging in yeast is “true?,” Moscow Univ. Biol. Sci. Bull., 2016, vol. 71, no. 1, pp. 11–13.CrossRefGoogle Scholar
  28. 28.
    Morgunova, G.V., Klebanov, A.A., and Khokhlov, A.N., Some remarks on the relationship between autophagy, cell aging, and cell proliferation restriction, Moscow Univ. Biol. Sci. Bull., 2016, vol. 71, no. 4, pp. 207–211.CrossRefGoogle Scholar
  29. 29.
    Khokhlov, A.N., Klebanov, A.A., Karmushakov, A.F., Shilovsky, G.A., Nasonov, M.M., and Morgunova, G.V., Testing of geroprotectors in experiments on cell cultures: choosing the correct model system, Moscow Univ. Biol. Sci. Bull., 2014, vol. 69, no. 1, pp. 10–14.CrossRefGoogle Scholar
  30. 30.
    Alinkina, E.S., Vorobyova, A.K., Misharina, T.A., Fatkullina, L.D., Burlakova, E.B., and Khokhlov, A.N., Cytogerontological studies of biological activity of oregano essential oil, Moscow Univ. Biol. Sci. Bull., 2012, vol. 67, no. 2, pp. 52–57.CrossRefGoogle Scholar
  31. 31.
    Yablonskaya, O.I., Ryndina, T.S., Voeikov, V.L., and Khokhlov, A.N., A paradoxical effect of hydrated C60- fullerene at an ultralow concentration on the viability and aging of cultured Chinese hamster cells, Moscow Univ. Biol. Sci. Bull., 2013, vol. 68, no. 2, pp. 63–68.CrossRefGoogle Scholar
  32. 32.
    Khokhlov, A.N., Morgunova, G.V., Ryndina, T.S., and Coll, F., Pilot study of a potential geroprotector, “Quinton Marine Plasma,” in experiments on cultured cells, Moscow Univ. Biol. Sci. Bull., 2015, vol. 70, no. 1, pp. 7–11.CrossRefGoogle Scholar
  33. 33.
    Morgunova, G.V. and Klebanov, A.A., Impairment of the viability of transformed Chinese hamster cells in a nonsubcultured culture under the influence of exogenous oxidized guanoside is manifested only in the stationary phase of growth, Moscow Univ. Biol. Sci. Bull., 2018, vol. 73, no. 3, pp. 124–129.CrossRefGoogle Scholar
  34. 34.
    Khokhlov, A.N. and Morgunova, G.V., On the constructing of survival curves for cultured cells in cytogerontological experiments: a brief note with three hierarchy diagrams, Moscow Univ. Biol. Sci. Bull., 2015, vol. 70, no. 2, pp. 67–71.CrossRefGoogle Scholar
  35. 35.
    Morgunova, G.V., Klebanov, A.A., and Khokhlov, A.N., Interpretation of data about the impact of biologically active compounds on viability of cultured cells of various origin from a gerontological point of view, Moscow Univ. Biol. Sci. Bull., 2016, vol. 71, no. 2, pp. 67–70.CrossRefGoogle Scholar
  36. 36.
    Khokhlov, A.N., Klebanov, A.A., and Morgunova, G.V., On choosing control objects in experimental gerontological research, Moscow Univ. Biol. Sci. Bull., 2018, vol. 73, no. 2, pp. 59–62.CrossRefGoogle Scholar
  37. 37.
    Khokhlov, A.N. and Morgunova, G.V., Testing of geroprotectors in experiments on cell cultures: pros and cons, in Anti-Aging Drugs: From Basic Research to Clinical Practice, Vaiserman, A.M., Ed., Royal Society of Chemistry, 2017, pp. 53–74.Google Scholar
  38. 38.
    Khokhlov, A.N., Klebanov, A.A., and Morgunova, G.V., Anti-aging drug discovery in experimental gerontological studies: from organism to cell and back, in Aging: Exploring a Complex Phenomenon, Ahmad, Sh.I., Ed., London: Taylor, 2018, pp. 577–595.Google Scholar
  39. 39.
    Charnov, E.L., On evolution of age of maturity and the adult lifespan, J. Evol. Biol., 1990, vol. 3, no. 1–2, pp. 139–144.CrossRefGoogle Scholar
  40. 40.
    Charnov, E.L. and Berrigan, D., Dimensionless numbers and life history evolution: age of maturity versus the adult lifespan, Evol. Ecol., 1990, vol. 4, no. 3, pp. 273–275.CrossRefGoogle Scholar
  41. 41.
    de Magalhães, J.P., Costa, J., and Church, G.M., An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts, J. Gerontol. A Biol. Sci. Med. Sci., 2007, vol. 62, no. 2, pp. 149–160.CrossRefGoogle Scholar
  42. 42.
    Bodnar, A.G., Ouellette, M., Frolkis, M., Holt, S.E., Chiu, C.P., Morin, G.B., Harley, C.B., Shay, J.W., Lichtsteiner, S., and Wright, W.E., Extension of lifespan by introduction of telomerase into normal human cells, Science, 1998, vol. 279, no. 5349, pp. 349–352.CrossRefGoogle Scholar

Copyright information

© Allerton Press, Inc. 2018

Authors and Affiliations

  1. 1.Evolutionary Cytogerontology Sector, School of BiologyMoscow State UniversityMoscowRussia

Personalised recommendations