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

• FOXO4-related peptides. FOXO4 can bind with p53 protein to induce cellular senescence.[7] A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.[7]

• Inhibitors of different members of the bcl-2 family of anti-apototic proteins.[8] Studies of cell cultures of senescent human umbilical vein endothelial cells have shown that both fisetin and quercetin induce apoptosis by inhibition of the anti-apoptotic protein Bcl-xL (a bcl-2 family member).[9]

• Src tyrosine kinase inhibitors.[10]

• Inhibitors of USP7 (Ubiquitin-specific processing protease 7)[11]

• Combination of dasatinib and quercetin[8][12][13]

• Fisetin[14]

• Navitoclax[15]
• Piperlongumine[16]

• Azithromycin and Roxithromycin[17]

• SSK1 (senescence-specific killing compound 1): A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker)[18]

See also

• Autophagy
• Geroprotector
• Venetoclax
• Senotherapy

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. Kirkland JL, Tchkonia T (2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine. doi:10.1111/joim.13141. PMC 7405395. PMID 32686219.
10. Rivera-Torres J, José ES (2019). "Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential". FRONTIERS IN PHARMACOLOGY. 10: 1011. doi:10.3389/fphar.2019.01011. PMC 6759511. PMID 31619990.
11. 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.
12. 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.
13. Palmer AK, Gustafson B, Kirkland JL, Smith U (2019). "Cellular senescence: at the nexus between ageing and diabetes". Diabetologia. 62 (10): 1835–1841. doi:10.1007/s00125-019-4934-x. PMC 6731336. PMID 31451866.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.

External links

• Killing ‘zombie’ cells to improve health in old age. The Conversation, Dominick Burton, Aston University, 17 March 2017

• Can Destroying Senescent Cells Treat Age-Related Disease? The Scientist, Katarina Zimmer, 1 March, 2020