Kazan medical journalKazan medical journalКазанский медицинский журнал0368-48142587-9359Eco-Vector62485210.17816/KMJ624852ReviewsОбзорыReview ArticlePossibilities of gene, cellular and pharmacological approaches to correct age-related changesВозможности генных, клеточных и фармакологических подходов для коррекции возрастных измененийhttps://orcid.org/0000-0002-0704-81416937-6311KitaevaKristina V.КитаеваКристина Викторовна
Russian Federation

Cand. Sci. (Biol.), Senior Researcher, OpenLab Genetic and Cellular Technologies Research Laboratory, Assoc. Prof., Depart. of Genetics

канд. биол. наук, ст. науч. сотр., НИЛ OpenLab генные и клеточные технологии, доц., каф. генетики

olleth@mail.ruhttps://orcid.org/0000-0002-8776-36628796-3760SolovyevaValeriya V.СоловьеваВалерия Владимировна
Russian Federation

Cand. Sci. (Biol.), Leading Researcher, OpenLab Genetic and Cellular Technologies Research Laboratory, Assoc. Prof, Depart. of Genetics

канд. биол. наук, ведущий науч. сотр., НИЛ OpenLab генные и клеточные технологии, доц., каф. генетики

solovyovavv@gmail.comhttps://orcid.org/0000-0002-3661-05277595-0257FilinIvan Yu.ФилинИван Юрьевич
Russian Federation

Research Fellow, OpenLab Genetic and Cellular Technologies Research Laboratory, Assistant, Depart. of Genetics

науч. сотр., НИЛ OpenLab генные и клеточные технологии, асс., каф. генетики

filin.ivy@gmail.comhttps://orcid.org/0000-0002-9435-340X8569-9002MukhamedshinaYana O.МухамедшинаЯна Олеговна
Russian Federation

MD, Dr. Sci. (Med.), Leading Researcher, OpenLab Genetic and Cellular Technologies Research Laboratory; Assoc. Prof., Depart. of Histology, Cytology and Embryology

д-р мед. наук, ведущий науч. сотр., НИЛ OpenLab генные и клеточные технологии; доц., каф. гистологии, цитологии и эмбриологии

YOMuhamedshina@kpfu.ruhttps://orcid.org/0000-0002-9427-57397031-5996RizvanovAlbert A.РизвановАльберт Анатольевич
Russian Federation

Dr. Sci. (Biol.), Chief Researcher, OpenLab Genetic and Cellular Technologies Research Laboratory, Prof., Depart. of Genetics

д-р биол. наук, гл. науч. сотр., НИЛ OpenLab генные и клеточные технологии, проф., каф. генетики

albert.Rizvanov@kpfu.ruKazan (Volga Region) Federal UniversityКазанский (Приволжский) федеральный университетKazan State Medical UniversityКазанский государственный медицинский университетAcademy of Sciences of the Republic of TatarstanАкадемия наук Республики Татарстан071120242711202410569749862512202301072024Copyright ©; 2024, Eco-VectorCopyright ©; 2024, Эко-Вектор2024Eco-VectorЭко-Векторhttp://creativecommons.org/licenses/by-nc-sa/4.0https://kazanmedjournal.ru/kazanmedj/article/view/624852

Improvement of the human habitat has led to an increase in average life expectancy. Long life goes hand in hand with old age, which reduces the quality of human life and it is an acute social problem. Thus, the search for approaches that can improve the quality of life, the ability to live it without age-related diseases is an extremely urgent task. Aging of the body begins with the aging of cells, in which the activation of the aging process occurs through the induction of specific signaling pathways, which irreversibly divides the life of any cell into “before and after”. Aging cells are able to influence their microenvironment, secreting more inflammatory signaling molecules and inducing pathological changes in neighboring cells. The accumulation and long-term preservation of aged cells lead to deterioration of the condition of tissues and organs, and ultimately to a decrease in the quality of life and an increased risk of death. Among the most promising approaches to the correction of aging and age-related diseases are pharmacological, gene and cell therapy. Increasing the expression of aging suppressor genes, using certain populations of native and genetically modified cells, as well as senolytic drugs can help delay aging and associated diseases for a more distant future. This review examines currently studied approaches and achievements in the field of anti-aging therapy, in particular gene therapy using adeno-associated vectors and approaches based on cell therapy.

