Senotherapy

Senotherapy 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 2019, much of the research remains preliminary and there are no drugs approved for this purpose.

Types

Senotherapeutics include:

• 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).

• 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]

• Senolytics – small molecules that specifically induce cell death in senescent cells,[15][16] targeting survival pathways and anti-apoptotic mechanisms, antibodies and antibody-mediated drug delivery medications. Unlike SASP inhibitors, senolytics can be effective by intermittent rather than continuous application.[17]

• Senomorphics – small molecules that suppress senescent phenotypes without cell killing[18]

• Gene therapy strategies – 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[3][19]

See also

• Geroprotector
• Senolytic

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. 34 (3): 756–767. doi:10.1002/stem.2255. PMC 4832316. 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. PMC 4549794. 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. Bibcode:2015Sci...350.1193B. 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 4911181. 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 2658552. 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 3387333. 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. Bibcode:2015NatSR...517895L. 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): E6301–10. Bibcode:2015PNAS..112E6301X. doi:10.1073/pnas.1515386112. PMC 4655580. 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: e12997. doi:10.7554/eLife.12997. PMC 4758946. 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 (7): 724–42. doi:10.15252/embj.201592862. PMC 4818766. PMID 26848154. 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. 15 (3): 428–35. doi:10.1111/acel.12445. PMC 4854923. PMID 26711051.
16. 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 4531078. PMID 25754370.
17. Khosla S, Farr JN, Tchkonia T, Kirkland JL (2020). "The role of cellular senescence in ageing and endocrine disease". Nature Reviews Endocrinology. 16 (5): 263–275. doi:10.1038/s41574-020-0335-y. PMC 7227781. PMID 32161396.
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): 422. Bibcode:2017NatCo...8..422F. doi:10.1038/s41467-017-00314-z. ISSN 2041-1723. PMC 5583353. PMID 28871086.
19. 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 4624921. PMID 25619689.

Further reading

• Kirkland JL, Tchkonia T (2016). "The Way Forward: Translation". Advances in Geroscience. Springer International Publishing. pp. 593–622. doi:10.1007/978-3-319-23246-1_19. ISBN 978-3-319-23245-4.
• Soto-Gamez A, Demaria M (2017). "Therapeutic interventions for aging: the case of cellular senescence". Drug Discovery Today. 22 (5): 786–795. doi:10.1016/j.drudis.2017.01.004. PMID 28111332.
• Niedernhofer LJ, Robbins PD (2018). "Senotherapeutics for healthy ageing". Nature Reviews Drug Discovery. 17 (5): 377. doi:10.1038/nrd.2018.44. PMID 29651106.