Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs

. 2022 Apr 10 ; 23 (8) : . [epub] 20220410

Jazyk angličtina Země Švýcarsko Médium electronic

Typ dokumentu časopisecké články, přehledy

Perzistentní odkaz   https://www.medvik.cz/link/pmid35456986

Grantová podpora
LM2018133 Ministry of School, Education, Youth and Sports of the Czech Republic
CZ.02.1.01/0.0/0.0/16_019/0000868 Ministry of School, Education, Youth and Sports of the Czech Republic
TE02000058 Technological agency of the Czech Republic
IGA_LF_2021_036 Palacky University in Olomouc

Cellular senescence is defined as irreversible cell cycle arrest caused by various processes that render viable cells non-functional, hampering normal tissue homeostasis. It has many endogenous and exogenous inducers, and is closely connected with age, age-related pathologies, DNA damage, degenerative disorders, tumor suppression and activation, wound healing, and tissue repair. However, the literature is replete with contradictory findings concerning its triggering mechanisms, specific biomarkers, and detection protocols. This may be partly due to the wide range of cellular and in vivo animal or human models of accelerated aging that have been used to study senescence and test senolytic drugs. This review summarizes recent findings concerning senescence, presents some widely used cellular and animal senescence models, and briefly describes the best-known senolytic agents.

Zobrazit více v PubMed

McHugh D., Gil J. Senescence and Aging: Causes, Consequences, and Therapeutic Avenues. J. Cell Biol. 2018;217:65–77. doi: 10.1083/jcb.201708092. PubMed DOI PMC

Hayflick L., Moorhead P.S. The Serial Cultivation of Human Diploid Cell Strains. Exp. Cell Res. 1961;25:585–621. doi: 10.1016/0014-4827(61)90192-6. PubMed DOI

Campisi J., D’Adda Di Fagagna F. Cellular Senescence: When Bad Things Happen to Good Cells. Nat. Rev. Mol. Cell Biol. 2007;8:729–740. doi: 10.1038/nrm2233. PubMed DOI

Adams P.D. Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence. Mol. Cell. 2009;36:2–14. doi: 10.1016/j.molcel.2009.09.021. PubMed DOI

Kuilman T., Michaloglou C., Mooi W.J., Peeper D.S. The Essence of Senescence. Genes Dev. 2010;24:2463–2479. doi: 10.1101/gad.1971610. PubMed DOI PMC

Yosef R., Pilpel N., Tokarsky-Amiel R., Biran A., Ovadya Y., Cohen S., Vadai E., Dassa L., Shahar E., Condiotti R., et al. Directed Elimination of Senescent Cells by Inhibition of BCL-W and BCL-XL. Nat. Commun. 2016;7:11190. doi: 10.1038/ncomms11190. PubMed DOI PMC

Hubackova S., Davidova E., Rohlenova K., Stursa J., Werner L., Andera L., Dong L.F., Terp M.G., Hodny Z., Ditzel H.J., et al. Selective Elimination of Senescent Cells by Mitochondrial Targeting Is Regulated by ANT2. Cell Death Differ. 2019;26:276–290. doi: 10.1038/s41418-018-0118-3. PubMed DOI PMC

Cai Y., Zhou H., Zhu Y., Sun Q., Ji Y., Xue A., Wang Y., Chen W., Yu X., Wang L., et al. Elimination of Senescent Cells by β-Galactosidase-Targeted Prodrug Attenuates Inflammation and Restores Physical Function in Aged Mice. Cell Res. 2020;30:574–589. doi: 10.1038/s41422-020-0314-9. PubMed DOI PMC

Herranz N., Gil J. Mechanisms and Functions of Cellular Senescence. J. Clin. Investig. 2018;128:1238–1246. doi: 10.1172/JCI95148. PubMed DOI PMC

Muñoz-Espín D., Serrano M. Cellular Senescence: From Physiology to Pathology. Nat. Rev. Mol. Cell Biol. 2014;15:482–496. doi: 10.1038/nrm3823. PubMed DOI

