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.[4]

Research

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials.[5][6] The majority of candidate senolytic compounds are repurposed anti-cancer molecules, such as the chemotherapeutic drug dasatinib and the experimental small molecule navitoclax.[7][8]

Soluble urokinase plasminogen activator surface receptor have been found to be highly expressed on senescent cells, leading researchers to use chimeric antigen receptor T cells to eliminate senescent cells in mice.[9][10]

According to reviews, it is thought that senolytics can be administered intermittently while being as effective as continuous administration. This could be an advantage of senolytic drugs and decrease adverse effects, for instance circumventing potential off-target effects.[5][11][12][13]

Recently, artificial intelligence has been used to discover new senolytics, resulting in the identification of structurally distinct senolytic compounds with more favorable medicinal chemistry properties than previous senolytic candidates.[14][15]

Senolytic candidates

Hypothetical candidates for senolytics based on early-stage research
Medication/target Description Tests as senolytic have been conducted in ...
human cell lines in vitro mice models xenograft model phase I trial phase II trial phase III trial
FOXO4-related peptides[12][16][11][5]FOXO4 binding to p53 protein retains it in the nucleus, which prevents it from interacting with mitochondria in the cytosol where it would activate caspases, leading to apoptosis (programmed cell death).[17] Instead, retention of p53 in the nucleus by FOXO4 promotes cellular senescence.[17] A peptide that binds with FOXO4 disrupts the p53-FOXO4 interaction, releasing p53 into the cytosol and triggering cell death.[17]Yes[17]Yes[17]
BCL-2 inhibitorsInhibitors of different members of the bcl-2 family of anti-apoptotic proteins.[12][18][19] 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).[5]Yes[5]
Src inhibitorsSrc tyrosine kinase inhibitors: dasatinib[20] – see "Combination of dasatinib and quercetin" below
USP7 inhibitorsInhibitors of USP7 (ubiquitin-specific processing protease 7)[16]Yes[21]Yes[21]
Dasatinib and Quercetin (D+Q)Combination of dasatinib and quercetin[19][18][13][12]YesYesYes[22][23]
Fisetin[12][18][11][5]Yes[24]Yes[24]
Navitoclax[12][5]xenograftYes[25]
SSK1Senescence-specific killing compound 1: A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker)[26]Yes[26]
BIRC5 knockoutCrispr/Cas9 BIRC5 Gene Knockout. Crispr/Cas9 is used to trigger apoptosis in relation to a specified gene sequence such as a cancer gene sequence or damage marker sequences.[27]Yes[27]
GLS1 inhibitorsTarget the enzyme kidney-type glutaminase 1 (GLS1). Senescent cells have a low pH due to their high lysosomal content and leaking lysosomal membranes. This low pH forms the basis of senescence-associated beta-galactosidase (SA-β-gal) staining of senescent cells. To help neutralize their low pH, senescent cells produce high levels of GLS1; inhibiting the activity of this enzyme exposes senescent cells to unsurvivably severe internal acidity, leading to cell death.[28]Yes[28]
Anti-GPNMB vaccineGlycoprotein nonmetastatic melanoma protein B (GPNMB). A protein that enrich senescent cells studied as molecular target for a senolytic vaccine in mice.[29]Yes[29]
Cardiac glycosides [12][11]Yes[30][31][32]xenograftYes[31]
25-hydroxycholesterol (25HC)[33]25-hydroxycholesterol targets CRYAB in multiple human and mouse cell typesYes[33]Yes[33]
Procyanidin C1Yes[34]Yes[34]
EF-24[18][11]Yes
HSP90 inhibitors[35]
CUDC-907[36]

Senomorphics

Senolytics eliminate senescent cells whereas senomorphics – with candidates such as Apigenin, Rapamycin and rapalog Everolimus – modulate properties of senescent cells without eliminating them, suppressing phenotypes of senescence, including the SASP.[12][11]