Улучшение среды обитания человека привело к увеличению средней продолжительности жизни. Длинная жизнь идёт рука об руку со старостью, которая снижает качество жизни человека и представляет собой острую социальную проблему. Таким образом, поиски подходов, которые способны улучшить качество жизни, возможность прожить её без возрастных заболеваний представляет собой крайне актуальную задачу. Старение организма начинается со старения клеток, в которых происходит активация процесса старения через индукцию специфических сигнальных путей, что необратимо делит жизнь любой клетки на «до и после». Стареющие клетки способны влиять на своё микроокружение, секретируя больше воспалительных сигнальных молекул и индуцируя патологические изменения в соседних клетках. Накопление и длительное сохранение постаревших клеток приводят к ухудшению состояния тканей и органов, а в конечном итоге к снижению качества жизни и повышению риска смерти. Среди наиболее перспективных подходов к коррекции старения и возрастных заболеваний — фармакологическая, генная и клеточная терапия. Повышение экспрессии генов-супрессоров старения, использование определённых популяций нативных и генетически-модифицированных клеток, а также сенолитических препаратов способно помочь отсрочить старение и связанные с ним заболевания на более отдалённую перспективу. В представленном обзоре рассмотрены исследуемые на сегодняшний день подходы и достижения в области антивозрастной терапии, в частности генная терапия с использованием аденоассоциированных векторов и подходы, основанные на клеточной терапии.