Liguori I., Russo G., Curcio F., Bulli G., Aran L., Della-Morte D., Gargiulo G., Testa G., Cacciatore F., Bonaduce D., et al. Oxidative Stress, Aging, and Diseases. Clin. Interv. Aging. 2018;13:757. doi: 10.2147/CIA.S158513. PubMed DOI PMC

Rajendran P., Alzahrani A.M., Hanieh H.N., Kumar S.A., Ben Ammar R., Rengarajan T., Alhoot M.A. Autophagy and Senescence: A New Insight in Selected Human Diseases. J. Cell. Physiol. 2019;234:21485–21492. doi: 10.1002/jcp.28895. PubMed DOI

Wang Y., Wang X.D., Lapi E., Sullivan A., Jia W., He Y.W., Ratnayaka I., Zhong S., Goldin R.D., Goemans C.G., et al. Autophagic Activity Dictates the Cellular Response to Oncogenic RAS. Proc. Natl. Acad. Sci. USA. 2012;109:13325–13330. doi: 10.1073/pnas.1120193109. PubMed DOI PMC

Kang C., Xu Q., Martin T.D., Li M.Z., Demaria M., Aron L., Lu T., Yankner B.A., Campisi J., Elledge S.J. The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4. Science. 2015;349:aaa5612. doi: 10.1126/science.aaa5612. PubMed DOI PMC

Fitzwalter B.E., Towers C.G., Sullivan K.D., Andrysik Z., Hoh M., Ludwig M., O’Prey J., Ryan K.M., Espinosa J.M., Morgan M.J., et al. Autophagy Inhibition Mediates Apoptosis Sensitization in Cancer Therapy by Relieving FOXO3a Turnover. Dev. Cell. 2018;44:555–565.e3. doi: 10.1016/j.devcel.2018.02.014. PubMed DOI PMC

Mariño G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-Consumption: The Interplay of Autophagy and Apoptosis. Nat. Rev. Mol. Cell Biol. 2014;15:81–94. doi: 10.1038/nrm3735. PubMed DOI PMC

Pérez-Mancera P.A., Young A.R.J., Narita M. Inside and out: The Activities of Senescence in Cancer. Nat. Rev. Cancer. 2014;14:547–558. doi: 10.1038/nrc3773. PubMed DOI

García-Prat L., Martínez-Vicente M., Perdiguero E., Ortet L., Rodríguez-Ubreva J., Rebollo E., Ruiz-Bonilla V., Gutarra S., Ballestar E., Serrano A.L., et al. Autophagy Maintains Stemness by Preventing Senescence. Nature. 2016;529:37–42. doi: 10.1038/nature16187. PubMed DOI

Rufini A., Tucci P., Celardo I., Melino G. Senescence and Aging: The Critical Roles of P53. Oncogene. 2013;32:5129–5143. doi: 10.1038/onc.2012.640. PubMed DOI

Al Bitar S., Gali-Muhtasib H. The Role of the Cyclin Dependent Kinase Inhibitor P21cip1/Waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics. Cancers. 2019;11:1475. doi: 10.3390/cancers11101475. PubMed DOI PMC

Benson E.K., Mungamuri S.K., Attie O., Kracikova M., Sachidanandam R., Manfredi J.J., Aaronson S.A. P53-Dependent Gene Repression through P21 Is Mediated by Recruitment of E2F4 Repression Complexes. Oncogene. 2014;33:3959–3969. doi: 10.1038/onc.2013.378. PubMed DOI PMC

Sharpless N.E., Sherr C.J. Forging a Signature of in vivo Senescence. Nat. Rev. Cancer. 2015;15:397–408. doi: 10.1038/nrc3960. PubMed DOI