See also

References

  1. ↑ Childs BG, Durik M, Baker DJ, van Deursen JM (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 JL, Tchkonia T (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 JM (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. ↑ Hu, Qinchao; Peng, Jianmin; Jiang, Laibo; Li, Wuguo; Su, Qiao; Zhang, Jiayu; Li, Huan; Song, Ming; Cheng, Bin; Xia, Juan; Wu, Tong (28 October 2020). "Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma". Cell Death & Disease. 11 (10): 925. doi:10.1038/s41419-020-03126-0. PMC 7595194. PMID 33116117.
  5. 1 2 3 4 5 6 7 Kirkland JL, Tchkonia T (November 2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine. 288 (5): 518–536. doi:10.1111/joim.13141. PMC 7405395. PMID 32686219.
  6. ↑ Baumann K (September 2018). "Rejuvenating senolytics". Nature Reviews. Molecular Cell Biology. 19 (9): 543. doi:10.1038/s41580-018-0047-5. PMID 30054558. S2CID 51726136.
  7. ↑ Blagosklonny MV (December 2013). "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy. 14 (12): 1092–1097. doi:10.4161/cbt.27350. PMC 3912031. PMID 24345884.
  8. ↑ Slack C, Alic N, Partridge L (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.
  9. ↑ Wagner V, Gil J (July 2020). "T cells engineered to target senescence". Nature. 583 (7814): 37–38. Bibcode:2020Natur.583...37W. doi:10.1038/d41586-020-01759-x. hdl:10044/1/80980. PMID 32601490.
  10. ↑ Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, et al. (July 2020). "Senolytic CAR T cells reverse senescence-associated pathologies". Nature. 583 (7814): 127–132. Bibcode:2020Natur.583..127A. doi:10.1038/s41586-020-2403-9. PMC 7583560. PMID 32555459.
  11. 1 2 3 4 5 6 Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, et al. (January 2021). "Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span". Annual Review of Pharmacology and Toxicology. 61 (1): 779–803. doi:10.1146/annurev-pharmtox-050120-105018. PMC 7790861. PMID 32997601.
  12. 1 2 3 4 5 6 7 8 Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F (February 2021). "Cellular senescence in ageing: from mechanisms to therapeutic opportunities". Nature Reviews. Molecular Cell Biology. 22 (2): 75–95. doi:10.1038/s41580-020-00314-w. PMC 8344376. PMID 33328614.
  13. 1 2 Palmer AK, Gustafson B, Kirkland JL, Smith U (October 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. ↑ Wong F, Omori S, Donghia NM, Zheng EJ, Collins JJ (May 2023). "Discovering small-molecule senolytics with deep neural networks". Nature Aging. 3 (6): 734–750. doi:10.1038/s43587-023-00415-z. PMID 37142829. S2CID 258506382.
  15. ↑ Smer-Barreto V, Quintanilla A, Elliott RJ, Dawson JC, Sun J, Campa VM, et al. (June 2023). "Discovery of senolytics using machine learning". Nature Communications. 14 (1): 3445. Bibcode:2023NatCo..14.3445S. doi:10.1038/s41467-023-39120-1. PMC 10257182. PMID 37301862.
  16. 1 2 Ge M, Hu L, Ao H, Zi M, Kong Q, He Y (April 2021). "Senolytic targets and new strategies for clearing senescent cells". Mechanisms of Ageing and Development. 195: 111468. doi:10.1016/j.mad.2021.111468. PMID 33741395. S2CID 232246367.
  17. 1 2 3 4 5 Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, et al. (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.
  18. 1 2 3 4 Li W, Qin L, Feng R, Hu G, Sun H, He Y, Zhang R (July 2019). "Emerging senolytic agents derived from natural products". Mechanisms of Ageing and Development. 181: 1–6. doi:10.1016/j.mad.2019.05.001. PMID 31077707. S2CID 147704626.
  19. 1 2 Hernandez-Segura A, Nehme J, Demaria M (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. S2CID 3534989.
  20. ↑ Rivera-Torres J, San José E (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.
