CELLULAR SENESCENCE: MOLECULAR BIOLOGY AND MORPHOLOGY

DOI: https://doi.org/10.29296/24999490-2022-04-03

А.V. Igrunkova(1), Y.М. Valieva(1), А.М. Kalinichenko(1), А.V. Kurkov(1), K.Yu. Popova(1), D.Yu. Shestakov(2), V.A. Zaborova(1)
1-Sechenov First Moscow State Medical University (Sechenov University), Trubetskay str., 8–2, Moscow, 119991, Russian Federation;
2-State Medical Institution Moscow Clinical Research Center named after A.S. Loginov DZM,
highway Enthusiasts, 86, Moscow, 111123, Russian Federation

Cellular senescence is a reaction of cells to damage, which consists in a full stop of the cell cycle, changes of the signaling pathways and secretory activity associated with aging. Regardless the inducing factor, cellular aging of different types have a similar morphological and molecular profile. The purpose of this review was to systematize scientific data on the molecular and morphological mechanisms of cellular aging. Material and methods: the main foreign and domestic sources were analyzed using the PubMed/Medline, RSCI/elibrary databases. Conclusion: The short-term persistence of biologically active substances, secreted by senescent cells, promote cell proliferation and regeneration of organs and tissues. The long-term presence of these cells, on the contrary, contributes to the inhibition of cell proliferation and synthetic activity, maintaining the pro-inflammatory environment. It negatively affects the structure and function of tissues and leads to chronic diseases, including atherosclerosis, hypertension, osteoarthritis and others, as well as oncology. The senescent cells detection in tissues is difficult due to the lack of morphologic features of these cells in standard light microscopy. It requires complex histochemical and immunohistochemical studies with several antibodies. Nowadays, various methods of regulating the number and secretory activity of senescence cells are studied. Two main directions include senolytic and senomorphic therapy. The first is aimed at the selective initiation of apoptosis in senescent cells, the second is aimed at reducing the synthetic activity in them. Different types of cellular senescence have similar morphological, biochemical and molecular features and pronounced effect on tissue structures. Deepening the knowledge about cellular senescence will allow developing universal pathogenetic drugs for the prevention and treatment of many diseases with persistence of cells with the senescent phenotype.
Keywords: 
cellular senescence, regeneration

Список литературы: 
  1. Goodpasture E.W. An anatomical study of senescence in dogs, with especial reference to the relation of cellular changes of age to tumors. The J. of Medical Research. 1918; 38 (2): 127.
  2. Gray J. The senescence of spermatozoa. J. of Experimental Biology. 1928; 5 (4): 345–61.
  3. Hayflick L., Moorhead P.S. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961; 25 (3): 585–621.
  4. Dierick J.F., Eliaers F., Remacle J., Raes M., Fey S.J., Larsen P.M., Toussaint O. Stress-induced premature senescence and replicative senescence are different phenotypes, proteomic evidence. Biochem Pharmacol. 2002; 64 (5–6): 1011–7. https://doi.org/10.1016/s0006-2952(02)01171-1
  5. Zhu H., Blake S., Kusuma F.K., Pearson R.B., Kang J., Chan K.T. Oncogene-induced senescence: From biology to therapy. Mech Ageing Dev. 2020; 187: 111229. https://doi.org/10.1016/j.mad.2020.111229
  6. Childs B.G., Gluscevic M., Baker D.J., Laberge R.M., Marquess D., Dananberg J., van Deursen J.M. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017; 16 (10): 718–35. https://doi.org/10.1038/nrd.2017.116
  7. Nelson D.M., McBryan T., Jeyapalan J.C., Sedivy J.M., Adams P.D. A comparison of oncogene-induced senescence and replicative senescence: implications for tumor suppression and aging. Age. 2014; 36 (3): 1049–65. doi: 10.1007/s11357-014-9637-0
  8. Kuilman T., Michaloglou C., Vredeveld L.C., Douma S., van Doorn R., Desmet C.J., Aarden L.A., Mooi W.J., Peeper D.S. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133 (6): 1019–31. https://doi.org/10.1016/j.cell.2008.03.039