Chen J., Huang X., Halicka D., Brodsky S., Avram A., Eskander J., Bloomgarden N.A., Darzynkiewicz Z., Goligorsky M.S. Contribution of P16INK4a and P21CIP1 Pathways to Induction of Premature Senescence of Human Endothelial Cells: Permissive Role of P53. Am. J. Physiol.-Heart Circ. Physiol. 2006;290:H1575–H1586. doi: 10.1152/ajpheart.00364.2005. PubMed DOI

Fiorentino F.P., Symonds C.E., MacAluso M., Giordano A. Senescence and P130/Rbl2: A New Beginning to the End. Cell Res. 2009;19:1044–1051. doi: 10.1038/cr.2009.96. PubMed DOI

Rayess H., Wang M.B., Srivatsan E.S. Cellular Senescence and Tumor Suppressor Gene P16. Int. J. Cancer. 2012;130:1715–1725. doi: 10.1002/ijc.27316. PubMed DOI PMC

Beauséjour C.M., Krtolica A., Galimi F., Narita M., Lowe S.W., Yaswen P., Campisi J. Reversal of Human Cellular Senescence: Roles of the P53 and P16 Pathways. EMBO J. 2003;22:4212–4222. doi: 10.1093/emboj/cdg417. PubMed DOI PMC

Helmbold H., Kömm K., Deppert W., Bohn W. Rb2/P130 Is the Dominating Pocket Protein in the P53–P21 DNA Damage Response Pathway Leading to Senescence. Oncogene. 2009;28:3456–3467. doi: 10.1038/onc.2009.222. PubMed DOI

Indovina P., Marcelli E., Casini N., Rizzo V., Giordano A. Emerging Roles of RB Family: New Defense Mechanisms against Tumor Progression. J. Cell. Physiol. 2013;228:525–535. doi: 10.1002/jcp.24170. PubMed DOI

Helmbold H., Deppert W., Bohn W. Regulation of Cellular Senescence by Rb2/P130. Oncogene. 2006;25:5257–5262. doi: 10.1038/sj.onc.1209613. PubMed DOI

Rayman J.B., Takahashi Y., Indjeian V.B., Dannenberg J.H., Catchpole S., Watson R.J., Riele H., Dynlacht B.D. E2F Mediates Cell Cycle-Dependent Transcriptional Repression in vivo by Recruitment of an HDAC1/MSin3B Corepressor Complex. Genes Dev. 2002;16:933–947. doi: 10.1101/gad.969202. PubMed DOI PMC

De Jesus B.B., Blasco M.A. Assessing Cell and Organ Senescence Biomarkers. Circ. Res. 2012;111:97–109. doi: 10.1161/CIRCRESAHA.111.247866. PubMed DOI PMC

Noren Hooten N., Evans M.K. Techniques to Induce and Quantify Cellular Senescence. J. Vis. Exp. 2017;2017:55533. doi: 10.3791/55533. PubMed DOI PMC

Adewoye A.B., Tampakis D., Follenzi A., Stolzing A. Multiparameter Flow Cytometric Detection and Quantification of Senescent Cells in vitro. Biogerontology. 2020;21:773–786. doi: 10.1007/s10522-020-09893-9. PubMed DOI PMC

Schmid N., Flenkenthaler F., Stöckl J.B., Dietrich K.G., Köhn F.M., Schwarzer J.U., Kunz L., Luckner M., Wanner G., Arnold G.J., et al. Insights into Replicative Senescence of Human Testicular Peritubular Cells. Sci. Rep. 2019;9:15052. doi: 10.1038/s41598-019-51380-w. PubMed DOI PMC

Dimri G.P., Lee X., Basile G., Acosta M., Scott G., Roskelley C., Medrano E.E., Linskens M., Rubelj I., Pereira-Smith O., et al. A Biomarker That Identifies Senescent Human Cells in Culture and in Aging Skin in vivo. Proc. Natl. Acad. Sci. USA. 1995;92:9363–9367. doi: 10.1073/pnas.92.20.9363. PubMed DOI PMC