agingsenolyticsenescent cellsanti-aging therapycell therapygene therapyстарениесенолитиксенесцентные клеткиантивозрастная терапияклеточная терапиягенная терапияKazan Federal UniversityКазанский федеральный университетFZSM-2023-0011Ros M, Carrascosa JM. Current nutritional and pharmacological anti-aging interventions. Biochim Biophys Acta Mol Basis Dis. 2020;1866:165612. doi: 10.1016/j.bbadis.2019.165612Ros M., Carrascosa J.M. Current nutritional and pharmacological anti-aging interventions // Biochim Biophys Acta Mol Basis Dis. 2020. Vol. 1866. P. 165612 doi: 10.1016/j.bbadis.2019.165612Austad SN, Hoffman JM. Is antagonistic pleiotropy ubiquitous in aging biology? Evol Med Public Health. 2018;2018:287–294. doi: 10.1093/emph/eoy033Austad S.N., Hoffman J.M. Is antagonistic pleiotropy ubiquitous in aging biology? // Evol Med Public Health. 2018. Vol. 2018. P. 287–294. doi: 10.1093/emph/eoy033Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436–453. doi: 10.1016/j.tcb.2018.02.001Hernandez-Segura A., Nehme J., Demaria M. Hallmarks of cellular senescence // Trends Cell Biol. 2018. Vol. 28. P. 436–453. doi: 10.1016/j.tcb.2018.02.001Ocampo A, Reddy P, Belmonte JCI. Anti-aging strategies based on cellular reprogramming. Trends Mol Med. 2016;22:725–738. doi: 10.1016/j.molmed.2016.06.005Ocampo A., Reddy P., Belmonte J.C.I. Anti-aging strategies based on cellular reprogramming // Trends Mol Med. 2016. Vol. 22. P. 725–738. doi: 10.1016/j.molmed.2016.06.005Burton DG, Krizhanovsky V. Physiological and pathological consequences of cellular senescence. Cell Mol Life Sci. 2014;71:4373–4386. doi: 10.1007/s00018-014-1691-3Burton D.G., Krizhanovsky V. Physiological and pathological consequences of cellular senescence // Cell Mol Life Sci. 2014. Vol. 71. P. 4373–4386. doi: 10.1007/s00018-014-1691-3Missiaen R, Anderson NM, Kim LC, Nance B, Burrows M, Skuli N, Carens M, Riscal R, Steensels A, Li F, Simon MC. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell Metab. 2022;34:1151–1167. doi: 10.1016/j.cmet.2022.06.010Missiaen R., Anderson N.M., Kim L.C., et al. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment // Cell Metab. 2022. Vol. 34. P. 1151–1167. doi: 10.1016/j.cmet.2022.06.010Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles' heel of senescent cells: From transcriptome to senolytic drugs. Aging Cell. 2015;14:644–658. doi: 10.1111/acel.12344Zhu Y., Tchkonia T., Pirtskhalava T., et al. The Achilles' heel of senescent cells: From transcriptome to senolytic drugs // Aging Cell. 2015. Vol. 14. P. 644–658. doi: 10.1111/acel.12344Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, Hollister-Lock J, van Deursen J, Weir G, Bonner-Weir S. Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab. 2019;30:129–142. doi: 10.1016/j.cmet.2019.05.006Aguayo-Mazzucato C., Andle J., Lee T.B.Jr., et al. Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes // Cell Metab. 2019. Vol. 30. P. 129–142. doi: 10.1016/j.cmet.2019.05.006Wang L, Wang B, Gasek NS, Zhou Y, Cohn RL, Martin DE, Zuo W, Flynn WF, Guo C, Jellison ER, Kim T, Prata LGPL, Palmer AK, Li M, Inman CL, Barber LS, Al-Naggar IMA, Zhou Y, Du W, Kshitiz, Kuchel GA, Meves A, Tchkonia T, Kirkland JL, Robson P, Xu M. Targeting p21 (Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 2022;34:75–89. doi: 10.1016/j.cmet.2021.11.002Wang L., Wang B., Gasek N.S., et al. Targeting p21(Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity // Cell Metab. 2022. Vol. 34. P. 75–89. doi: 10.1016/j.cmet.2021.11.002Blagosklonny MV. Selective anti-cancer agents as anti-aging drugs. Cancer Biol Ther. 2013;14:1092–1097. doi: 10.4161/cbt.27350Blagosklonny M.V. Selective anti-cancer agents as anti-aging drugs // Cancer Biol Ther. 2013. Vol. 14. P. 1092–1097. doi: 10.4161/cbt.27350Zoncu R, Efeyan A, Sabatini DM. mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21–35. doi: 10.1038/nrm3025Zoncu R., Efeyan A., Sabatini D.M. mTOR: From growth signal integration to cancer, diabetes and ageing // Nat Rev Mol Cell Biol. 2011. Vol. 12. P. 21–35. doi: 10.1038/nrm3025Bourgeois B, Madl T. Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Lett. 2018;592:2083–2097. doi: 10.1002/1873-3468.13057Bourgeois B., Madl T. Regulation of cellular senescence via the FOXO4-p53 axis // FEBS Lett. 2018. Vol. 592. P. 2083–2097. doi: 10.1002/1873-3468.13057Park HK, Yoon NG, Lee JE, Hu S, Yoon S, Kim SY, Hong JH, Nam D, Chae YC, Park JB, Kang BH. Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1. Exp Mol Med. 2020;52:79–91. doi: 10.1038/s12276-019-0360-xPark H.K., Yoon N.G., Lee J.E., et al. Unleashing the full potential of Hsp90 inhibitors as cancer therapeutics through simultaneous inactivation of Hsp90, Grp94, and TRAP1 // Exp Mol Med. 2020. Vol. 52. P. 79–91. doi: 10.1038/s12276-019-0360-xChen DD, Peng X, Wang Y, Jiang M, Xue M, Shang G, Liu X, Jia X, Liu B, Lu Y, Mu H, Zhang F, Hu Y. HSP-90 acts as a senomorphic target in senescent retinal pigmental epithelial cells. Aging (Albany NY). 2021;13:21547–21570. doi: 10.18632/aging.203496Chen D.D., Peng X., Wang Y., et al. HSP-90 acts as a senomorphic target in senescent retinal pigmental epithelial cells // Aging (Albany NY). 2021. Vol. 13. P. 21547–21570. doi: 10.18632/aging.203496Tao ZF, Hasvold L, Wang L, Wang X, Petros AM, Park CH, Boghaert ER, Catron ND, Chen J, Colman PM, Czabotar PE, Deshayes K, Fairbrother WJ, Flygare JA, Hymowitz SG, Jin S, Judge RA, Koehler MF, Kovar PJ, Lessene G, Mitten MJ, Ndubaku CO, Nimmer P, Purkey HE, Oleksijew A, Phillips DC, Sleebs BE, Smith BJ, Smith ML, Tahir SK, Watson KG, Xiao Y, Xue J, Zhang H, Zobel K, Rosenberg SH, Tse C, Leverson JD, Elmore SW, Souers AJ. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity. ACS Med Chem Lett. 2014;5:1088–1093. doi: 10.1021/ml5001867Tao Z.F., Hasvold L., Wang L., et al. Discovery of a potent and selective BCL-XL inhibitor with in vivo activity // ACS Med Chem Lett. 2014. Vol. 5. P. 1088–1093. doi: 10.1021/ml5001867Wei Y, Zhang L, Wang C, Li Z, Luo M, Xie G, Yang X, Li M, Ren S, Zhao D, Gao R, Gong JN. Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer. Animal Model Exp Med. 2023;6:245–254. doi: 10.1002/ame2.12330Wei Y., Zhang L., Wang C., et al. Anti-apoptotic protein BCL-XL as a therapeutic vulnerability in gastric cancer // Animal Model Exp Med. 2023. Vol. 6. P. 245–254. doi: 10.1002/ame2.12330Moujalled D, Southon AG, Saleh E, Brinkmann K, Ke F, Iliopoulos M, Cross RS, Jenkins MR, Nhu D, Wang Z, Shi MX, Kluck RM, Lessene G, Grabow S, Bush AI, Strasser A. BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. Cell Death Differ. 2022;29:1335–1348. doi: 10.1038/s41418-022-00977-2Moujalled D., Southon A.G., Saleh E., et al. BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells // Cell Death Differ. 2022. Vol. 29. P. 1335–1348. doi: 10.1038/s41418-022-00977-2Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M. Identification and characterization of cardiac glycosides as senolytic compounds. Nat Commun. 2019;10:4731. doi: 10.1038/s41467-019-12888-xTriana-Martínez F., Picallos-Rabina P., Da Silva-Álvarez S., et al. Identification and characterization of cardiac glycosides as senolytic compounds // Nat Commun. 2019. Vol. 10. P. 4731. doi: 10.1038/s41467-019-12888-xSeo EJ, Efferth T, Panossian A. Curcumin downregulates expression of opioid-related nociceptin receptor gene (OPRL1) in isolated neuroglia cells. Phytomedicine. 2018;50:285–299. doi: 10.1016/j.phymed.2018.09.202Seo E.J., Efferth T., Panossian A. Curcumin downregulates expression of opioid-related nociceptin receptor gene (OPRL1) in isolated neuroglia cells // Phytomedicine. 2018. Vol. 50. P. 285–299. doi: 10.1016/j.phymed.2018.09.202Lee DY, Lee SJ, Chandrasekaran P, Lamichhane G, O'Connell JF, Egan JM, Kim Y. Dietary curcumin attenuates hepatic cellular senescence by suppressing the MAPK/NF-kappa B signaling pathway in aged mice. Antioxidants (Basel). 2023;12:1–14. doi: 10.3390/antiox12061165Lee D.Y., Lee S.J., Chandrasekaran P., et al. Dietary curcumin attenuates hepatic cellular senescence by suppressing the MAPK/NF-kappa B signaling pathway in aged mice // Antioxidants (Basel). 