Senolytic

{{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.{{cite journal | vauthors = Childs BG, Durik M, Baker DJ, van Deursen JM | title = Cellular senescence in aging and age-related disease: from mechanisms to therapy | journal = Nature Medicine | volume = 21 | issue = 12 | pages = 1424–1435 | date = December 2015 | pmid = 26646499 | pmc = 4748967 | doi = 10.1038/nm.4000 }} A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases.{{cite journal | vauthors = Kirkland JL, Tchkonia T | title = Clinical strategies and animal models for developing senolytic agents | journal = Experimental Gerontology | volume = 68 | pages = 19–25 | date = August 2015 | pmid = 25446976 | pmc = 4412760 | doi = 10.1016/j.exger.2014.10.012 }}{{cite journal | vauthors = van Deursen JM | title = Senolytic therapies for healthy longevity | journal = Science | volume = 364 | issue = 6441 | pages = 636–637 | date = May 2019 | pmid = 31097655 | pmc = 6816502 | doi = 10.1126/science.aaw1299 | bibcode = 2019Sci...364..636V }} Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.{{cite journal | vauthors=Chambers ES, Akbar AN | title=Can blocking inflammation enhance immunity during aging? | journal=The Journal of Allergy and Clinical Immunology | volume=145 | issue=5 | pages=1323–1331 | year=2020 | doi= 10.1016/j.jaci.2020.03.016 | pmid=32386656| url=https://discovery.ucl.ac.uk/10108233/3/Akbar_JACI%20review%20280220%20TOP.pdf }}

A related concept is "senostatic", which means to suppress senescence.{{cite journal |last1=Hu |first1=Qinchao |last2=Peng |first2=Jianmin |last3=Jiang |first3=Laibo |last4=Li |first4=Wuguo |last5=Su |first5=Qiao |last6=Zhang |first6=Jiayu |last7=Li |first7=Huan |last8=Song |first8=Ming |last9=Cheng |first9=Bin |last10=Xia |first10=Juan |last11=Wu |first11=Tong |title=Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma |journal=Cell Death & Disease |date=28 October 2020 |volume=11 |issue=10 |page=925 |doi=10.1038/s41419-020-03126-0 |pmid=33116117 |pmc=7595194 }}

Research

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials.{{cite journal | vauthors = Baumann K | title = Rejuvenating senolytics | journal = Nature Reviews. Molecular Cell Biology | volume = 19 | issue = 9 | pages = 543 | date = September 2018 | pmid = 30054558 | doi = 10.1038/s41580-018-0047-5 | s2cid = 51726136 }}{{clarify|date=December 2019}} The majority of candidate senolytic compounds are repurposed anti-cancer molecules, such as the chemotherapeutic drug dasatinib and the experimental small molecule navitoclax.{{cite journal | vauthors = Blagosklonny MV | title = Selective anti-cancer agents as anti-aging drugs | journal = Cancer Biology & Therapy | volume = 14 | issue = 12 | pages = 1092–1097 | date = December 2013 | pmid = 24345884 | pmc = 3912031 | doi = 10.4161/cbt.27350 }}{{cite journal | vauthors = Slack C, Alic N, Partridge L | title = Could cancer drugs provide ammunition against aging? | journal = Cell Cycle | volume = 15 | issue = 2 | pages = 153–155 | date = 6 January 2016 | pmid = 26587873 | pmc = 4825846 | doi = 10.1080/15384101.2015.1118905 }}

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.{{cite journal | vauthors = Wagner V, Gil J | title = T cells engineered to target senescence | journal = Nature | volume = 583 | issue = 7814 | pages = 37–38 | date = July 2020 | pmid = 32601490 | doi = 10.1038/d41586-020-01759-x | doi-access = free | bibcode = 2020Natur.583...37W | hdl = 10044/1/80980 | hdl-access = free }}{{cite journal | vauthors = 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 | display-authors = 6 | title = Senolytic CAR T cells reverse senescence-associated pathologies | journal = Nature | volume = 583 | issue = 7814 | pages = 127–132 | date = July 2020 | pmid = 32555459 | pmc = 7583560 | doi = 10.1038/s41586-020-2403-9 | bibcode = 2020Natur.583..127A }}

