ON THE CHOICE OF CONTROL OBJECTS IN EXPERIMENTAL GERONTOLOGICAL RESEARCH

Recently, a large number of papers have appeared that describe the successful use of various biologically active compounds (mitochondrial antioxidants, antidiabetic biguanides, mimetics of dietary restriction, etc.) as geroprotectors. However, in our opinion, in most cases, the positive results of such studies are determined by a “successful” selection of control objects. As such, animals with some abnormalities are often used, so that any favorable effect on the corresponding pathological processes leads to an increase in life span. Besides, control animals can be normal, i.e. wild type, but placed in some extreme conditions, which can be overcome precisely by certain biologically active compounds. Thus, treatment of pathologies is present, and not an effect on the fundamental processes of aging. There is a point of view, according to which the results of Clive McСay’s experiments, which have significantly prolonged the life of rats by limiting caloric intake, are determined, firstly, by the fact that the control animals were fed ad libitum (which is not at all characteristic of animals in the wild), and secondly, because the Fisher-344 rats used in experiments are short-lived. The above considerations seem to concern also gerontological experiments on cultured cells. In particular, we sometimes hear from our colleagues remarks about the model of “stationary phase aging” of cell cultures used in our laboratory due to the fact that most of the experiments are carried out on transformed rather than normal cells. However, this approach seems to us quite justified, because the phenomenon of “stationary phase”/chronological aging is common to a wide variety of cells, including bacteria, yeasts, cyanobacteria, mycoplasmas, animal and plant cells. Herewith cells with unlimited mitotic potential do not change either from experiment to experiment or during long-term cultivation both with and without (in the framework of stationary phase aging model) subcultivation, which cannot be said of normal diploid fibroblasts, whose telomeres are shortened with each division (and from the moment of seeding of the cells to their entering the stationary phase of growth they can divide up to 10 times!). We believe that to search for effective geroprotectors, which provide an impact on the fundamental mechanisms of aging, it is necessary to conduct studies on “maximally healthy” animals, or on “maximally stable” model systems.

1. McCay C.M., Crowell M.F., Maynard L.A. The effect of retarded growth upon the length of life span and upon the ultimate body size // J. Nutr. 1935. Vol. 10. N 1. P. 63–79.

2. Chesky J.A., Rockstein M. Life span characteristics in the male Fischer rat // Exp. Aging Res. 1976. Vol. 2. N 5. P. 399–407.

3. Carey J.R., Judge D.S. Longevity records: life spans of mammals, birds, amphibians, reptiles, and fish. Odense monographs on population aging, 8. Odense: Odense Univ. Press, 2000. 214 pp.

4. Nistiar F., Racz O., Lukacinova A., Hubkova B., No-vakova J., Lovasova E., Sedlakova E. Age dependency on some physiological and biochemical parameters of male Wi-star rats in controlled environment // J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. 2012. Vol. 47. N 9. P. 1224–1233.

5. Maronpot R.R., Nyska A., Foreman J.E., Ramot Y. The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms) // Crit. Rev. Toxicol. 2016. Vol. 46. N 8. P. 641–675.

6. McCay C. M., Pope F., Lunsford W. Experimental prolongation of the life span // Bull. N. Y. Acad. Med. 1956. Vol. 32. N 2. P. 91–101.

7. Khokhlov A.N. From Carrel to Hayflick and back, or what we got from the 100-year cytogerontological studies // Biophysics. 2010. Vol. 55. N 5. P. 859–864.

8. Wei L., Li Y., He J., Khokhlov A.N. Teaching the cell biology of aging at the Harbin Institute of Technology and Moscow State University // Moscow Univ. Biol. Sci. Bull. 2012. Vol. 67. N 1. P. 13–16.

9. Khokhlov A.N., Klebanov A.A., Morgunova G.V. Does aging have a purpose? // Moscow Univ. Biol. Sci. Bull. 2017. Vol. 72. N 4. P. 222–224.

10. Takeda T., Hosokawa M., Takeshita S., Irino M., Higuchi K., Matsushita T., Tomita Y., Yasuhira K., Ha mamoto H., Shimizu K., Ishii M., Yamamuro T. A new murine model of accelerated senescence // Mech. Ageing Dev. 1981. Vol. 17. N 2. P. 183–194.

11. Takeda T., Hosokawa M., Higuchi K. Senescence-accelerated mouse (SAM): a novel murine model of senescence // Exp. Gerontol. 1997. Vol. 32. N 1–2. P. 105–109.

12. Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice // Neurochem. Res. 2009. Vol. 34. N 4. P. 639–659.

13. Yuneva M.O., Bulygina E.R., Gallant S.C., Kramarenko G.G., Stvolinsky S.L., Semyonova M.L., Boldy rev A.A. Effect of carnosine on age-induced changes in senescence-accelerated mice // J. Anti-Aging Med. 1999. Vol. 2. N 4. P. 337–342.