2023. Vol. 12. P. 1–14. doi: 10.3390/antiox12061165Nam S, Kim D, Cheng JQ, Zhang S, Lee JH, Buettner R, Mirosevich J, Lee FY, Jove R. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 2005;65:9185–9189. doi: 10.1158/0008-5472.CAN-05-1731Nam S., Kim D., Cheng J.Q., et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells // Cancer Res. 2005. Vol. 65. P. 9185–9189. doi: 10.1158/0008-5472.CAN-05-1731Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18–28. doi: 10.1016/j.ebiom.2018.09.015Yousefzadeh M.J., Zhu Y., McGowan S.J., et al. Fisetin is a senotherapeutic that extends health and lifespan // EBioMedicine. 2018. Vol. 36. P. 18–28. doi: 10.1016/j.ebiom.2018.09.015Huang Y, He Y, Makarcyzk MJ, Lin H. Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes. Front Bioeng Biotechnol. 2021;9:677576. doi: 10.3389/fbioe.2021.677576Huang Y., He Y., Makarcyzk M.J., Lin H. Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes // Front Bioeng Biotechnol. 2021. Vol. 9. P. 677576. doi: 10.3389/fbioe.2021.677576Iida K, Naiki T, Naiki-Ito A, Suzuki S, Kato H, Nozaki S, Nagai T, Etani T, Nagayasu Y, Ando R, Kawai N, Yasui T, Takahashi S. Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway. Cancer Sci. 2020;111:1165–1179. doi: 10.1111/cas.14334Iida K., Naiki T., Naiki-Ito A., et al. Luteolin suppresses bladder cancer growth via regulation of mechanistic target of rapamycin pathway // Cancer Sci. 2020. Vol. 111. P. 1165–1179. doi: 10.1111/cas.14334Takaya K, Ishii T, Asou T, Kishi K. Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model. Rejuvenation Res. 2023;26:9–20. doi: 10.1089/rej.2022.0048Takaya K., Ishii T., Asou T., Kishi K. Navitoclax (ABT-263) rejuvenates human skin by eliminating senescent dermal fibroblasts in a mouse/human chimeric model // Rejuvenation Res. 2023. Vol. 26. P. 9–20. doi: 10.1089/rej.2022.0048Chung H, Kim C. Nutlin-3a for age-related macular degeneration. Aging (Albany NY). 2022;14:5614–5616. doi: 10.18632/aging.204187Chung H., Kim C. Nutlin-3a for age-related macular degeneration // Aging (Albany NY). 2022. Vol. 14. P. 5614–5616. doi: 10.18632/aging.204187Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, Zhou D, Zheng G. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY). 2016;8:2915–2926. doi: 10.18632/aging.101100Wang Y., Chang J., Liu X., et al. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents // Aging (Albany NY). 2016. Vol. 8. P. 2915–2926. doi: 10.18632/aging.101100Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell. 2017;16:564–574. doi: 10.1111/acel.12587Wang R., Yu Z., Sunchu B., et al. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism // Aging Cell. 2017. Vol. 16. P. 564–574. doi: 10.1111/acel.12587Powers MV, Valenti M, Miranda S, Maloney A, Eccles SA, Thomas G, Clarke PA, Workman P. Mode of cell death induced by the HSP-90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX. Oncotarget. 2013;4:1963–1975. doi: 10.18632/oncotarget.1419Powers M.V., Valenti M., Miranda S., et al. Mode of cell death induced by the HSP-90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic BAX // Oncotarget. 2013. Vol. 4. P. 1963–1975. doi: 10.18632/oncotarget.1419Harris DT, Hilgaertner J, Simonson C, Ablin RJ, Badowski M. Cell-based therapy for epithelial wounds. Cytotherapy. 2012;14:802–810. doi: 10.3109/14653249.2012.671520Harris D.T., Hilgaertner J., Simonson C., et al. Cell-based therapy for epithelial wounds // Cytotherapy. 2012. Vol. 14. P. 802–810. doi: 10.3109/14653249.2012.671520Pippias M, Jager KJ, Åsberg A, Berger SP, Finne P, Heaf JG, Kerschbaum J, Lempinen M, Magaz Á, Massy ZA, Stel VS. Young deceased donor kidneys show a survival benefit over older donor kidneys in transplant recipients aged 20–50 years: A study by the ERA-EDTA Registry. Nephrol Dial Transplant. 2020;35:534–543. doi: 10.1093/ndt/gfy268Pippias M., Jager K.J., Åsberg A., et al. Young deceased donor kidneys show a survival benefit over older donor kidneys in transplant recipients aged 20–50 years: A study by the ERA-EDTA Registry // Nephrol Dial Transplant. 