Сенотерапевтики () — это лечебные средства или стратегии, предназначенные для лечения клеточного старенияChilds et al. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy Nature Medicine Jafari Mahtab (2015). Healthspan Pharmacology. Rejuvenation Research., 18(6): 573—580. .Zhang, L., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022). Targeting Cellular Senescence with Senotherapeutics: Senolytics and Senomorphics. The FEBS journal. .
К сенотерапевтикам относятся:
1. геропротекторы — средства для профилактики старения путём ослабления таких триггеров старения как: повреждение ДНКMisra, J., Mohanty, S. T., Madan, S., Fernandes, J. A., Hal Ebetino, F., Russell, R. G. G. and Bellantuono, I. (2015), Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function. STEM CELLS. Wahlestedt, M., Pronk, C. J., & Bryder, D. (2015). Concise Review: Hematopoietic Stem Cell Aging and the Prospects for Rejuvenation. Stem cells translational medicine, 4(2), 186—194. , окислительный стрессEisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., … & Fussi, H. (2009). Induction of autophagy by spermidine promotes longevity. Nature cell biology, 11(11), 1305—1314. , протеотоксический стрессPride, H., Yu, Z., Sunchu, B., Mochnick, J., Coles, A., Zhang, Y., … & Pérez, V. I. (2015). Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species. Biochemical and biophysical research communications, 457(4), 669—675. , повреждение теломерBlackburn, E. H., Epel, E. S., & Lin, J. (2015). Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science, 350(6265), 1193—1198. .
К числу геропротекторов следует также отнести геронейропротекторы такие как фисетин, куркумин, монтелукаст и их производные, такие как CMS121, получаемый из фисетина, и J147, получаемый из куркуминаLarrick, J. W., Larrick, J. W., & Mendelsohn, A. R. (2018). ATP Synthase, a Target for Dementia and Aging? . Rejuvenation research, 21(1), 61-66.
2. агенты, препятствующие секреции SASP (senescence‐associated secretory phenotype)Hae-Ok, B., & Gyesoon, Y. (2015). From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes. BMB reports, 48(10), 549—558. Young, A. R., & Narita, M. (2009). SASP reflects senescence . EMBO reports, 10(3), 228—230. , так называемые сеноморфики (senomorphics), включая:
глюкокортикоидыLaberge, R. M., Zhou, L., Sarantos, M. R., Rodier, F., Freund, A., de Keizer, P. L., … & Desprez, P. Y. (2012). Glucocorticoids suppress selected components of the senescence‐associated secretory phenotype. Aging cell, 11(4), 569—578. , статины, такие как симвастатинLiu, S., Uppal, H., Demaria, M., Desprez, P. Y., Campisi, J., & Kapahi, P. (2015). Simvastatin suppresses breast cancer cell proliferation induced by senescent cells . Scientific reports, 5, 17895. ингибиторы JAK1/2 такие как RuxolitinibXu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., … & Giorgadze, N. (2015). JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age . Proceedings of the National Academy of Sciences, 112(46), E6301-E6310, Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., … & Jensen, M. D. (2015). Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife, e12997. DOI: https://dx.doi.org/10.7554/eLife.12997, NF-κB и p38, IL-1α и IL-6 блокаторы. Такие как например или изоквебеколSébastien Cardinal et al., & Normand Voyer (2017). Synthesis and anti-inflammatory activity of isoquebecol. Bioorganic & Medicinal Chemistry, активаторы процессов удаления митохондрийCorreia-Melo C, Marques FD, Anderson R, et al., & Passos JF (2016). Mitochondria are required for pro-ageing features of the senescent phenotype . The EMBO Journal, , и т. д.; 3. средства / стратегии предназначенные для уничтожения постаревших клеток: сенолитики — малые молекулы, которые специфически индуцируют гибель стареющих клетокChang J., Wang Y.,Shao L. et al., & Zhou D. (2015). Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; et al., (2015). The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. , антитела и опосредованная ими доставка лекарств, агенты, которые могут препятствовать ослаблению иммунной системы при старенииStahl, E. C., & Brown, B. N. (2015). Cell Therapy Strategies to Combat Immunosenescence. Organogenesis, (just-accepted), , клетки иммунной системы (NK-клетки, В-клеткиHenry, C. J., Casás-Selves, M., Kim, J., Zaberezhnyy, V., Aghili, L., Daniel, A. E., … & Klawitter, J. (2015). Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors . The Journal of clinical investigation, 125(12),, Т-клетки).