Debacq-Chainiaux F., Erusalimsky J.D., Campisi J., Toussaint O. Protocols to Detect Senescence-Associated Beta-Galactosidase (SA-Βgal) Activity, a Biomarker of Senescent Cells in Culture and in vivo. Nat. Protoc. 2009;4:1798–1806. doi: 10.1038/nprot.2009.191. PubMed DOI

Itahana K., Itahana Y., Dimri G.P. Colorimetric Detection of Senescence-Associated β Galactosidase. Methods Mol. Biol. 2013;965:143–156. doi: 10.1007/978-1-62703-239-1_8. PubMed DOI PMC

Piechota M., Sunderland P., Wysocka A., Nalberczak M., Sliwinska M.A., Radwanska K., Sikora E. Is Senescence-Associated β-Galactosidase a Marker of Neuronal Senescence? Oncotarget. 2016;7:81099–81109. doi: 10.18632/oncotarget.12752. PubMed DOI PMC

de Mera-Rodríguez J.A., Álvarez-Hernán G., Gañán Y., Martín-Partido G., Rodríguez-León J., Francisco-Morcillo J. Is Senescence-Associated β-Galactosidase a Reliable in vivo Marker of Cellular Senescence during Embryonic Development? Front. Cell Dev. Biol. 2021;9:36. doi: 10.3389/fcell.2021.623175. PubMed DOI PMC

Hildebrand D.G., Lehle S., Borst A., Haferkamp S., Essmann F., Schulze-Osthoff K. α-Fucosidase as a Novel Convenient Biomarker for Cellular Senescence. Cell Cycle. 2013;12:1922–1927. doi: 10.4161/cc.24944. PubMed DOI PMC

Terman A., Brunk U.T. Lipofuscin: Mechanisms of Formation and Increase with Age. APMIS. 1998;106:265–276. doi: 10.1111/j.1699-0463.1998.tb01346.x. PubMed DOI

Terman A., Brunk U.T. Lipofuscin. Int. J. Biochem. Cell Biol. 2004;36:1400–1404. doi: 10.1016/j.biocel.2003.08.009. PubMed DOI

Salmonowicz H., Passos J.F. Detecting Senescence: A New Method for an Old Pigment. Aging Cell. 2017;16:432–434. doi: 10.1111/acel.12580. PubMed DOI PMC

Mah L.-J., El-Osta A., Karagiannis T.C. ΓH2AX as a Molecular Marker of Aging and Disease. Epigenetics. 2010;5:129–136. doi: 10.4161/epi.5.2.11080. PubMed DOI

De Jager M., Dronkert M.L.G., Modesti M., Beerens C.E.M.T., Kanaar R., Van Gent D.C. DNA-Binding and Strand-Annealing Activities of Human Mre11: Implications for Its Roles in DNA Double-Strand Break Repair Pathways. Nucleic Acids Res. 2001;29:1317–1325. doi: 10.1093/nar/29.6.1317. PubMed DOI PMC

Sancar A., Lindsey-Boltz L.A., Ünsal-Kaçmaz K., Linn S. Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints. Annu. Rev. Biochem. 2004;73:39–85. doi: 10.1146/annurev.biochem.73.011303.073723. PubMed DOI

Wang B., Matsuoka S., Carpenter P.B., Elledge S.J. 53BP1, a Mediator of the DNA Damage Checkpoint. Science. 2002;298:1435–1438. doi: 10.1126/science.1076182. PubMed DOI

Stucki M., Jackson S.P. ΓH2AX and MDC1: Anchoring the DNA-Damage-Response Machinery to Broken Chromosomes. DNA Repair. 2006;5:534–543. doi: 10.1016/j.dnarep.2006.01.012. PubMed DOI

Takai H., Smogorzewska A., De Lange T. DNA Damage Foci at Dysfunctional Telomeres. Curr. Biol. 2003;13:1549–1556. doi: 10.1016/S0960-9822(03)00542-6. PubMed DOI

