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Сенотерапевтики (англ. Senotherapeutics) — это лечебные средства или стратегии, предназначенные для лечения клеточного старения[1][2].

К сенотерапевтикам относятся:

1. геропротекторы — средства для профилактики старения путём ослабления таких триггеров старения как: повреждение ДНК[3][4] , окислительный стресс[5], протеотоксический стресс[6], повреждение теломер[7].

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 куркумина[8][9]

2. агенты, препятствующие секреции SASP (senescence‐associated secretory phenotype)[10][11], включая:

3. средства / стратегии предназначенные для уничтожения постаревших клеток: сенолитики — малые молекулы, которые специфически индуцируют гибель стареющих клеток[18][19], антитела и опосредованная ими доставка лекарств, агенты, которые могут препятствовать ослаблению иммунной системы при старении[20], клетки иммунной системы (NK-клетки, В-клетки[21], Т-клетки).

4. Препараты, которые подавляют фенотип старения у клеток не вызывая изменения количества клеток, называют сеноморфиками[22][23]

5. средства / стратегии генной терапии предназначенные для редактирования генов организма с целью повышения его устойчивости к старению, старческим заболеваниям[24] и продления его жизни[25][25][26][27][28][29][30][31][32][33][34][35].

ПримечанияПравить

  1. Childs et al. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy Nature Medicine {{doi:10.1038/nm.4000}}
  2. Jafari Mahtab (2015). Healthspan Pharmacology. Rejuvenation Research., 18(6): 573—580. DOI:10.1089/rej.2015.1774.
  3. Misra, 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. DOI:10.1002/stem.2255
  4. 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.
  5. Eisenberg, 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. DOI:10.1038/ncb1975
  6. Pride, 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. DOI:10.1016/j.bbrc.2015.01.046
  7. Blackburn, 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. DOI:10.1126/science.aab3389
  8. Researchers report new methods to identify Alzheimer’s drug candidates that have anti-aging properties
  9. Larrick, J. W., Larrick, J. W., & Mendelsohn, A. R. (2018). ATP Synthase, a Target for Dementia and Aging?. Rejuvenation research, 21(1), 61-66.
  10. 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. PMID 26129674
  11. Young, A. R., & Narita, M. (2009). SASP reflects senescence. EMBO reports, 10(3), 228—230. DOI:10.1038/embor.2009.22
  12. Laberge, 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. DOI:10.1111/j.1474-9726.2012.00818.x
  13. Liu, 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. DOI:10.1038/srep17895
  14. Xu, 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, DOI: 10.1073/pnas.1515386112
  15. 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
  16. Sébastien Cardinal et al., & Normand Voyer (2017). Synthesis and anti-inflammatory activity of isoquebecol. Bioorganic & Medicinal Chemistry
  17. Correia-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, PMID 26848154, DOI:10.15252/embj.201592862
  18. Chang 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 DOI:10.1038/nm.4010
  19. Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; et al., (2015). The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. DOI:10.1111/acel.12344
  20. Stahl, E. C., & Brown, B. N. (2015). Cell Therapy Strategies to Combat Immunosenescence. Organogenesis, (just-accepted), DOI:10.1080/15476278.2015.1120046
  21. Henry, 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),
  22. Fuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing; McGowan, Sara J.; Zhu, Yi; Brooks, Robert W.; Grassi, Diego; Gregg, Siobhan Q.; Stripay, Jennifer L. (2017). Identification of HSP90 inhibitors as a novel class of senolytics. Nature Communications. 8(1). DOI:[//dx.doi.org/10.1038%2Fs41467-017-00314-z 10.1038/s41467-017-00314-z
  23. Niedernhofer L.J, Robbins P.D. (2018). Senotherapeutics for healthy ageing Nature Reviews Drug Discovery, DOI:10.1038/nrd.2018.44
  24. Fortney 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. DOI:10.1371/journal.pgen.1005728
  25. 1 2 Andrews, 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.
  26. 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. DOI:10.1002/emmm.201200245
  27. 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. DOI:10.1016/j.celrep.2015.07.047
  28. 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. DOI:10.1089/rej.2015.1780.
  29. 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. DOI:10.1016/j.cell.2014.12.016
  30. 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 DOI:10.1016/j.celrep.2013.07.030
  31. 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 Office
  32. Yun-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 DOI:10.1073/pnas.1514511113
  33. 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), 307 DOI:10.1186/s12957-015-0717-0
  34. Kurosu, 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 DOI:10.1126/science.1112766
  35. 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 DOI:10.1016/j.cell.2007.05.038

ЛитератураПравить

  • Schmitt, R. (2017). Senotherapy: growing old and staying young?. Pflügers Archiv-European Journal of Physiology, 1-9. DOI:10.1007/s00424-017-1972-4 PMID 28389776
  • Xu, 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, DOI: 10.1073/pnas.1515386112
  • Niccolò Viviani (2015). Meet the Woman experimenting anti-aging gene therapies (on herself). Exosphere Stories.
  • Antonio Regalado (2015). A Tale of Do-It-Yourself Gene Therapy. An American biotech CEO claims she is the first to undergo gene therapy to reverse aging. MIT Technology Review.
  • Pyo, J. O., Yoo, S. M., Ahn, H. H., Nah, J., Hong, S. H., Kam, T. I., … & Jung, Y. K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nature communications, 4. Article number: 2300 DOI:10.1038/ncomms3300
  • Darren J. Baker, Bennett G. Childs, Matej Durik, Melinde E. Wijers, Cynthia J. Sieben, Jian Zhong, Rachel A. Saltness, Karthik B. Jeganathan, Grace Casaclang Verzosa, Abdulmohammad Pezeshki, Khashayarsha Khazaie, Jordan D. Miller & Jan M. van Deursen (2016). Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature DOI:10.1038/nature16932
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  • North, B. J., Rosenberg, M. A., Jeganathan, K. B., Hafner, A. V., Michan, S., Dai, J., … & van Deursen, J. M. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. The EMBO journal, e201386907. DOI:10.15252/embj.201386907
  • Wu, J. J., Liu, J., Chen, E. B., Wang, J. J., Cao, L., Narayan, N., … & Lago, C. U. (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 DOI:10.1016/j.celrep.2013.07.030
  • Pollock, K., Dahlenburg, H., Nelson, H., Fink, K. D., Cary, W., Hendrix, K., … & Nacey, C. (2016). Human Mesenchymal Stem Cells Genetically Engineered to Overexpress Brain-derived Neurotrophic Factor Improve Outcomes in Huntington’s disease Mouse Models. Molecular therapy: the journal of the American Society of Gene Therapy. DOI:10.1038/mt.2016.12
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