Biology:Senolytic

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Short description: Type of molecule that may be able to induce death of senescent cells


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][clarification needed] 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 inhibitors Inhibitors 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 inhibitors Src tyrosine kinase inhibitors: dasatinib[20] – see "Combination of dasatinib and quercetin" below
USP7 inhibitors Inhibitors 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] Yes Yes Yes[22][23]
Fisetin[12][18][11][5] Yes[24] Yes[24]
Navitoclax[12][5] xenograft Yes[25]
SSK1 Senescence-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 knockout Crispr/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 inhibitors Target 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 vaccine Glycoprotein 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] xenograft Yes[31]
25-hydroxycholesterol (25HC)[33] 25-hydroxycholesterol targets CRYAB in multiple human and mouse cell types Yes[33] Yes[33]
Procyanidin C1 Yes[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. ↑ "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine 21 (12): 1424–1435. December 2015. doi:10.1038/nm.4000. PMID 26646499. 
  2. ↑ "Clinical strategies and animal models for developing senolytic agents". Experimental Gerontology 68: 19–25. August 2015. doi:10.1016/j.exger.2014.10.012. PMID 25446976. 
  3. ↑ "Senolytic therapies for healthy longevity". Science 364 (6441): 636–637. May 2019. doi:10.1126/science.aaw1299. PMID 31097655. Bibcode: 2019Sci...364..636V. 
  4. ↑ Hu, Qinchao; Peng, Jianmin; Jiang, Laibo; Li, Wuguo; Su, Qiao; Zhang, Jiayu; Li, Huan; Song, Ming et al. (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. PMID 33116117. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Senolytic drugs: from discovery to translation". Journal of Internal Medicine 288 (5): 518–536. November 2020. doi:10.1111/joim.13141. PMID 32686219. 
  6. ↑ "Rejuvenating senolytics". Nature Reviews. Molecular Cell Biology 19 (9): 543. September 2018. doi:10.1038/s41580-018-0047-5. PMID 30054558. 
  7. ↑ "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy 14 (12): 1092–1097. December 2013. doi:10.4161/cbt.27350. PMID 24345884. 
  8. ↑ "Could cancer drugs provide ammunition against aging?". Cell Cycle 15 (2): 153–155. 6 January 2016. doi:10.1080/15384101.2015.1118905. PMID 26587873. 
  9. ↑ "T cells engineered to target senescence". Nature 583 (7814): 37–38. July 2020. doi:10.1038/d41586-020-01759-x. PMID 32601490. Bibcode: 2020Natur.583...37W. 
  10. ↑ "Senolytic CAR T cells reverse senescence-associated pathologies". Nature 583 (7814): 127–132. July 2020. doi:10.1038/s41586-020-2403-9. PMID 32555459. Bibcode: 2020Natur.583..127A. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span". Annual Review of Pharmacology and Toxicology 61 (1): 779–803. January 2021. doi:10.1146/annurev-pharmtox-050120-105018. PMID 32997601. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 "Cellular senescence in ageing: from mechanisms to therapeutic opportunities". Nature Reviews. Molecular Cell Biology 22 (2): 75–95. February 2021. doi:10.1038/s41580-020-00314-w. PMID 33328614. 
  13. ↑ 13.0 13.1 "Cellular senescence: at the nexus between ageing and diabetes". Diabetologia 62 (10): 1835–1841. October 2019. doi:10.1007/s00125-019-4934-x. PMID 31451866. 
  14. ↑ "Discovering small-molecule senolytics with deep neural networks". Nature Aging 3 (6): 734–750. May 2023. doi:10.1038/s43587-023-00415-z. PMID 37142829. 
  15. ↑ "Discovery of senolytics using machine learning". Nature Communications 14 (1): 3445. June 2023. doi:10.1038/s41467-023-39120-1. PMID 37301862. Bibcode: 2023NatCo..14.3445S. 