Herbig U., Jobling W.A., Chen B.P.C., Chen D.J., Sedivy J.M. Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, P53, and P21CIP1, but Not P16INK4a. Mol. Cell. 2004;14:501–513. doi: 10.1016/S1097-2765(04)00256-4. PubMed DOI

Olovnikov A.M. Telomeres, Telomerase, and Aging: Origin of the Theory. Exp. Gerontol. 1996;31:443–448. doi: 10.1016/0531-5565(96)00005-8. PubMed DOI

Parrinello S., Samper E., Krtolica A., Goldstein J., Melov S., Campisi J. Oxygen Sensitivity Severely Limits the Replicative Lifespan of Murine Fibroblasts. Nat. Cell Biol. 2003;5:741–747. doi: 10.1038/ncb1024. PubMed DOI PMC

Correia-Melo C., Marques F.D., Anderson R., Hewitt G., Hewitt R., Cole J., Carroll B.M., Miwa S., Birch J., Merz A., et al. Mitochondria Are Required for Pro-Ageing Features of the Senescent Phenotype. EMBO J. 2016;35:724–742. doi: 10.15252/embj.201592862. PubMed DOI PMC

Pole A., Dimri M., Dimri G.P. Oxidative Stress, Cellular Senescence and Ageing. AIMS Mol. Sci. 2016;3:300–324. doi: 10.3934/molsci.2016.3.300. DOI

Agrawal K., Das V., Táborská N., Gurský J., Džubák P., Hajdúch M. Differential Regulation of Methylation-Regulating Enzymes by Senescent Stromal Cells Drives Colorectal Cancer Cell Response to DNA-Demethylating Epi-Drugs. Stem Cells Int. 2018;2018:6013728. doi: 10.1155/2018/6013728. PubMed DOI PMC

Aird K.M., Zhang R. Detection of Senescence-Associated Heterochromatin Foci (SAHF) Methods Mol. Biol. 2013;965:185–196. doi: 10.1007/978-1-62703-239-1_12. PubMed DOI PMC

Zhang R., Chen W., Adams P.D. Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci. Mol. Cell. Biol. 2007;27:2343–2358. doi: 10.1128/MCB.02019-06. PubMed DOI PMC

Rodier F., Muñoz D.P., Teachenor R., Chu V., Le O., Bhaumik D., Coppé J.P., Campeau E., Beauséjour C.M., Kim S.H., et al. DNA-SCARS: Distinct Nuclear Structures That Sustain Damage-Induced Senescence Growth Arrest and Inflammatory Cytokine Secretion. J. Cell Sci. 2011;124:68–81. doi: 10.1242/jcs.071340. PubMed DOI PMC

Freund A., Laberge R.-M., Demaria M., Campisi J. Lamin B1 Loss Is a Senescence-Associated Biomarker. Mol. Biol. Cell. 2012;23:2066–2075. doi: 10.1091/mbc.e11-10-0884. PubMed DOI PMC

Gratzner H.G. Monoclonal Antibody to 5-Bromo- and 5-Iododeoxyuridine: A New Reagent for Detection of DNA Replication. Science. 1982;218:474–475. doi: 10.1126/science.7123245. PubMed DOI

Buck S.B., Bradford J., Gee K.R., Agnew B.J., Clarke S.T., Salic A. Detection of S-Phase Cell Cycle Progression Using 5-Ethynyl-2′-Deoxyuridine Incorporation with Click Chemistry, an Alternative to Using 5-Bromo-2′-Deoxyuridine Antibodies. Biotechniques. 2008;44:927–929. doi: 10.2144/000112812. PubMed DOI

Scholzen T., Gerdes J. The Ki-67 Protein: From the Known and the Unknown. J. Cell. Physiol. 2000;182:311–322. doi: 10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9. PubMed DOI

Zhang H. Molecular Signaling and Genetic Pathways of Senescence: Its Role in Tumorigenesis and Aging. J. Cell. Physiol. 2007;210:567–574. doi: 10.1002/jcp.20919. PubMed DOI