4. Препараты, которые подавляют фенотип старения у клеток не вызывая изменения количества клеток, называют сеноморфикамиFuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing; McGowan, Sara J.; Zhu, Yi; Brooks, Robert W.; Grassi, Diego; Gregg, Siobhan Q.; Stripay, Jennifer L. (2017). [http://www.nature.com/articles/s41467-017-00314-z Identification of HSP90 inhibitors as a novel class of senolytics. Nature Communications. 8(1). Niedernhofer L.J, Robbins P.D. (2018). Senotherapeutics for healthy ageing Nature Reviews Drug Discovery, Примером подобных веществ может служить SR12343Zhang, L., Zhao, J., Mu, X., McGowan, S. J., Angelini, L., O'Kelly, R. D., ... & Robbins, P. D. (2021). Novel small molecule inhibition of IKK/NF‐κB activation reduces markers of senescence and improves healthspan in mouse models of aging. Aging cell, 20(12), e13486.
5. средства / стратегии генной терапии предназначенные для редактирования генов организма с целью повышения его устойчивости к старению, старческим заболеваниямFortney K, Dobriban E, Garagnani P, Pirazzini C, Monti D, Mari D, et al. (2015) Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. PLoS Genet 11(12): e1005728. и продления его жизниAndrews, W. H., Brown, L. K., Mohammadpour, H., & Briggs, L. A. (2015). Enhancing Health in Mammals Using Telomerase Reverse Transcriptase Gene Therapy . U.S. Patent No. 20,150,322,416. Washington, DC: U.S. Patent and Trademark Office.de Jesus, B. B., Vera, E., Schneeberger, K., Tejera, A. M., Ayuso, E., Bosch, F., & Blasco, M. A. (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer . EMBO molecular medicine, 4(8), 691—704. Xiong, S., Patrushev, N., Forouzandeh, F., Hilenski, L., & Alexander, R. W. (2015). PGC-1α modulates telomere function and DNA damage in protecting against aging-related chronic diseases . Cell reports, 12(9), 1391—1399. Mendelsohn Andrew R. and Larrick James W. (2015). Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence. Rejuvenation Research., 18(5): 479—483. .Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., … & Li, X. (2015). Reduced expression of MYC increases longevity and enhances healthspan. Cell, 160(3), 477—488. Wu, J. J., Liu, J., Chen, E. B., Wang, J. J., Cao, L., Narayan, N., … & Finkel, T. (2013). Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell reports, 4(5), 913—920 Kirkland, J. L., Tchkonia, T., Van Deursen, J., & Baker, D. J. (2015). TRANSGENIC ANIMALS CAPABLE OF BEING INDUCED TO DELETE SENESCENT CELLS . U.S. Patent No. 20,150,296,755. Washington, DC: U.S. Patent and Trademark OfficeYun-Hee Youm, Tamas L. Horvath, David J. Mangelsdorf, Steven A. Kliewer, and Vishwa Deep Dixit (2016).Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution . PNAS Sun, H., Gao, Y., Lu, K., Zhao, G., Li, X., Li, Z., & Chang, H. (2015). Overexpression of Klotho suppresses liver cancer progression and induces cell apoptosis by negatively regulating wnt/β-catenin signaling pathway. World journal of surgical oncology, 13(1), 307Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., … & Shimomura, I. (2005). Suppression of aging in mice by the hormone Klotho . Science, 309(5742), 1829—1833 Yan, L., Vatner, D. E., O’Connor, J. P., Ivessa, A., Ge, H., Chen, W., … & Vatner, S. F. (2007). Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell, 130(2), 247—258 .
Примечания
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