  16. ↑ 16.0 16.1 "Senolytic targets and new strategies for clearing senescent cells". Mechanisms of Ageing and Development 195: 111468. April 2021. doi:10.1016/j.mad.2021.111468. PMID 33741395. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging". Cell 169 (1): 132–147.e16. March 2017. doi:10.1016/j.cell.2017.02.031. PMID 28340339. 
  18. ↑ 18.0 18.1 18.2 18.3 "Emerging senolytic agents derived from natural products". Mechanisms of Ageing and Development 181: 1–6. July 2019. doi:10.1016/j.mad.2019.05.001. PMID 31077707. 
  19. ↑ 19.0 19.1 "Hallmarks of Cellular Senescence". Trends in Cell Biology 28 (6): 436–453. June 2018. doi:10.1016/j.tcb.2018.02.001. PMID 29477613. https://pure.rug.nl/ws/files/61206288/1_s2.0_S0962892418300205_main.pdf. 
  20. ↑ "Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential". Frontiers in Pharmacology 10: 1011. 2019. doi:10.3389/fphar.2019.01011. PMID 31619990. 
  21. ↑ 21.0 21.1 "Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity". Aging Cell 19 (3): e13117. March 2020. doi:10.1111/acel.13117. PMID 32064756. 
  22. ↑ "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. September 2019. doi:10.1016/j.ebiom.2019.08.069. PMID 31542391. 
  23. ↑ "Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study". eBioMedicine 40: 554–563. February 2019. doi:10.1016/j.ebiom.2018.12.052. PMID 30616998. 
  24. ↑ 24.0 24.1 "Fisetin is a senotherapeutic that extends health and lifespan". eBioMedicine 36: 18–28. October 2018. doi:10.1016/j.ebiom.2018.09.015. PMID 30279143. 
  25. ↑ "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. June 2008. doi:10.1158/1078-0432.CCR-07-4622. PMID 18519752. 
  26. ↑ 26.0 26.1 "Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice". Cell Research 30 (7): 574–589. July 2020. doi:10.1038/s41422-020-0314-9. PMID 32341413. 
  27. ↑ 27.0 27.1 "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. 2019-11-27. doi:10.2147/BLCTT.S230383. PMID 31819702. 
  28. ↑ 28.0 28.1 "Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders". Science 371 (6526): 265–270. January 2021. doi:10.1126/science.abb5916. PMID 33446552. Bibcode: 2021Sci...371..265J. 
  29. ↑ 29.0 29.1 "Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice". Nature Aging 1 (12): 1117–1126. December 2021. doi:10.1038/s43587-021-00151-2. PMID 37117524. 
  30. ↑ "Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy". Aging Cell 20 (9): e13447. September 2021. doi:10.1111/acel.13447. PMID 34355491. 
  31. ↑ 31.0 31.1 "Identification and characterization of Cardiac Glycosides as senolytic compounds". Nature Communications 10 (1): 4731. October 2019. doi:10.1038/s41467-019-12888-x. PMID 31636264. Bibcode: 2019NatCo..10.4731T. 
  32. ↑ "Cardiac glycosides are broad-spectrum senolytics". Nature Metabolism 1 (11): 1074–1088. November 2019. doi:10.1038/s42255-019-0122-z. PMID 31799499. 
  33. ↑ 33.0 33.1 33.2 "Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types". iScience 25 (2): 103848. February 2022. doi:10.1016/j.isci.2022.103848. PMID 35198901. Bibcode: 2022iSci...25j3848L. 
  34. ↑ 34.0 34.1 "The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice". Nature Metabolism 3 (12): 1706–1726. December 2021. doi:10.1038/s42255-021-00491-8. PMID 34873338. 
  35. ↑ "Hsp90 inhibitors as senolytic drugs to extend healthy aging". Cell Cycle (Informa UK Limited) 17 (9): 1048–1055. 2018-05-03. doi:10.1080/15384101.2018.1475828. PMID 29886783. 
  36. ↑ "Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic". Aging (Impact Journals) 15 (9): 2373–2394. 2023-03-28. doi:10.18632/aging.204616. PMID 36988504. 

Further reading



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