Qian Y., Zhang J., Yan B., Chen X. DEC1, a Basic Helix-Loop-Helix Transcription Factor and a Novel Target Gene of the P53 Family, Mediates P53-Dependent Premature Senescence*|Elsevier Enhanced Reader. [(accessed on 12 April 2021)];J. Biol. Chem. 2008 283:2896–2905. doi: 10.1074/jbc.M708624200. Available online: https://reader.elsevier.com/reader/sd/pii/S0021925820555385?token=088C94F7A5AE15857D34F420A29A72A3BE5345F5D1D288FFC595813C13C107D9B6E1F7759CFB209D116494F9DD7EAC6D&originRegion=eu-west-1&originCreation=20210412194802. PubMed DOI PMC

Ruiz L., Traskine M., Ferrer I., Castro E., Leal J.F.M., Kaufman M., Carnero A. Characterization of the P53 Response to Oncogene-Induced Senescence. PLoS ONE. 2008;3:e3230. doi: 10.1371/journal.pone.0003230. PubMed DOI PMC

Cuollo L., Antonangeli F., Santoni A., Soriani A. The Senescence-Associated Secretory Phenotype (Sasp) in the Challenging Future of Cancer Therapy and Age-Related Diseases. Biology. 2020;9:485. doi: 10.3390/biology9120485. PubMed DOI PMC

Basisty N., Kale A., Jeon O.H., Kuehnemann C., Payne T., Rao C., Holtz A., Shah S., Sharma V., Ferrucci L., et al. A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development. PLoS Biol. 2020;18:e3000599. doi: 10.1371/journal.pbio.3000599. PubMed DOI PMC

Mrazkova B., Dzijak R., Imrichova T., Kyjacova L., Barath P., Dzubak P., Holub D., Hajduch M., Nahacka Z., Andera L., et al. Induction, Regulation and Roles of Neural Adhesion Molecule L1CAM in Cellular Senescence. Aging. 2018;10:434–462. doi: 10.18632/aging.101404. PubMed DOI PMC

Coppé J.P., Desprez P.Y., Krtolica A., Campisi J. The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annu. Rev. Pathol. 2010;5:99–118. doi: 10.1146/annurev-pathol-121808-102144. PubMed DOI PMC

Althubiti M., Lezina L., Carrera S., Jukes-Jones R., Giblett S.M., Antonov A., Barlev N., Saldanha G.S., Pritchard C.A., Cain K., et al. Characterization of Novel Markers of Senescence and Their Prognostic Potential in Cancer. Cell Death Dis. 2014;5:e1528. doi: 10.1038/cddis.2014.489. PubMed DOI PMC

Soto-Gamez A., Quax W.J., Demaria M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J. Mol. Biol. 2019;431:2629–2643. doi: 10.1016/j.jmb.2019.05.036. PubMed DOI

Lee H.W., Heo C.H., Sen D., Byun H.O., Kwak I.H., Yoon G., Kim H.M. Ratiometric Two-Photon Fluorescent Probe for Quantitative Detection of β-Galactosidase Activity in Senescent Cells. Anal. Chem. 2014;86:10001–10005. doi: 10.1021/ac5031013. PubMed DOI

Zhang J., Li C., Dutta C., Fang M., Zhang S., Tiwari A., Werner T., Luo F.T., Liu H. A Novel Near-Infrared Fluorescent Probe for Sensitive Detection of β-Galactosidase in Living Cells. Anal. Chim. Acta. 2017;968:97–104. doi: 10.1016/j.aca.2017.02.039. PubMed DOI PMC

Lozano-Torres B., Galiana I., Rovira M., Garrido E., Chaib S., Bernardos A., Muñoz-Espín D., Serrano M., Martínez-Máñez R., Sancenón F. An OFF-ON Two-Photon Fluorescent Probe for Tracking Cell Senescence in vivo. J. Am. Chem. Soc. 2017;139:8808–8811. doi: 10.1021/jacs.7b04985. PubMed DOI

Wang Y., Liu J., Ma X., Cui C., Deenik P.R., Henderson P.K.P., Sigler A.L., Cui L. Real-Time Imaging of Senescence in Tumors with DNA Damage. Sci. Rep. 2019;9:2102. doi: 10.1038/s41598-019-38511-z. PubMed DOI PMC

Becker T., Haferkamp S. Senescence and Senescence-Related Disorders. InTech; Vienna, Austria: 2013. Molecular Mechanisms of Cellular Senescence.