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.{{cite journal | vauthors = Robbins PD, Jurk D, Khosla S, Kirkland JL, LeBrasseur NK, Miller JD, Passos JF, Pignolo RJ, Tchkonia T, Niedernhofer LJ | display-authors = 6 | title = Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span | journal = Annual Review of Pharmacology and Toxicology | volume = 61 | issue = 1 | pages = 779–803 | date = January 2021 | pmid = 32997601 | pmc = 7790861 | doi = 10.1146/annurev-pharmtox-050120-105018 }}{{cite journal | vauthors = Di Micco R, Krizhanovsky V, Baker D, d'Adda di Fagagna F | title = Cellular senescence in ageing: from mechanisms to therapeutic opportunities | journal = Nature Reviews. Molecular Cell Biology | volume = 22 | issue = 2 | pages = 75–95 | date = February 2021 | pmid = 33328614 | pmc = 8344376 | doi = 10.1038/s41580-020-00314-w }}

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.{{cite journal | vauthors = Wong F, Omori S, Donghia NM, Zheng EJ, Collins JJ | title = Discovering small-molecule senolytics with deep neural networks | journal = Nature Aging | pages = 734–750 | date = May 2023 | volume = 3 | issue = 6 | pmid = 37142829 | doi = 10.1038/s43587-023-00415-z | s2cid = 258506382 }}{{cite journal | vauthors = 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 | display-authors = 6 | title = Discovery of senolytics using machine learning | journal = Nature Communications | volume = 14 | issue = 1 | pages = 3445 | date = June 2023 | pmid = 37301862 | pmc = 10257182 | doi = 10.1038/s41467-023-39120-1 | bibcode = 2023NatCo..14.3445S }}

