Senolytic

A senolytic (from the words senescence and -lytic, "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans.[1] A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases.[2][3] A related concept is "senostatic", which means to suppress senescence.

Research

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials.[4] The majority of candidate senolytic compounds are repurposed anti-cancer molecules, such as the chemotherapeutic drug dasatinib and the experimental small molecule navitoclax.[5][6]

Senolytic candidates

Clinical trials

Although there have been few clinical trials conducted on senolytic candidates to date, one human trial showed that the senolytic candidates dasatinib and quercetin, when administered in combination, may affect the number of senescent cells in certain tissues in humans with diabetic kidney disease.[10]

See also

References
  1. Childs, Bennett G; Durik, Matej; Baker, Darren J; van Deursen, Jan M (8 December 2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–1435. doi:10.1038/nm.4000. PMC 4748967. PMID 26646499.
  2. Kirkland, James L.; Tchkonia, Tamara (August 2015). "Clinical strategies and animal models for developing senolytic agents". Experimental Gerontology. 68: 19–25. doi:10.1016/j.exger.2014.10.012. PMC 4412760. PMID 25446976.
  3. van Deursen, Jan M. (16 May 2019). "Senolytic therapies for healthy longevity". Science. 364 (6441): 636–637. Bibcode:2019Sci...364..636V. doi:10.1126/science.aaw1299. PMC 6816502. PMID 31097655.
  4. Baumann, Kim (27 July 2018). "Rejuvenating senolytics". Nature Reviews Molecular Cell Biology. 19 (9): 543. doi:10.1038/s41580-018-0047-5. PMID 30054558.
  5. Blagosklonny, Mikhail V (28 October 2014). "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy. 14 (12): 1092–1097. doi:10.4161/cbt.27350. PMC 3912031. PMID 24345884.
  6. Slack, Cathy; Alic, Nazif; Partridge, Linda (6 January 2016). "Could cancer drugs provide ammunition against aging?". Cell Cycle. 15 (2): 153–155. doi:10.1080/15384101.2015.1118905. PMC 4825846. PMID 26587873.
  7. Baar, Marjolein P.; Brandt, Renata M.C.; Putavet, Diana A.; Klein, Julian D.D.; Derks, Kasper W.J.; Bourgeois, Benjamin R.M.; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A.; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A.; van IJcken, Wilfred F.; Houtsmuller, Adriaan B.; Pothof, Joris; de Bruin, Ron W.F.; Madl, Tobias; Hoeijmakers, Jan H.J.; Campisi, Judith; de Keizer, Peter L.J. (March 2017). "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". Cell. 169 (1): 132–147.e16. doi:10.1016/j.cell.2017.02.031. PMC 5556182. PMID 28340339.
  8. Hernandez-Segura, Alejandra; Nehme, Jamil; Demaria, Marco (June 2018). "Hallmarks of Cellular Senescence" (PDF). Trends in Cell Biology. 28 (6): 436–453. doi:10.1016/j.tcb.2018.02.001. PMID 29477613.
  9. He, Yonghan; Li, Wen; Lv, Dongwen; Zhang, Xin; Zhang, Xuan; Ortiz, Yuma T.; Budamagunta, Vivekananda; Campisi, Judith; Zheng, Guangrong; Zhou, Daohong (16 February 2020). "Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity". Aging Cell. 19 (3): e13117. doi:10.1111/acel.13117. PMC 7059172. PMID 32064756.
  10. Hickson, LaTonya J.; Langhi Prata, Larissa G.P.; Bobart, Shane A.; Evans, Tamara K.; Giorgadze, Nino; Hashmi, Shahrukh K.; Herrmann, Sandra M.; Jensen, Michael D.; Jia, Qingyi; Jordan, Kyra L.; Kellogg, Todd A.; Khosla, Sundeep; Koerber, Daniel M.; Lagnado, Anthony B.; Lawson, Donna K.; LeBrasseur, Nathan K.; Lerman, Lilach O.; McDonald, Kathleen M.; McKenzie, Travis J.; Passos, João F.; Pignolo, Robert J.; Pirtskhalava, Tamar; Saadiq, Ishran M.; Schaefer, Kalli K.; Textor, Stephen C.; Victorelli, Stella G.; Volkman, Tammie L.; Xue, Ailing; Wentworth, Mark A.; Wissler Gerdes, Erin O.; Zhu, Yi; Tchkonia, Tamara; Kirkland, James L. (September 2019). "Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease". EBioMedicine. 47: 446–456. doi:10.1016/j.ebiom.2019.08.069. PMC 6796530. PMID 31542391.
  11. Yousefzadeh, Matthew J.; Zhu, Yi; McGowan, Sara J.; Angelini, Luise; Fuhrmann-Stroissnigg, Heike; Xu, Ming; Ling, Yuan Yuan; Melos, Kendra I.; Pirtskhalava, Tamar; Inman, Christina L.; McGuckian, Collin; Wade, Erin A.; Kato, Jonathon I.; Grassi, Diego; Wentworth, Mark; Burd, Christin E.; Arriaga, Edgar A.; Ladiges, Warren L.; Tchkonia, Tamara; Kirkland, James L.; Robbins, Paul D.; Niedernhofer, Laura J. (October 2018). "Fisetin is a senotherapeutic that extends health and lifespan". EBioMedicine. 36: 18–28. doi:10.1016/j.ebiom.2018.09.015. PMC 6197652. PMID 30279143.
  12. Shoemaker, Alex R.; Mitten, Michael J.; Adickes, Jessica; Ackler, Scott; Refici, Marion; Ferguson, Debra; Oleksijew, Anatol; O'Connor, Jacqueline M.; Wang, Baole; Frost, David J.; Bauch, Joy; Marsh, Kennan; Tahir, Steven K.; Yang, Xiufen; Tse, Christin; Fesik, Stephen W.; Rosenberg, Saul H.; Elmore, Steven W. (1 June 2008). "Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models". Clinical Cancer Research. 14 (11): 3268–3277. doi:10.1158/1078-0432.CCR-07-4622. PMID 18519752.
  13. Wang, Yingying; Chang, Jianhui; Liu, Xingui; Zhang, Xuan; Zhang, Suping; Zhang, Xin; Zhou, Daohong; Zheng, Guangrong (19 November 2016). "Discovery of piperlongumine as a potential novel lead for the development of senolytic agents". Aging. 8 (11): 2915–2926. doi:10.18632/aging.101100. PMC 5191878. PMID 27913811.
  14. Ozsvari, Bela; Nuttall, John R.; Sotgia, Federica; Lisanti, Michael P. (14 November 2018). "Azithromycin and Roxithromycin define a new family of "senolytic" drugs that target senescent human fibroblasts". Aging. 10 (11): 3294–3307. doi:10.18632/aging.101633. PMC 6286845. PMID 30428454.
  15. Cai, Yusheng; Zhou, Huanhuan; Zhu, Yinhua; Sun, Qi; Ji, Yin; Xue, Anqi; Wang, Yuting; Chen, Wenhan; Yu, Xiaojie; Wang, Longteng; Chen, Han; Li, Cheng; Luo, Tuoping; Deng, Hongkui (27 April 2020). "Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice". Cell Research: 1–16. doi:10.1038/s41422-020-0314-9. PMC 7184167. PMID 32341413.
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