Eriksson D., Stigbrand T. Radiation-Induced Cell Death Mechanisms. Tumor Biol. 2010;31:363–372. doi: 10.1007/s13277-010-0042-8. PubMed DOI

Wang Y., Wang Y., Liu S., Liu Y., Xu H., Liang J., Zhu J., Zhang G., Su W., Dong W., et al. Upregulation of EID3 Sensitizes Breast Cancer Cells to Ionizing Radiation-Induced Cellular Senescence. Biomed. Pharmacother. 2018;107:606–614. doi: 10.1016/j.biopha.2018.08.022. PubMed DOI

Wang Y., Boerma M., Zhou D. Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases. Radiat. Res. 2016;186:153–161. doi: 10.1667/RR14445.1. PubMed DOI PMC

Dolan D.W.P., Zupanic A., Nelson G., Hall P., Miwa S., Kirkwood T.B.L., Shanley D.P. Integrated Stochastic Model of DNA Damage Repair by Non-Homologous End Joining and P53/P21- Mediated Early Senescence Signalling. PLoS Comput. Biol. 2015;11:e1004246. doi: 10.1371/journal.pcbi.1004246. PubMed DOI PMC

Day R.M., Snow A.L., Panganiban R.A.M. Radiation-Induced Accelerated Senescence: A Fate Worse than Death? Cell Cycle. 2014;13:2011–2012. doi: 10.4161/cc.29457. PubMed DOI PMC

Gladyshev V.N. The Free Radical Theory of Aging Is Dead. Long Live the Damage Theory! Antioxid. Redox Signal. 2014;20:727–731. doi: 10.1089/ars.2013.5228. PubMed DOI PMC

Chen Q., Fischer A., Reagan J.D., Yan L.J., Ames B.N. Oxidative DNA Damage and Senescence of Human Diploid Fibroblast Cells. Proc. Natl. Acad. Sci. USA. 1995;92:4337–4341. doi: 10.1073/pnas.92.10.4337. PubMed DOI PMC

López-Otín C., Blasco M.A., Partridge L., Serrano M., Kroemer G. The Hallmarks of Aging. Cell. 2013;153:1194. doi: 10.1016/j.cell.2013.05.039. PubMed DOI PMC

Chen Q.M., Bartholomew J.C., Campisi J., Acosta M., Reagan J.D., Ames B.N. Molecular Analysis of H2O2-Induced Senescent-like Growth Arrest in Normal Human Fibroblasts: P53 and Rb Control G1 Arrest but Not Cell Replication. Biochem. J. 1998;332:43–50. doi: 10.1042/bj3320043. PubMed DOI PMC

Chen J.-H., Ozanne S.E., Hales C.N. Biological Aging. Humana Press; Totowa, NJ, USA: 2007. Methods of Cellular Senescence Induction Using Oxidative Stress; pp. 179–189. PubMed

Serrano M., Lin A.W., McCurrach M.E., Beach D., Lowe S.W. Oncogenic Ras Provokes Premature Cell Senescence Associated with Accumulation of P53 and P16(INK4a) Cell. 1997;88:593–602. doi: 10.1016/S0092-8674(00)81902-9. PubMed DOI

Gupta R., Wajapeyee N. Induction of Cellular Senescence by Oncogenic RAS. Methods Mol. Biol. 2013;1048:127–133. doi: 10.1007/978-1-62703-556-9_10. PubMed DOI