  21. 1 2 He Y, Li W, Lv D, Zhang X, Zhang X, Ortiz YT, et al. (March 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.
  22. ↑ Hickson LJ, Langhi Prata LG, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, et al. (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.
  23. ↑ Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, et al. (February 2019). "Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study". eBioMedicine. 40: 554–563. doi:10.1016/j.ebiom.2018.12.052. PMC 6412088. PMID 30616998.
  24. 1 2 Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, et al. (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.
  25. ↑ Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, et al. (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.
  26. 1 2 Cai Y, Zhou H, Zhu Y, Sun Q, Ji Y, Xue A, et al. (July 2020). "Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice". Cell Research. 30 (7): 574–589. doi:10.1038/s41422-020-0314-9. PMC 7184167. PMID 32341413.
  27. 1 2 Narimani M, Sharifi M, Jalili A (2019-11-27). "Knockout Of BIRC5 Gene By CRISPR/Cas9 Induces Apoptosis And Inhibits Cell Proliferation In Leukemic Cell Lines, HL60 And KG1". Blood and Lymphatic Cancer: Targets and Therapy. 9: 53–61. doi:10.2147/BLCTT.S230383. PMC 6885567. PMID 31819702.
  28. 1 2 Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, et al. (January 2021). "Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders". Science. 371 (6526): 265–270. Bibcode:2021Sci...371..265J. doi:10.1126/science.abb5916. PMID 33446552. S2CID 231606800.
  29. 1 2 Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, et al. (December 2021). "Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice". Nature Aging. 1 (12): 1117–1126. doi:10.1038/s43587-021-00151-2. PMID 37117524. S2CID 245068564.
  30. ↑ L'Hôte V, Courbeyrette R, Pinna G, Cintrat JC, Le Pavec G, Delaunay-Moisan A, et al. (September 2021). "Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy". Aging Cell. 20 (9): e13447. doi:10.1111/acel.13447. PMC 8564827. PMID 34355491.
  31. 1 2 Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, et al. (October 2019). "Identification and characterization of Cardiac Glycosides as senolytic compounds". Nature Communications. 10 (1): 4731. Bibcode:2019NatCo..10.4731T. doi:10.1038/s41467-019-12888-x. PMC 6803708. PMID 31636264.
  32. ↑ Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, et al. (November 2019). "Cardiac glycosides are broad-spectrum senolytics". Nature Metabolism. 1 (11): 1074–1088. doi:10.1038/s42255-019-0122-z. PMC 6887543. PMID 31799499.
  33. 1 2 3 Limbad C, Doi R, McGirr J, Ciotlos S, Perez K, Clayton ZS, et al. (February 2022). "Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types". iScience. 25 (2): 103848. Bibcode:2022iSci...25j3848L. doi:10.1016/j.isci.2022.103848. PMC 8851282. PMID 35198901.
  34. 1 2 Xu Q, Fu Q, Li Z, Liu H, Wang Y, Lin X, et al. (December 2021). "The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice". Nature Metabolism. 3 (12): 1706–1726. doi:10.1038/s42255-021-00491-8. PMC 8688144. PMID 34873338.
  35. ↑ Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD (2018-05-03). "Hsp90 inhibitors as senolytic drugs to extend healthy aging". Cell Cycle. Informa UK Limited. 17 (9): 1048–1055. doi:10.1080/15384101.2018.1475828. PMC 6110594. PMID 29886783.
  36. ↑ Al-Mansour F, Alraddadi A, He B, Saleh A, Poblocka M, Alzahrani W, Cowley S, Macip S (2023-03-28). "Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic". Aging. Impact Journals. 15 (9): 2373–2394. doi:10.18632/aging.204616. PMC 10120895. PMID 36988504. S2CID 257804078.

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