Senotherapeutics

Senotherapeutics refers to therapeutic agents and strategies that specifically target cellular senescence,[1] an altered cell state associated with ageing and age-related diseases.

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. Agents/strategies which can enhance immune clearance of senescent cells (an ageing immune system likely impairs senescent cell clearance leading to their accumulation[18][19]), immune system cells (NK cells, B cells, T cells).
  5. 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[20][21][22][23][24][25][26][27][28][29][30]

References

  1. ↑ 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: n/a. doi:10.1002/stem.2255.
  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.
  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.
  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: n/a. 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. PMID 25754370. Retrieved March 2015. Check date values in: |access-date= (help)
  18. ↑ 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.
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ Mendelsohn, Andrew R.; 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): 479–83. doi:10.1089/rej.2015.1780. PMID 26414604.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ Ortega-Molina, Ana; Efeyan, Alejo; Lopez-Guadamillas, Elena; Muñoz-Martin, Maribel; Gómez-López, Gonzalo; Cañamero, Marta; Mulero, Francisca; Pastor, Joaquin; Martinez, Sonia; Romanos, Eduardo; Mar Gonzalez-Barroso, M.; Rial, Eduardo; Valverde, Angela M.; Bischoff, James R.; Serrano, Manuel (2012). "Pten Positively Regulates Brown Adipose Function, Energy Expenditure, and Longevity". Cell Metabolism. 15 (3): 382–94. doi:10.1016/j.cmet.2012.02.001. PMID 22405073. Ptentg mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence.
  28. ↑ Matheu, Ander; Maraver, Antonio; Collado, Manuel; Garcia-Cao, Isabel; Cañamero, Marta; Borras, Consuelo; Flores, Juana M.; Klatt, Peter; Viña, Jose; Serrano, Manuel (2009). "Anti-aging activity of theInk4/Arflocus". Aging Cell. 8 (2): 152–61. doi:10.1111/j.1474-9726.2009.00458.x. PMID 19239418. the Ink4/Arf locus has an anti-aging effect, by favouring quiescence and preventing unnecessary proliferation.
  29. ↑ Kurosu, H.; Yamamoto, M; Clark, J. D.; Pastor, J. V.; Nandi, A; Gurnani, P; McGuinness, O. P.; Chikuda, H; Yamaguchi, M; Kawaguchi, H; Shimomura, I; Takayama, Y; Herz, J; Kahn, C. R.; Rosenblatt, K. P.; Kuro-o, M (2005). "Suppression of Aging in Mice by the Hormone Klotho". Science. 309 (5742): 1829–33. doi:10.1126/science.1112766. PMC 2536606Freely accessible. PMID 16123266.
  30. ↑ 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. Klotho when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition.

Further reading

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