= Senolytic candidates =

rowspan="2" \| Medication/target ! style="min-width: 500px;" rowspan="2" \| Description ! colspan="6" \| Tests as senolytic have been conducted in ...
class="wikitable sortable mw-collapsible" \|+ Hypothetical candidates for senolytics based on early-stage research
human cell lines in vitro !mice models !xenograft model !phase I trial !phase II trial !phase 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).{{cite journal \| vauthors = 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 \| display-authors = 6 \| title = Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging \| journal = Cell \| volume = 169 \| issue = 1 \| pages = 132–147.e16 \| date = March 2017 \| pmid = 28340339 \| pmc = 5556182 \| doi = 10.1016/j.cell.2017.02.031 }} 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.	{{Yes}}	{{Yes}}
BCL-2 inhibitors	Inhibitors of different members of the bcl-2 family of anti-apoptotic proteins.{{cite journal \| vauthors = Li W, Qin L, Feng R, Hu G, Sun H, He Y, Zhang R \| title = Emerging senolytic agents derived from natural products \| journal = Mechanisms of Ageing and Development \| volume = 181 \| pages = 1–6 \| date = July 2019 \| pmid = 31077707 \| doi = 10.1016/j.mad.2019.05.001 \| s2cid = 147704626 }}{{cite journal \| vauthors = Hernandez-Segura A, Nehme J, Demaria M \| title = Hallmarks of Cellular Senescence \| journal = Trends in Cell Biology \| volume = 28 \| issue = 6 \| pages = 436–453 \| date = June 2018 \| pmid = 29477613 \| doi = 10.1016/j.tcb.2018.02.001 \| s2cid = 3534989 \| url = https://pure.rug.nl/ws/files/61206288/1_s2.0_S0962892418300205_main.pdf }} 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).{{cite journal \| vauthors = Kirkland JL, Tchkonia T \| title = Senolytic drugs: from discovery to translation \| journal = Journal of Internal Medicine \| volume = 288 \| issue = 5 \| pages = 518–536 \| date = November 2020 \| pmid = 32686219 \| pmc = 7405395 \| doi = 10.1111/joim.13141 }}	{{Yes}}
Src inhibitors	Src tyrosine kinase inhibitors: dasatinib{{cite journal \| vauthors = Rivera-Torres J, San José E \| title = Src Tyrosine Kinase Inhibitors: New Perspectives on Their Immune, Antiviral, and Senotherapeutic Potential \| journal = Frontiers in Pharmacology \| volume = 10 \| pages = 1011 \| date = 2019 \| pmid = 31619990 \| pmc = 6759511 \| doi = 10.3389/fphar.2019.01011 \| doi-access = free }} – see "Combination of dasatinib and quercetin" below
USP7 inhibitors	Inhibitors of USP7 (ubiquitin-specific processing protease 7){{cite journal \| vauthors = Ge M, Hu L, Ao H, Zi M, Kong Q, He Y \| title = Senolytic targets and new strategies for clearing senescent cells \| journal = Mechanisms of Ageing and Development \| volume = 195 \| pages = 111468 \| date = April 2021 \| pmid = 33741395 \| doi = 10.1016/j.mad.2021.111468 \| s2cid = 232246367 }}	{{Yes}}{{cite journal \| vauthors = He Y, Li W, Lv D, Zhang X, Zhang X, Ortiz YT, Budamagunta V, Campisi J, Zheng G, Zhou D \| display-authors = 6 \| title = Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity \| journal = Aging Cell \| volume = 19 \| issue = 3 \| pages = e13117 \| date = March 2020 \| pmid = 32064756 \| pmc = 7059172 \| doi = 10.1111/acel.13117 }}	{{Yes}}
Dasatinib and Quercetin (D+Q)	Combination of dasatinib and quercetin{{cite journal \| vauthors = Palmer AK, Gustafson B, Kirkland JL, Smith U \| title = Cellular senescence: at the nexus between ageing and diabetes \| journal = Diabetologia \| volume = 62 \| issue = 10 \| pages = 1835–1841 \| date = October 2019 \| pmid = 31451866 \| pmc = 6731336 \| doi = 10.1007/s00125-019-4934-x }}	{{Yes}}	{{Yes}}		{{Yes}}{{cite journal \| vauthors = 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 \| display-authors = 6 \| title = Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease \| journal = eBioMedicine \| volume = 47 \| pages = 446–456 \| date = September 2019 \| pmid = 31542391 \| pmc = 6796530 \| doi = 10.1016/j.ebiom.2019.08.069 }}{{cite journal \| vauthors = Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL \| display-authors = 6 \| title = Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study \| journal = eBioMedicine \| volume = 40 \| pages = 554–563 \| date = February 2019 \| pmid = 30616998 \| pmc = 6412088 \| doi = 10.1016/j.ebiom.2018.12.052 }}
Fisetin		{{Yes}}{{cite journal \| vauthors = Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ \| display-authors = 6 \| title = Fisetin is a senotherapeutic that extends health and lifespan \| journal = eBioMedicine \| volume = 36 \| pages = 18–28 \| date = October 2018 \| pmid = 30279143 \| pmc = 6197652 \| doi = 10.1016/j.ebiom.2018.09.015 }}	{{Yes}}
Navitoclax			xenograft	{{Yes}}{{cite journal \| vauthors = Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O'Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW \| display-authors = 6 \| title = Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models \| journal = Clinical Cancer Research \| volume = 14 \| issue = 11 \| pages = 3268–3277 \| date = June 2008 \| pmid = 18519752 \| doi = 10.1158/1078-0432.CCR-07-4622 \| s2cid = 15786367 \| doi-access = }}
