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 4748967. 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: 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. 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. 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. 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. 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. PMID 26129674.
  9. ↑ Young, Andrew R J; Narita, Masashi (2009). "SASP reflects senescence". EMBO reports 10 (3): 228. doi:10.1038/embor.2009.22. 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. doi:10.1111/j.1474-9726.2012.00818.x. 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 4677323. 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. 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 4762215. 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. doi:10.1111/acel.12344. PMID 25754370. Retrieved March 2015.
  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. doi:10.1002/emmm.201200245. 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. 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. 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. doi:10.1016/j.cell.2014.12.016. 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. doi:10.1016/j.celrep.2013.07.030. 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. 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. 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 2536606. 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. doi:10.1523/JNEUROSCI.5791-12.2015. PMID 25673831. Klotho when overexpressed, extends mammalian lifespan, increases synaptic plasticity, and enhances cognition.

Further reading

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