Senolytic Explained

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] Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.[4]

A related concept is "senostatic", which means to suppress senescence.[5]

Research

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials.[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.[11] [12]

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.[13] [14]

Senolytic candidates

Hypothetical candidates for senolytics based on early-stage research
Medication/targetDescriptionTests as senolytic have been conducted in ...
human cell lines in vitromice modelsxenograft modelphase I trialphase II trialphase III trial
FOXO4-related peptides 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).[15] Instead, retention of p53 in the nucleus by FOXO4 promotes cellular senescence. A peptide that binds with FOXO4 disrupts the p53-FOXO4 interaction, releasing p53 into the cytosol and triggering cell death.
BCL-2 inhibitors Inhibitors of different members of the bcl-2 family of anti-apoptotic proteins.[16] [17] 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).[18]
Src inhibitors Src tyrosine kinase inhibitors: dasatinib[19] – see "Combination of dasatinib and quercetin" below
USP7 inhibitors Inhibitors of USP7 (ubiquitin-specific processing protease 7)[20] [21]
Dasatinib and Quercetin (D+Q) Combination of dasatinib and quercetin[22] [23] [24]
[25]
xenograft [26]
SSK1 Senescence-specific killing compound 1: A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker)[27]
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.[28]
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.[29]
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.[30]
Cardiac glycosides [31] [32] [33] xenograft
25-hydroxycholesterol (25HC)[34] 25-hydroxycholesterol targets CRYAB in multiple human and mouse cell types
[35]
HSP90 inhibitors[36]
CUDC-907[37]