SSK1	Senescence-specific killing compound 1: A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker){{cite journal \| vauthors = Cai Y, Zhou H, Zhu Y, Sun Q, Ji Y, Xue A, Wang Y, Chen W, Yu X, Wang L, Chen H, Li C, Luo T, Deng H \| display-authors = 6 \| title = Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice \| journal = Cell Research \| volume = 30 \| issue = 7 \| pages = 574–589 \| date = July 2020 \| pmid = 32341413 \| pmc = 7184167 \| doi = 10.1038/s41422-020-0314-9 }}		{{Yes}}
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.{{cite journal \| vauthors = Narimani M, Sharifi M, Jalili A \| title = Knockout Of BIRC5 Gene By CRISPR/Cas9 Induces Apoptosis And Inhibits Cell Proliferation In Leukemic Cell Lines, HL60 And KG1 \| journal = Blood and Lymphatic Cancer: Targets and Therapy\| volume = 9 \| pages = 53–61 \| date = 2019-11-27 \| pmid = 31819702 \| pmc = 6885567 \| doi = 10.2147/BLCTT.S230383 \| doi-access = free }}	{{Yes}}
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.{{cite journal \| vauthors = Johmura Y, Yamanaka T, Omori S, Wang TW, Sugiura Y, Matsumoto M, Suzuki N, Kumamoto S, Yamaguchi K, Hatakeyama S, Takami T, Yamaguchi R, Shimizu E, Ikeda K, Okahashi N, Mikawa R, Suematsu M, Arita M, Sugimoto M, Nakayama KI, Furukawa Y, Imoto S, Nakanishi M \| display-authors = 6 \| title = Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders \| journal = Science \| volume = 371 \| issue = 6526 \| pages = 265–270 \| date = January 2021 \| pmid = 33446552 \| doi = 10.1126/science.abb5916 \| s2cid = 231606800 \| bibcode = 2021Sci...371..265J }}	{{Yes}}
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.{{cite journal \| vauthors = Suda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, Matsumoto N, Yoshida Y, Mikawa R, Katayama A, Wada J, Seki M, Suzuki Y, Iwama A, Nakagami H, Nagasawa A, Morishita R, Sugimoto M, Okuda S, Tsuchida M, Ozaki K, Nakanishi-Matsui M, Minamino T \| display-authors = 6 \| title = Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice \| journal = Nature Aging \| volume = 1 \| issue = 12 \| pages = 1117–1126 \| date = December 2021 \| pmid = 37117524 \| doi = 10.1038/s43587-021-00151-2 \| s2cid = 245068564 }}		{{Yes}}
Cardiac glycosides		{{Yes}}{{cite journal \| vauthors = L'Hôte V, Courbeyrette R, Pinna G, Cintrat JC, Le Pavec G, Delaunay-Moisan A, Mann C, Thuret JY \| display-authors = 6 \| title = Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy \| journal = Aging Cell \| volume = 20 \| issue = 9 \| pages = e13447 \| date = September 2021 \| pmid = 34355491 \| pmc = 8564827 \| doi = 10.1111/acel.13447 }}{{cite journal \| vauthors = Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, Pietrocola F, Llanos S, Rodilla V, Soprano E, Pedrosa P, Ferreirós A, Barradas M, Hernández-González F, Lalinde M, Prats N, Bernadó C, González P, Gómez M, Ikonomopoulou MP, Fernández-Marcos PJ, García-Caballero T, Del Pino P, Arribas J, Vidal A, González-Barcia M, Serrano M, Loza MI, Domínguez E, Collado M \| display-authors = 6 \| title = Identification and characterization of Cardiac Glycosides as senolytic compounds \| journal = Nature Communications \| volume = 10 \| issue = 1 \| pages = 4731 \| date = October 2019 \| pmid = 31636264 \| pmc = 6803708 \| doi = 10.1038/s41467-019-12888-x \| bibcode = 2019NatCo..10.4731T }}{{cite journal \| vauthors = Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J \| display-authors = 6 \| title = Cardiac glycosides are broad-spectrum senolytics \| journal = Nature Metabolism \| volume = 1 \| issue = 11 \| pages = 1074–1088 \| date = November 2019 \| pmid = 31799499 \| pmc = 6887543 \| doi = 10.1038/s42255-019-0122-z }}	xenograft	{{Yes}}
25-hydroxycholesterol (25HC){{cite journal \| vauthors = Limbad C, Doi R, McGirr J, Ciotlos S, Perez K, Clayton ZS, Daya R, Seals DR, Campisi J, Melov S \| display-authors = 6 \| title = Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types \| journal = iScience \| volume = 25 \| issue = 2 \| pages = 103848 \| date = February 2022 \| pmid = 35198901 \| pmc = 8851282 \| doi = 10.1016/j.isci.2022.103848 \| bibcode = 2022iSci...25j3848L }}	25-hydroxycholesterol targets CRYAB in multiple human and mouse cell types	{{Yes}}	{{Yes}}
Procyanidin C1		{{Yes}}{{cite journal \| vauthors = Xu Q, Fu Q, Li Z, Liu H, Wang Y, Lin X, He R, Zhang X, Ju Z, Campisi J, Kirkland JL, Sun Y \| display-authors = 6 \| title = The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice \| journal = Nature Metabolism \| volume = 3 \| issue = 12 \| pages = 1706–1726 \| date = December 2021 \| pmid = 34873338 \| pmc = 8688144 \| doi = 10.1038/s42255-021-00491-8 }}	{{Yes}}
EF-24		{{Yes}}
HSP90 inhibitors{{cite journal \| vauthors = Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD \| title = Hsp90 inhibitors as senolytic drugs to extend healthy aging \| journal = Cell Cycle \| volume = 17 \| issue = 9 \| pages = 1048–1055 \| date = 2018-05-03 \| pmid = 29886783 \| pmc = 6110594 \| doi = 10.1080/15384101.2018.1475828 \| publisher = Informa UK Limited }}
CUDC-907{{cite journal \| vauthors = Al-Mansour F, Alraddadi A, He B, Saleh A, Poblocka M, Alzahrani W, Cowley S, Macip S \| title = Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic \| journal = Aging \| volume = 15 \| issue = 9 \| pages = 2373–2394 \| date = 2023-03-28 \| doi = 10.18632/aging.204616 \| publisher = Impact Journals \| pmid = 36988504 \| pmc = 10120895 \| s2cid = 257804078 \| doi-access = free }}

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.

Senolytic

Research

= Senolytic candidates =

Senomorphics

See also

References

Further reading