14. Li L., Ng T.B., Gao W., Li W., Fu M., Niu S.M., Zhao L., Chen R.R., Liu F. Antioxidant activity of gallic acid from rose flowers in senescence accelerated mice // Life Sci. 2005. Vol. 77. N 2. P. 230–240.

15. Chan Y.C., Hosoda K., Tsai C.J., Yamamoto S., Wang M.F. Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice // J. Nutr. Sci. Vitaminol. (Tokyo). 2006. Vol. 52. N 4. P. 266–273.

16. Kolosova N.G., Stefanova N.A., Korbolina E.E., Fur-sova A.Zh., Kozhevnikova O.S. Senescence-acce lerated OXYS rats: a genetic model of premature aging and age-related diseases // Adv. Gerontol. 2014. Vol. 4. N. 4. P. 294–298.

17. Morley J.E., Armbrecht H.J., Farr S.A., Kumar V.B. The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease // Biochim. Biophys. Acta. 2012. Vol. 1822. N 5. P. 650–656.

18. Stefanova N.A., Kolosova N.G. Evolution of Alzheimer’s disease pathogenesis conception // Moscow Univ. Biol. Sci. Bull. 2016. Vol. 71. N 1. P. 4–10.

19. Kolosova N.G., Muraleva N.A., Zhdankina A.A., Stefanova N.A., Fursova A.Z., Blagosklonny M.V. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats // Am. J. Pathol. 2012. Vol. 181. N 2. P. 472–477.

20. Loshchenova P.S., Sinitsyna O.I., Fedoseeva L.A., Stefanova N.A., Kolosova N.G. Influence of antioxidant SkQ1 on accumulation of mitochondrial DNA deletions in the hippocampus of senescence-accelerated OXYS rats // Biochemistry (Moscow). 2015. Vol. 80. N 5. P. 596–603.

21. Kolosova N.G., Vitovtov A.O., Stefanova N.A. Met-formin reduces the signs of sarcopenia in old OXYS rats // Adv. Gerontol. 2016. Vol. 6. N 1. P. 70–74.

22. Shabalina I.G., Vyssokikh M.Y., Gibanova N., Csikasz R.I., Edgar D., Hallden-Waldemarson A., Rozhdestvenskaya Z., Bakeeva L.E., Vays V.B., Pustovidko A.V., Skula -chev M.V., Cannon B., Skulachev V.P., Nedergaard J. Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1 // Aging (Albany NY). 2017. Vol. 9. N 2. P. 315–336.

23. Anisimov V.N., Egorov M.V., Krasilshchikova M.S. et al. Effects of the mitochondria-targeted antioxidant SkQ1 on lifespan of rodents // Aging (Albany NY). 2011. Vol. 3. N 11. P. 1110–1119.

24. Frolkis V.V., Muradian Kh.K. Life span prolongation. Boca Raton: CRC Press, 1991. 427 pp.

25. Khokhlov A.N., Klebanov A.A., Morgunova G.V. Anti-aging drug discovery in experimental gerontological studies: from organism to cell and back // Aging: exploring a complex phenomenon / Ed. Sh.I. Ahmad. Boca Raton: Taylor & Francis, 2018. P. 577–595.

26. Khokhlov A.N., Morgunova G.V. Testing of geroprotectors in experiments on cell cultures: pros and cons // Anti-aging drugs: From basic research to clinical practice / Ed. A.M. Vaiserman. Royal Society of Chemistry, 2017. P. 53–74.

27. Morgunova G.V., Klebanov A.A., 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. N 2. P. 62–70.

28. Khokhlov A.N., 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. N 2. P. 67–71.

29. Khokhlov A.N. Which aging in yeast is “true”? // Moscow Univ. Biol. Sci. Bull. 2016. Vol. 71. N 1. P. 11–13.

30. Morgunova G.V., Klebanov A.A., Marotta F., Khokhlov A.N. Culture medium pH and stationary phase/chronological aging of different cells // Moscow Univ. Biol. Sci. Bull. 2017. Vol. 72. N 2. P. 47–51.

31. Khokhlov A.N. Evolution of the term “cellular senescence” and its impact on the current cytogerontological research // Moscow Univ. Biol. Sci. Bull. 2013. Vol. 68. N 4. P. 158–161.

32. von Zglinicki T., Saretzki G., Döcke W., Lotze C. Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? // Exp. Cell Res. 1995. Vol. 220. N 1. P. 186–193.

33. Saretzki G., Feng J., von Zglinicki T., Villeponteau B. Similar gene expression pattern in senescent and hyperoxic-treated fibroblasts // J. Gerontol. A Biol. Sci. Med. Sci. 1998. Vol. 53. N 6. P. B438–B442.

34. von Zglinicki T., Pilger R., Sitte N. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts // Free Radic. Biol. Med. 2000. Vol. 28. N 1. P. 64–74.

35. Khokhlov A.N. Stationary cell cultures as a tool for gerontological studies // Ann. N.Y. Acad. Sci. 1992. Vol. 663. P. 475–476.