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

Further reading

Notes and References

  1. Childs BG, Durik M, Baker DJ, van Deursen JM . Cellular senescence in aging and age-related disease: from mechanisms to therapy . Nature Medicine . 21 . 12 . 1424–1435 . December 2015 . 26646499 . 4748967 . 10.1038/nm.4000 .
  2. Kirkland JL, Tchkonia T . Clinical strategies and animal models for developing senolytic agents . Experimental Gerontology . 68 . 19–25 . August 2015 . 25446976 . 4412760 . 10.1016/j.exger.2014.10.012 .
  3. van Deursen JM . Senolytic therapies for healthy longevity . Science . 364 . 6441 . 636–637 . May 2019 . 31097655 . 6816502 . 10.1126/science.aaw1299 . 2019Sci...364..636V .
  4. Chambers ES, Akbar AN . Can blocking inflammation enhance immunity during aging? . . 145 . 5 . 1323–1331 . 2020 . 10.1016/j.jaci.2020.03.016 . 32386656.
  5. Hu . Qinchao . Peng . Jianmin . Jiang . Laibo . Li . Wuguo . Su . Qiao . Zhang . Jiayu . Li . Huan . Song . Ming . Cheng . Bin . Xia . Juan . Wu . Tong . Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma . Cell Death & Disease . 28 October 2020 . 11 . 10 . 925 . 10.1038/s41419-020-03126-0 . 33116117 . 7595194 .
  6. Baumann K . Rejuvenating senolytics . Nature Reviews. Molecular Cell Biology . 19 . 9 . 543 . September 2018 . 30054558 . 10.1038/s41580-018-0047-5 . 51726136 .
  7. Blagosklonny MV . Selective anti-cancer agents as anti-aging drugs . Cancer Biology & Therapy . 14 . 12 . 1092–1097 . December 2013 . 24345884 . 3912031 . 10.4161/cbt.27350 .
  8. Slack C, Alic N, Partridge L . Could cancer drugs provide ammunition against aging? . Cell Cycle . 15 . 2 . 153–155 . 6 January 2016 . 26587873 . 4825846 . 10.1080/15384101.2015.1118905 .
  9. Wagner V, Gil J . T cells engineered to target senescence . Nature . 583 . 7814 . 37–38 . July 2020 . 32601490 . 10.1038/d41586-020-01759-x . free . 2020Natur.583...37W . 10044/1/80980 . free .
  10. Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Peerschke E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, Lowe SW . 6 . Senolytic CAR T cells reverse senescence-associated pathologies . Nature . 583 . 7814 . 127–132 . July 2020 . 32555459 . 7583560 . 10.1038/s41586-020-2403-9 . 2020Natur.583..127A .
  11. Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, Passos JF, Pignolo RJ, Tchkonia T, Niedernhofer LJ . 6 . Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span . Annual Review of Pharmacology and Toxicology . 61 . 1 . 779–803 . January 2021 . 32997601 . 7790861 . 10.1146/annurev-pharmtox-050120-105018 .
  12. Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F . Cellular senescence in ageing: from mechanisms to therapeutic opportunities . Nature Reviews. Molecular Cell Biology . 22 . 2 . 75–95 . February 2021 . 33328614 . 8344376 . 10.1038/s41580-020-00314-w .
  13. Wong F, Omori S, Donghia NM, Zheng EJ, Collins JJ . Discovering small-molecule senolytics with deep neural networks . Nature Aging . 734–750 . May 2023 . 3 . 6 . 37142829 . 10.1038/s43587-023-00415-z . 258506382 .
  14. Smer-Barreto V, Quintanilla A, Elliott RJ, Dawson JC, Sun J, Campa VM, Lorente-Macías Á, Unciti-Broceta A, Carragher NO, Acosta JC, Oyarzún DA . 6 . Discovery of senolytics using machine learning . Nature Communications . 14 . 1 . 3445 . June 2023 . 37301862 . 10257182 . 10.1038/s41467-023-39120-1 . 2023NatCo..14.3445S .
  15. Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RW, Madl T, Hoeijmakers JH, Campisi J, de Keizer PL . 6 . Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging . Cell . 169 . 1 . 132–147.e16 . March 2017 . 28340339 . 5556182 . 10.1016/j.cell.2017.02.031 .
  16. Li W, Qin L, Feng R, Hu G, Sun H, He Y, Zhang R . Emerging senolytic agents derived from natural products . Mechanisms of Ageing and Development . 181 . 1–6 . July 2019 . 31077707 . 10.1016/j.mad.2019.05.001 . 147704626 .
  17. Hernandez-Segura A, Nehme J, Demaria M . Hallmarks of Cellular Senescence . Trends in Cell Biology . 28 . 6 . 436–453 . June 2018 . 29477613 . 10.1016/j.tcb.2018.02.001 . 3534989 .
  18. Kirkland JL, Tchkonia T . Senolytic drugs: from discovery to translation . Journal of Internal Medicine . 288 . 5 . 518–536 . November 2020 . 32686219 . 7405395 . 10.1111/joim.13141 .
  19. Rivera-Torres J, San José E . Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential . Frontiers in Pharmacology . 10 . 1011 . 2019 . 31619990 . 6759511 . 10.3389/fphar.2019.01011 . free .
  20. Ge M, Hu L, Ao H, Zi M, Kong Q, He Y . Senolytic targets and new strategies for clearing senescent cells . Mechanisms of Ageing and Development . 195 . 111468 . April 2021 . 33741395 . 10.1016/j.mad.2021.111468 . 232246367 .
  21. He Y, Li W, Lv D, Zhang X, Zhang X, Ortiz YT, Budamagunta V, Campisi J, Zheng G, Zhou D . 6 . Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity . Aging Cell . 19 . 3 . e13117 . March 2020 . 32064756 . 7059172 . 10.1111/acel.13117 .
  22. Palmer AK, Gustafson B, Kirkland JL, Smith U . Cellular senescence: at the nexus between ageing and diabetes . Diabetologia . 62 . 10 . 1835–1841 . October 2019 . 31451866 . 6731336 . 10.1007/s00125-019-4934-x .
  23. Hickson LJ, Langhi Prata LG, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL . 6 . 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 . 31542391 . 6796530 . 10.1016/j.ebiom.2019.08.069 .
  24. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL . 6 . Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study . eBioMedicine . 40 . 554–563 . February 2019 . 30616998 . 6412088 . 10.1016/j.ebiom.2018.12.052 .
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  28. Narimani M, Sharifi M, Jalili A . 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 . 31819702 . 6885567 . 10.2147/BLCTT.S230383 . free .
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