  9. Zhang W., Yang J., Chen Y., Xue R., Mao Z., Lu W., Jiang Y. Lycorine hydrochloride suppresses stress-induced premature cellular senescence by stabilizing the genome of human cells. Aging Cell. 2021; 20 (2): e13307. https://doi.org/10.1111/acel.13307
  10. 10. Si C., Wang J., Ma W., Hua H., Zhang M., Qian W., Zhou B., Luo D. Circular RNA expression profile in human fibroblast premature senescence after repeated ultraviolet B irradiations revealed by microarray. J. Cell. Physiol. 2019; 234 (10): 18156–68. https://doi.org/10.1002/jcp.28449
  11. Kural K.C., Tandon N., Skoblov M., Kel-Margoulis O.V., Baranova A.V. Pathways of aging: comparative analysis of gene signatures in replicative senescence and stress induced premature senescence. BMC Genomics. 2016; 17 (14): 1030. https://doi.org/10.1186/s12864-016-3352-4
  12. Kuilman T., Michaloglou C., Mooi W.J., Peeper D.S. The essence of senescence. Genes Dev. 2010; 24 (22): 2463–79. https://doi.org/10.1101/gad.1971610
  13. Martinez-Zamudio R.I., Robinson L., Roux P.F., Bischof O. SnapShot: Cellular Senescence Pathways. Cell. 2017; 170 (4): 816-e1. https://doi.org/10.1016/j.cell.2017.07.049
  14. Narita M., Nunez S., Heard E., Narita M., Lin A.W., Hearn S.A., Spector D.L., Hannon G.J., Lowe S.W. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113 (6): 703–16. https://doi.org/10.1016/s0092-8674(03)00401-x
  15. Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S. Soto-Gamez W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88 (5): 593–602. https://doi.org/10.1016/s0092-8674(00)81902-9
  16. A., Quax W.J., Demaria M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J. Mol. Biol. 2019; 431 (15): 2629–43. https://doi.org/10.1016/j.jmb.2019.05.036
  17. Basu A. The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy. Pharmacol Ther. 2022; 230: 107943. https://doi.org/10.1016/j.pharmthera.2021.107943
  18. Yosef R., Pilpel N., Tokarsky-Amiel R., Biran A., Ovadya Y., Cohen S., Vadai E., Dassa L., Shahar E., Condiotti R., Ben-Porath I., Krizhanovsky V. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016; 7 (1): 11190. https://doi.org/10.1038/ncomms11190
  19. Acosta J.C., O’Loghlen A., Banito A., Guijarro M.V., Augert A., Raguz S., Fumagalli M., Da Costa M., Brown C., Popov N., Takatsu Y., Melamed J., d’Adda di Fagagna F., Bernard D., Hernando E., Gil J. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008; 133 (6): 1006–18. https://doi.org/10.1016/j.cell.2008.03.038
  20. Kang C., Xu Q., Martin T.D., Li M.Z., Demaria M., Aron L., Lu T., Yankner B.A., Campisi J., Elledge S.J. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015; 349 (6255): aaa5612. https://doi.org/10.1126/science.aaa5612
  21. Munoz-Espin D., Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014; 15 (7): 482–96. https://doi.org/10.1038/nrm3823
  22. Kumar A., Bano D., Ehninger D. Cellular senescence in vivo: From cells to tissues to pathologies. Mech Ageing Dev. 2020; 190: 111308. https://doi.org/10.1016/j.mad.2020.111308
  23. Freyter B.M., Abd Al-Razaq M.A., Isermann A., Dietz A., Azimzadeh O., Hekking L., Gomolka M., Rube C.E. Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy. Cells. 2022; 11 (2): 273. https://doi.org/10.3390/cells11020273
  24. Hernandez-Segura A., Nehme J., Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018; 28 (6): 436–53. https://doi.org/10.1016/j.tcb.2018.02.001
  25. Freund A., Laberge R.M., Demaria M., Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. 2012; 23 (11): 2066–75. https://doi.org/10.1091/mbc.E11-10-0884
  26. Tuttle C.S.L., Waaijer M.E.C., Slee-Valentijn M.S., Stijnen T., Westendorp R., Maier A.B. Cellular senescence and chronological age in various human tissues: A systematic review and meta-analysis. Aging Cell. 2020; 19 (2): e13083. https://doi.org/10.1111/acel.13083
  27. Rufini A., Tucci P., Celardo I., Melino G. Senescence and aging: the critical roles of p53. Oncogene. 2013; 32 (43): 5129–43. https://doi.org/10.1038/onc.2012.640
  28. Rhinn M., Ritschka B., Keyes W.M. Cellular senescence in development, regeneration and disease. Development. 2019; 146 (20): dev151837. https://doi.org/10.1242/dev.151837
  29. Cristofalo V.J. SA beta Gal staining: biomarker or delusion. Exp Gerontol. 2005; 40 (10): 836–8. https://doi.org/10.1016/j.exger.2005.08.005
