Senotherapeutics

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Senotherapeutics is an early-stage basic research field for development of possible therapeutic agents and strategies to specifically target cellular senescence,[1] an altered cell state associated with ageing and age-related diseases. The name derives from intent of the proposed anti-aging drug to halt "senescence".[1] As of 2017, much of the research remains preliminary and there are no drugs approved for this purpose.

Types

Senotherapeutics include:

  1. Geroprotectors – agents/strategies which prevent or reverse the senescent state by preventing triggers of cellular senescence, such as DNA damage,[2][3][4] oxidative stress,[5] proteotoxic stress,[6] telomere shortening [7] (i.e. telomerase activators).
  2. SASP inhibitors – agents interfering with pro-inflammatory senescence‐associated secretory phenotype (SASP)[8][9] production, including:
    1. Glucocorticoids as potent suppressors of selected components of the SASP[10]
    2. Statins such as simvastatin, that can reduce the expression of pro-inflammatory cytokines (IL-6, IL-8, and MCP-1)[11]
    3. JAK1/2 inhibitors such as ruxolitinib[12][13]
    4. NF-κB and p38 inhibitors
    5. IL-1α blockers
    6. Mitochondrial depleters in the case of impaired mitophagy[14]
  3. Senolytics – small molecules that specifically induce cell death in senescent cells,[15][16][17] targeting survival pathways and anti-apoptotic mechanisms, antibodies and antibody-mediated drug delivery medications.
  4. Senomorphics - small molecules that suppress senescent phenotypes without cell killing[18]
  5. Agents/strategies which can enhance immune clearance of senescent cells (an ageing immune system likely impairs senescent cell clearance leading to their accumulation[19][20]), immune system cells (NK cells, B cells, T cells).
  6. Gene therapy agents/strategies intended to edit the genes of the cells of an organism in order to increase their resistance to aging, senile diseases and to prolong the life of the organism[21][22][23][24][25]