2020. Vol. 35. P. 534–543. doi: 10.1093/ndt/gfy268Iske J, Matsunaga T, Zhou H, Tullius SG. Donor and recipient age-mismatches: The potential of transferring senescence. Front Immunol. 2021;12:671479. doi: 10.3389/fimmu.2021.671479Iske J., Matsunaga T., Zhou H., Tullius S.G. Donor and recipient age-mismatches: The potential of transferring senescence // Front Immunol. 2021. Vol. 12. P. 671479. doi: 10.3389/fimmu.2021.671479Keren A, Bertolini M, Keren Y, Ullmann Y, Paus R, Gilhar A. Human organ rejuvenation by VEGF-A: Lessons from the skin. Sci Adv. 2022;8:eabm6756. doi: 10.1126/sciadv.abm6756Keren A., Bertolini M., Keren Y., et al. Human organ rejuvenation by VEGF-A: Lessons from the skin // Sci Adv. 2022. Vol. 8. Р. eabm6756. doi: 10.1126/sciadv.abm6756Wang L, Wei J, Da Fonseca Ferreira A, Wang H, Zhang L, Zhang Q, Bellio MA, Chu XM, Khan A, Jayaweera D, Hare JM, Dong C. Rejuvenation of senescent endothelial progenitor cells by extracellular vesicles derived from mesenchymal stromal cells. JACC Basic Transl Sci. 2020;5:1127–1141. doi: 10.1016/j.jacbts.2020.08.005Wang L., Wei J., Da Fonseca Ferreira A., et al. Rejuvenation of senescent endothelial progenitor cells by extracellular vesicles derived from mesenchymal stromal cells // JACC Basic Transl Sci. 2020. Vol. 5. P. 1127–1141. doi: 10.1016/j.jacbts.2020.08.005Grigorian-Shamagian L, Liu W, Fereydooni S, Middleton RC, Valle J, Cho JH, Marban E. Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats. Eur Heart J. 2017;38:2957–2967. doi: 10.1093/eurheartj/ehx454Grigorian-Shamagian L., Liu W., Fereydooni S., et al. Cardiac and systemic rejuvenation after cardiosphere-derived cell therapy in senescent rats // Eur Heart J. 2017. Vol. 38. P. 2957–2967. doi: 10.1093/eurheartj/ehx454Brunet A, Goodell MA, Rando TA. Ageing and rejuvenation of tissue stem cells and their niches. Nat Rev Mol Cell Biol. 2023;24:45–62. doi: 10.1038/s41580-022-00510-wBrunet A., Goodell M.A., Rando T.A. Ageing and rejuvenation of tissue stem cells and their niches // Nat Rev Mol Cell Biol. 2023. Vol. 24. P. 45–62. doi: 10.1038/s41580-022-00510-wChulpanova DS, Kitaeva KV, Tazetdinova LG, James V, Rizvanov AA, Solovyeva VV. Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment. Front Pharmacol. 2018;9:1–10. doi: 10.3389/fphar.2018.00259Chulpanova D.S., Kitaeva K.V., Tazetdinova L.G., et al. Application of mesenchymal stem cells for therapeutic agent delivery in anti-tumor treatment // Front Pharmacol. 2018. Vol. 9. P. 1–10. doi: 10.3389/fphar.2018.00259Awad ME, Hussein KA, Helwa I, Abdelsamid MF, Aguilar-Perez A, Mohsen I, Hunter M, Hamrick MW, Isales CM, Elsalanty M, Hill WD, Fulzele S. Meta-analysis and evidence base for the efficacy of autologous bone marrow mesenchymal stem cells in knee cartilage repair: Methodological guidelines and quality assessment. Stem Cells Int. 2019;2019:3826054. doi: 10.1155/2019/3826054Awad M.E., Hussein K.A., Helwa I., et al. Meta-analysis and evidence base for the efficacy of autologous bone marrow mesenchymal stem cells in knee cartilage repair: Methodological guidelines and quality assessment // Stem Cells Int. 2019. Vol. 2019. P. 3826054. doi: 10.1155/2019/3826054Gasanova SYu. Cell therapy for destructive pancreatitis. Pirogov Russian Journal of Surgery. 2022;(9):50–55. (In Russ.) doi: 10.17116/hirurgia202209150Гасанова С.Ю. Применение клеточной терапии при лечении деструктивного панкреатита // Хирургия. Журнал им. Н.И. Пирогова. 2022. № 9. С. 50–55. doi: 10.17116/hirurgia202209150Gjerde C, Mustafa K, Hellem S, Rojewski M, Gjengedal H, Yassin MA, Feng X, Skaale S, Berge T, Rosen A, Shi XQ, Ahmed AB, Gjertsen BT, Schrezenmeier H, Layrolle P. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther. 2018;9:213. doi: 10.1186/s13287-018-0951-9Gjerde C., Mustafa K., Hellem S., et al. Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial // Stem Cell Res Ther. 2018. Vol. 9. P. 213. doi: 10.1186/s13287-018-0951-9Zarei F, Abbaszadeh A. Application of cell therapy for anti-aging facial skin. Curr Stem Cell Res Ther. 2019;14:244–248. doi: 10.2174/1574888X13666181113113415Zarei F., Abbaszadeh A. Application of cell therapy for anti-aging facial skin // Curr Stem Cell Res Ther. 2019. Vol. 14. P. 244–248. doi: 10.2174/1574888X13666181113113415Zhang DY, Gao T, Xu RJ, Sun L, Zhang CF, Bai L, Chen W, Liu KY, Zhou Y, Jiao X, Zhang GH, Guo RL, Li JX, Gao Y, Jiao WJ, Tian H. SIRT3 transfection of aged human bone marrow-derived mesenchymal stem cells improves cell therapy-mediated myocardial repair. Rejuvenation Res. 2020;23:453–464. doi: 10.1038/s41598-023-40543-5Zhang DY, Gao T, Xu RJ, et al. SIRT3 transfection of aged human bone marrow-derived mesenchymal stem cells improves cell therapy-mediated myocardial repair // Rejuvenation Res. 2020. Vol. 23. P. 453–464. doi: 10.1038/s41598-023-40543-5Primorac D, Molnar V, Rod E, Jelec Z, Cukelj F, Matisic V, Vrdoljak T, Hudetz D, Hajsok H, Boric I. Knee osteoarthritis: A review of pathogenesis and state-of-the-art non-operative therapeutic considerations. Genes (Basel). 2020;11:854. doi: 10.3390/genes11080854Primorac D., Molnar V., Rod E., et al. Knee osteoarthritis: A review of pathogenesis and state-of-the-art non-operative therapeutic considerations // Genes (Basel). 2020. Vol. 11. P. 854. doi: 10.3390/genes11080854Yang JM, Chung S, Yun K, Kim B, So S, Kang S, Kang E, Lee JY. Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats. Exp Mol Med. 2021;53:631–642. doi: 10.1038/s12276-021-00588-wYang J.M., Chung S., Yun K., et al. Long-term effects of human induced pluripotent stem cell-derived retinal cell transplantation in Pde6b knockout rats // Exp Mol Med. 2021. Vol. 53. P. 631–642. doi: 10.1038/s12276-021-00588-wMartin-Lopez M, Gonzalez-Munoz E, Gomez-Gonzalez E, Sanchez-Pernaute R, Marquez-Rivas J, Fernandez-Munoz B. Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies. J Clin Neurosci. 2021;94:76–85. doi: 10.1016/j.jocn.2021.09.042Martin-Lopez M., Gonzalez-Munoz E., Gomez-Gonzalez E., et al. Modeling chronic cervical spinal cord injury in aged rats for cell therapy studies // J Clin Neurosci. 2021. Vol. 94. P. 76–85. doi: 10.1016/j.jocn.2021.09.042Liu D, Zhu M, Zhang Y, Diao Y. Crossing the blood-brain barrier with AAV vectors. Metab Brain Dis. 2021;36:45–52. doi: 10.1007/s11011-020-00630-2Liu D., Zhu M., Zhang Y., Diao Y. Crossing the blood-brain barrier with AAV vectors // Metab Brain Dis. 2021. Vol. 36. P. 45–52. doi: 10.1007/s11011-020-00630-2Epstein BE, Schaffer DV. Combining engineered nucleases with adeno-associated viral vectors for therapeutic gene editing. Adv Exp Med Biol. 2017;1016:29–42. doi: 10.1007/978-3-319-63904-8_2Epstein B.E., Schaffer D.V. Combining engineered nucleases with adeno-associated viral vectors for therapeutic gene editing // Adv Exp Med Biol. 2017. Vol. 1016. P. 29–42. doi: 10.1007/978-3-319-63904-8_2Jaijyan DK, Selariu A, Cruz-Cosme R, Tong M, Yang S, Stefa A, Kekich D, Sadoshima J, Herbig U, Tang Q, Church G, Parrish EL, Zhu H. New intranasal and injectable gene therapy for healthy life extension. Proc Natl Acad Sci USA. 2022;119:e2121499119. doi: 10.1073/pnas.2121499119Jaijyan D.K., Selariu A., Cruz-Cosme R., et al. New intranasal and injectable gene therapy for healthy life extension // Proc Natl Acad Sci USA. 2022. Vol. 119. P. e2121499119. doi: 10.1073/pnas.2121499119Li Z, Zhang Y, Sui S, Hua Y, Zhao A, Tian X, Wang R, Guo W, Yu W, Zou K, Deng W, He L, Zou L. Targeting HMGB3/hTERT axis for radioresistance in cervical cancer. J Exp Clin Cancer Res. 2020;39:243. doi: 10.1186/s13046-020-01737-1Li Z., Zhang Y., Sui S., et al. Targeting HMGB3/hTERT axis for radioresistance in cervical cancer // J Exp Clin Cancer Res. 2020. Vol. 39. P. 243. doi: 10.1186/s13046-020-01737-1Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima Y. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010;398:513–518. doi: 10.1016/j.bbrc.2010.06.110Yamazaki Y., Imura A., Urakawa I., et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects // Biochem Biophys Res Commun. 2010. Vol. 398. P. 513–518. doi: 10.1016/j.bbrc.2010.06.110Xiang T, Luo X, Zeng C, Li S, Ma M, Wu Y. Klotho ameliorated cognitive deficits in a temporal lobe epilepsy rat model by inhibiting ferroptosis. Brain Res. 2021;1772:147668. doi: 10.1016/j.brainres.2021.147668Xiang T., Luo X., Zeng C., et al. Klotho ameliorated cognitive deficits in a temporal lobe epilepsy rat model by inhibiting ferroptosis // Brain Res. 2021. Vol. 1772. P. 147668. doi: 10.1016/j.brainres.2021.147668Xiang T, Luo X, Ye L, Huang H, Wu Y. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway. Epilepsy Behav. 2022;128:108509. doi: 10.1016/j.yebeh.2021.108509Xiang T., Luo X., Ye L., et al. Klotho alleviates NLRP3 inflammasome-mediated neuroinflammation in a temporal lobe epilepsy rat model by activating the Nrf2 signaling pathway // Epilepsy Behav. 2022. Vol. 128. P. 108509. doi: 10.1016/j.yebeh.2021.108509Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension. 2009;54:810–817. doi: 10.1161/HYPERTENSIONAHA.109.134320Wang Y., Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage // Hypertension. 2009. Vol. 54. P. 810–817. doi: 10.1161/HYPERTENSIONAHA.109.134320Roig-Soriano J, Grinan-Ferre C, Espinosa-Parrilla JF, Abraham CR, Bosch A, Pallas M, Chillon M. AAV-mediated expression of secreted and transmembrane aKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice. Aging Cell. 2022;21:e13581. doi: 10.1111/acel.13581Roig-Soriano J., Grinan-Ferre C., Espinosa-Parrilla J.F., et al. AAV-mediated expression of secreted and transmembrane aKlotho isoforms rescues relevant aging hallmarks in senescent SAMP8 mice // Aging Cell. 2022. Vol. 21. P. e13581. doi: 10.1111/acel.13581Fan J, Wang S, Chen K, Sun Z. Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels. Cell Mol Life Sci. 2022;79:494. doi: 10.1007/s00018-022-04512-xFan J., Wang S., Chen K., Sun Z. Aging impairs arterial compliance via Klotho-mediated downregulation of B-cell population and IgG levels // Cell Mol Life Sci. 2022. Vol. 79. P. 494. doi: 10.1007/s00018-022-04512-xSewell PE, Ediriweera D, Gomez Rios E, Guadarrama OA, Eusebio Y, Gonzalez L, Parrish EL. Safety study of AAV hTert and Klotho gene transfer therapy for dementia. J Regen Biol Med. 2021;3:1–15. doi: 10.37191/Mapsci-2582-385X-3(6)-097Sewell P.E., Ediriweera D., Gomez Rios E., et al. Safety study of AAV hTert and Klotho gene transfer therapy for dementia // J Regen Biol Med. 2021. Vol. 3. P. 1–15. doi: 10.37191/Mapsci-2582-385X-3(6)-097Jimenez V, Jambrina C, Casana E, Sacristan V, Muñoz S, Darriba S, Rodó J, Mallol C, Garcia M, León X, Marcó S, Ribera A, Elias I, Casellas A, Grass I, Elias G, Ferré T, Motas S, Franckhauser S, Mulero F, Navarro M, Haurigot V, Ruberte J, Bosch F. FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol Med. 2018;10:1–24. doi: 10.15252/emmm.201708791Jimenez V., Jambrina C., Casana E., et al. FGF21 gene therapy as treatment for obesity and insulin resistance // EMBO Mol Med. 2018. Vol. 10. P. 1–24. doi: 10.15252/emmm.201708791Villarroya J, Gallego-Escuredo JM, Delgado-Angles A, Cairo M, Moure R, Gracia Mateo M, Domingo JC, Domingo P, Giralt M, Villarroya F. Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue. Aging Cell. 2018;17:e12822. doi: 10.1111/acel.12822Villarroya J., Gallego-Escuredo J.M., Delgado-Angles A., et al. Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue // Aging Cell. 2018. Vol. 17. P. e12822. doi: 10.1111/acel.12822Davidsohn N, Pezone M, Vernet A, Graveline A, Oliver D, Slomovic S, Punthambaker S, Sun X, Liao R, Bonventre JV, Church GM. A single combination gene therapy treats multiple age-related diseases. Proc Natl Acad Sci USA. 2019;116:23505–23511. doi: 10.1073/pnas.1910073116Davidsohn N., Pezone M., Vernet A., et al. A single combination gene therapy treats multiple age-related diseases // Proc Natl Acad Sci USA. 2019. Vol. 116. P. 23505–23511. doi: 10.1073/pnas.1910073116