  30. Coryell P.R., Diekman B.O., Loeser R.F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat Rev Rheumatol. 2021; 17 (1): 47–57. https://doi.org/10.1038/s41584-020-00533-7
  31. Hall B.M., Balan V., Gleiberman A.S., Strom E., Krasnov P., Virtuoso L.P., Rydkina E., Vujcic S., Balan K., Gitlin I., Leonova K., Polinsky A., Chernova O.B., Gudkov A.V. Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY). 2016; 8 (7): 1294–315. https://doi.org/10.18632/aging.100991
  32. de Magalhaes J.P., Passos J.F. Stress, cell senescence and organismal ageing. Mech Ageing Dev. 2018; 170: 2–9. https://doi.org/10.1016/j.mad.2017.07.001
  33. Nelson G., Kucheryavenko O., Wordsworth J., von Zglinicki T. The senescent bystander effect is caused by ROS-activated NF-kappaB signalling. Mech Ageing Dev. 2018; 170: 30–6. https://doi.org/10.1016/j.mad.2017.08.005
  34. Ritschka B., Storer M., Mas A., Heinzmann F., Ortells M.C., Morton J.P., Sansom O.J., Zender L., Keyes W.M. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 2017; 31 (2): 172–83. https://doi.org/10.1101/gad.290635.116
  35. Demaria M., Ohtani N., Youssef S.A., Rodier F., Toussaint W., Mitchell J.R., Laberge R.M., Vijg J., Van Steeg H., Dolle M.E., Hoeijmakers J.H., de Bruin A., Hara E., Campisi J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014; 31 (6): 722–33. https://doi.org/10.1016/j.devcel.2014.11.012
  36. Harding K.G., Moore K., Phillips T.J. Wound chronicity and fibroblast senescence--implications for treatment. Int Wound J. 2005; 2 (4): 364–8. https://doi.org/10.1111/j.1742-4801.2005.00149.x
  37. Lim D.X.E., Richards T., Kanapathy M., Sudhaharan T., Wright G.D., Phillips A.R.J., Becker D.L. Extracellular matrix and cellular senescence in venous leg ulcers. Sci Rep. 2021; 11 (1): 20168. https://doi.org/10.1038/s41598-021-99643-9
  38. Yun M.H., Davaapil H., Brockes J.P. Recurrent turnover of senescent cells during regeneration of a complex structure. Elife. 2015; 4: e05505. https://doi.org/10.7554/eLife.05505
  39. Song P., An J., Zou M.H. Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases. Cells. 2020; 9 (3): 671. https://doi.org/10.3390/cells9030671
  40. Paez-Ribes M., Gonzalez-Gualda E., Doherty G.J., Munoz-Espin D. Targeting senescent cells in translational medicine. EMBO Mol Med. 2019; 11 (12): e10234. https://doi.org/10.15252/emmm.201810234
  41. Ritschka B., Knauer-Meyer T., Goncalves D.S., Mas A., Plassat J.L., Durik M., Jacobs H., Pedone E., Di Vicino U., Cosma M.P., Keyes W.M. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev. 2020; 34 (7–8): 489–94. https://doi.org/10.1101/gad.332643.119
  42. Niedernhofer L.J., Robbins P.D. Senotherapeutics for healthy ageing. Nat Rev Drug Discov. 2018; 17 (5): 377. https://doi.org/10.1038/nrd.2018.44
  43. Herranz N., Gallage S., Mellone M., Wuestefeld T., Klotz S., Hanley C.J., Raguz S., Acosta J.C., Innes A.J., Banito A.J. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Bio. 2015; 17 (9): 1205–17. https://doi.org/10.1038/ncb3225
  44. Laberge R.-M., Sun Y., Orjalo A.V., Patil C.K., Freund A., Zhou L., Curran S.C., Davalos A.R., Wilson-Edell K.A., Liu S.J. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Bio. 2015; 17 (8): 1049–61. https://doi.org/10.1038/ncb3195
  45. Hou J., Cui C., Kim S., Sung C., Choi C. Ginsenoside F1 suppresses astrocytic senescence-associated secretory phenotype. Chem Biol. Interact. 2018; 283: 75–83. https://doi.org/10.1016/j.cbi.2018.02.002
  46. Moiseeva O., Deschênes-Simard X., St-Germain E., Igelmann S., Huot G., Cadar A.E., Bourdeau V., Pollak M.N., Ferbeyre G.J.A.c. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. 2013; 12 (3): 489–98. https://doi.org/10.1111/acel.12075
  47. Burton D.G.A., Stolzing A. Cellular senescence: Immunosurveillance and future immunotherapy. Ageing Res Rev. 2018; 43: 17–25. https://doi.org/10.1016/j.arr.2018.02.001
  48. Kim K.M., Noh J.H., Bodogai M., Martindale J.L., Yang X., Indig F.E., Basu S.K., Ohnuma K., Morimoto C., Johnson P.F., Biragyn A., Abdelmohsen K., Gorospe M. Identification of senescent cell surface targetable protein DPP4. Genes Dev. 2017; 31 (15): 1529–34. https://doi.org/10.1101/gad.302570.117