References

  1. ^ a b Childs BG, Durik M, Baker DJ, van Deursen JM (2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–35. doi:10.1038/nm.4000. PMC 4748967Freely accessible. PMID 26646499. 
  2. ^ Misra, Juhi; Mohanty, Sindhu T.; Madan, Sanjeev; Fernandes, James A.; Hal Ebetino, F.; Russell, R. Graham G.; Bellantuono, Ilaria (2015). "Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function". Stem Cells. 34: 756–767. doi:10.1002/stem.2255. PMC 4832316Freely accessible. PMID 26679354. 
  3. ^ Xiong, Shiqin; Patrushev, Nikolay; Forouzandeh, Farshad; Hilenski, Lula; Alexander, R. Wayne (2015). "PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases". Cell Reports. 12 (9): 1391–9. doi:10.1016/j.celrep.2015.07.047. PMID 26299964. 
  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, Tobias; Knauer, Heide; Schauer, Alexandra; Büttner, Sabrina; Ruckenstuhl, Christoph; Carmona-Gutierrez, Didac; Ring, Julia; Schroeder, Sabrina; Magnes, Christoph; Antonacci, Lucia; Fussi, Heike; Deszcz, Luiza; Hartl, Regina; Schraml, Elisabeth; Criollo, Alfredo; Megalou, Evgenia; Weiskopf, Daniela; Laun, Peter; Heeren, Gino; Breitenbach, Michael; Grubeck-Loebenstein, Beatrix; Herker, Eva; Fahrenkrog, Birthe; Fröhlich, Kai-Uwe; Sinner, Frank; Tavernarakis, Nektarios; Minois, Nadege; Kroemer, Guido; Madeo, Frank (2009). "Induction of autophagy by spermidine promotes longevity". Nature Cell Biology. 11 (11): 1305–14. doi:10.1038/ncb1975. PMID 19801973. 
  6. ^ Pride, Harrison; Yu, Zhen; Sunchu, Bharath; Mochnick, Jillian; Coles, Alexander; Zhang, Yiqiang; Buffenstein, Rochelle; Hornsby, Peter J.; Austad, Steven N.; Pérez, Viviana I. (2015). "Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species". Biochemical and Biophysical Research Communications. 457 (4): 669–75. doi:10.1016/j.bbrc.2015.01.046. PMID 25615820. 
  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): 1193–8. doi:10.1126/science.aab3389. PMID 26785477. 
  8. ^ Byun, H. O.; Lee, Y. K.; Kim, J. M.; Yoon, G (2015). "From cell senescence to age-related diseases: Differential mechanisms of action of senescence-associated secretory phenotypes". BMB reports. 48 (10): 549–58. doi:10.5483/bmbrep.2015.48.10.122. PMC 4911181Freely accessible. PMID 26129674. 
  9. ^ Young, Andrew R J; Narita, Masashi (2009). "SASP reflects senescence". EMBO Reports. 10 (3): 228–30. doi:10.1038/embor.2009.22. PMC 2658552Freely accessible. PMID 19218920. 
  10. ^ Laberge, Remi-Martin; Zhou, Lili; Sarantos, Melissa R.; Rodier, Francis; Freund, Adam; De Keizer, Peter L. J.; Liu, Su; Demaria, Marco; Cong, Yu-Sheng; Kapahi, Pankaj; Desprez, Pierre-Yves; Hughes, Robert E.; Campisi, Judith (2012). "Glucocorticoids suppress selected components of the senescence-associated secretory phenotype". Aging Cell. 11 (4): 569–78. doi:10.1111/j.1474-9726.2012.00818.x. PMC 3387333Freely accessible. PMID 22404905. 
  11. ^ Liu, Su; Uppal, Harpreet; Demaria, Marco; Desprez, Pierre-Yves; Campisi, Judith; Kapahi, Pankaj (2015). "Simvastatin suppresses breast cancer cell proliferation induced by senescent cells". Scientific Reports. 5: 17895. doi:10.1038/srep17895. PMC 4677323Freely accessible. PMID 26658759. 
  12. ^ Xu, Ming; Tchkonia, Tamara; Ding, Husheng; Ogrodnik, Mikolaj; Lubbers, Ellen R.; Pirtskhalava, Tamar; White, Thomas A.; Johnson, Kurt O.; Stout, Michael B.; Mezera, Vojtech; Giorgadze, Nino; Jensen, Michael D.; Lebrasseur, Nathan K.; Kirkland, James L. (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. doi:10.1073/pnas.1515386112. PMC 4655580Freely accessible. PMID 26578790. 
  13. ^ Xu, Ming; Palmer, Allyson K; Ding, Husheng; Weivoda, Megan M; Pirtskhalava, Tamar; White, Thomas A; Sepe, Anna; Johnson, Kurt O; Stout, Michael B; Giorgadze, Nino; Jensen, Michael D; Lebrasseur, Nathan K; Tchkonia, Tamar; Kirkland, James L (2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". ELife. 4. doi:10.7554/eLife.12997. PMC 4758946Freely accessible. PMID 26687007. 
  14. ^ Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SW, Czapiewski R, Greaves L, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF (2016). "Mitochondria are required for pro-ageing features of the senescent phenotype". The EMBO Journal. 35: 724–42. doi:10.15252/embj.201592862. PMID 26848154. Retrieved 2016-02-06. 60% of the SASP genes which are significantly different between proliferating and senescent were reversed upon mitochondrial depletion, whereas only 5% were exacerbated 
  15. ^ Zhu, Yi; Tchkonia, T; Fuhrmann-Stroissnigg, H; Dai, HM; Ling, YY; Stout, MB; Pirtskhalava, T; Giorgadze, N; Johnson, KO; Giles, CB; Wren, JD; Niedernhofer, LJ; Robbins, PD; Kirkland, JL (2015). "Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors". Aging Cell. doi:10.1111/acel.12445. PMID 26711051. 
  16. ^ Chang, Jianhui; Wang, Yingying; Shao, Lijian; Laberge, Remi-Martin; Demaria, Marco; Campisi, Judith; Janakiraman, Krishnamurthy; Sharpless, Norman E; Ding, Sheng; Feng, Wei; Luo, Yi; Wang, Xiaoyan; Aykin-Burns, Nukhet; Krager, Kimberly; Ponnappan, Usha; Hauer-Jensen, Martin; Meng, Aimin; Zhou, Daohong (2015). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22 (1): 78–83. doi:10.1038/nm.4010. PMC 4762215Freely accessible. PMID 26657143. 
  17. ^ Zhu, Yi; Tchkonia, Tamara; Pirtskhalava, Tamar; Gower, Adam; Ding, Husheng; Giorgadze, Nino; Palmer, Allyson K.; Ikeno, Yuji; Borden, Gene; Lenburg, Marc; O'Hara, Steven P.; LaRusso, Nicholas F.; Miller, Jordan D.; Roos, Carolyn M.; Verzosa, Grace C.; LeBrasseur, Nathan K.; Wren, Jonathan D.; Farr, Joshua N.; Khosla, Sundeep; Stout, Michael B.; McGowan, Sara J.; Fuhrmann-Stroissnigg, Heike; Gurkar, Aditi U.; Zhao, Jing; Colangelo, Debora; Dorronsoro, Akaitz; Ling, Yuan Yuan; Barghouthy, Amira S.; Navarro, Diana C.; Sano, Tokio; Robbins, Paul D.; Niedernhofer, Laura J.; Kirkland, James L. (2015). "The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs". Aging Cell. 14 (4): 644–58. doi:10.1111/acel.12344. PMC 4531078Freely accessible. PMID 25754370. Retrieved 1 March 2015. 
  18. ^ Fuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing; McGowan, Sara J.; Zhu, Yi; Brooks, Robert W.; Grassi, Diego; Gregg, Siobhan Q.; Stripay, Jennifer L. (2017-09-04). "Identification of HSP90 inhibitors as a novel class of senolytics". Nature Communications. 8 (1). doi:10.1038/s41467-017-00314-z. ISSN 2041-1723. 
  19. ^ Burton, D. G. A.; Faragher, R. G. A. (2015). "Cellular senescence: From growth arrest to immunogenic conversion". AGE. 37 (2). doi:10.1007/s11357-015-9764-2. 
  20. ^ Sagiv, A., Burton, D.G.A,. Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B. and Krizhanovsky, V. (2016). NKG2D ligands mediate immunosurveillance of senescent cells Aging
  21. ^ Bernardes De Jesus, Bruno; Vera, Elsa; Schneeberger, Kerstin; Tejera, Agueda M.; Ayuso, Eduard; Bosch, Fatima; Blasco, Maria 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. PMC 3494070Freely accessible. PMID 22585399. 
  22. ^ Xiong, Shiqin; Patrushev, Nikolay; Forouzandeh, Farshad; Hilenski, Lula; Alexander, R. Wayne (2015). "PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases". Cell Reports. 12 (9): 1391–9. doi:10.1016/j.celrep.2015.07.047. PMID 26299964. 
  23. ^ Hofmann, Jeffrey W.; Zhao, Xiaoai; De Cecco, Marco; Peterson, Abigail L.; Pagliaroli, Luca; Manivannan, Jayameenakshi; Hubbard, Gene B.; Ikeno, Yuji; Zhang, Yongqing; Feng, Bin; Li, Xiaxi; Serre, Thomas; Qi, Wenbo; Van Remmen, Holly; Miller, Richard A.; Bath, Kevin G.; De Cabo, Rafael; Xu, Haiyan; Neretti, Nicola; Sedivy, John M. (2015). "Reduced Expression of MYC Increases Longevity and Enhances Healthspan". Cell. 160 (3): 477–88. doi:10.1016/j.cell.2014.12.016. PMC 4624921Freely accessible. PMID 25619689. 
  24. ^ Wu, J. Julie; Liu, Jie; Chen, Edmund B.; Wang, Jennifer J.; Cao, Liu; Narayan, Nisha; Fergusson, Marie M.; Rovira, Ilsa I.; Allen, Michele; Springer, Danielle A.; Lago, Cory U.; Zhang, Shuling; Dubois, Wendy; Ward, Theresa; Decabo, Rafael; Gavrilova, Oksana; Mock, Beverly; Finkel, Toren (2013). "Increased Mammalian Lifespan and a Segmental and Tissue-Specific Slowing of Aging after Genetic Reduction of mTOR Expression". Cell Reports. 4 (5): 913–20. doi:10.1016/j.celrep.2013.07.030. PMC 3784301Freely accessible. PMID 23994476. 
  25. ^ Dubal, D. B.; Zhu, L.; Sanchez, P. E.; Worden, K.; Broestl, L.; Johnson, E.; Ho, K.; Yu, G.-Q.; Kim, D.; Betourne, A.; Kuro-o, M.; Masliah, E.; Abraham, C. R.; Mucke, L. (2015). "Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice". Journal of Neuroscience. 35 (6): 2358–71. doi:10.1523/JNEUROSCI.5791-12.2015. PMC 4323521Freely accessible. PMID 25673831. 

Further reading

  • Kirkland JL, Tchkonia T (2016). "The Way Forward: Translation". Advances in Geroscience. Springer International Publishing: 593–622. doi:10.1007/978-3-319-23246-1_19. ISBN 978-3-319-23245-4. Retrieved 2016-03-13. 
  • Soto-Gamez A, Demaria M (2017). "Therapeutic interventions for aging: the case of cellular senescence". Drug Discovery Today. doi:10.1016/j.drudis.2017.01.004. 
  • Niedernhofer LJ, Robbins PD (2018). "Senotherapeutics for healthy ageing". Nature Reviews Drug Discovery. Macmillan Publishers Limited, part of Springer Nature. doi:10.1038/nrd.2018.44. 
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