Zhang F., Zakaria S.M., Högqvist Tabor V., Singh M., Tronnersjö S., Goodwin J., Selivanova G., Bartek J., Castell A., Larsson L.G. MYC and RAS Are Unable to Cooperate in Overcoming Cellular Senescence and Apoptosis in Normal Human Fibroblasts. Cell Cycle. 2018;17:2697–2715. doi: 10.1080/15384101.2018.1553339. PubMed DOI PMC

The NIA Aging Cell Repository: Facilitating Research with Aging Cells; National Institute on Aging: Bethesda, MD, USA. [(accessed on 19 April 2021)]; Available online: https://www.nia.nih.gov/research/blog/2018/05/nia-aging-cell-repository-facilitating-research-aging-cells.

Kudlow B.A., Kennedy B.K., Monnat R.J. Werner and Hutchinson-Gilford Progeria Syndromes: Mechanistic Basis of Human Progeroid Diseases. Nat. Rev. Mol. Cell Biol. 2007;8:394–404. doi: 10.1038/nrm2161. PubMed DOI

Harkema L., Youssef S.A., De Bruin A. Pathology of Mouse Models of Accelerated Aging. Vet. Pathol. 2016;53:366–389. doi: 10.1177/0300985815625169. PubMed DOI

Yousefzadeh M.J., Melos K.I., Angelini L., Burd C.E., Robbins P.D., Niedernhofer L.J. Methods in Molecular Biology. Volume 1896. Humana Press Inc.; Totowa, NJ, USA: 2019. Mouse Models of Accelerated Cellular Senescence; pp. 203–230. PubMed PMC

Sorrentino J.A., Krishnamurthy J., Tilley S., Alb J.G., Burd C.E., Sharpless N.E. P16INK4a Reporter Mice Reveal Age-Promoting Effects of Environmental Toxicants. J. Clin. Investig. 2014;124:169–173. doi: 10.1172/JCI70960. PubMed DOI PMC

Le O.N.L., Rodier F., Fontaine F., Coppe J.P., Campisi J., DeGregori J., Laverdière C., Kokta V., Haddad E., Beauséjour C.M. Ionizing Radiation-Induced Long-Term Expression of Senescence Markers in Mice Is Independent of P53 and Immune Status. Aging Cell. 2010;9:398–409. doi: 10.1111/j.1474-9726.2010.00567.x. PubMed DOI PMC

Seol M.-A., Jung U., Eom S., Kim S.-H., Park H.-R., Jo S.-K. Chronic Induction of Senescence Marker in Gamma-Irradiation Mice; Proceedings of the Transactions of the Korean Nuclear Society Autumn Meeting; Gyeongju, Korea. 27–28 October 2011.

Seol M.A., Jung U., Eom H.S., Kim S.H., Park H.R., Jo S.K. Prolonged Expression of Senescence Markers in Mice Exposed to Gamma-Irradiation. J. Vet. Sci. 2012;13:331–338. doi: 10.4142/jvs.2012.13.4.331. PubMed DOI PMC

Tong J., Hei T.K. Aging and Age-Related Health Effects of Ionizing Radiation. Radiat. Med. Prot. 2020;1:15–23. doi: 10.1016/j.radmp.2020.01.005. DOI

Kudlova N., Slavik H., Duskova P., Furst T., Srovnal J., Bartek J., Mistrik M., Hajduch M. An Efficient, Non-Invasive Approach for in-vivo Sampling of Hair Follicles: Design and Applications in Monitoring DNA Damage and Aging. Aging. 2021;13:25004–25024. doi: 10.18632/aging.203744. PubMed DOI PMC

Li S.Y., Du M., Dolence E.K., Fang C.X., Mayer G.E., Ceylan-Isik A.F., LaCour K.H., Yang X., Wilbert C.J., Sreejayan N., et al. Aging Induces Cardiac Diastolic Dysfunction, Oxidative Stress, Accumulation of Advanced Glycation Endproducts and Protein Modification. Aging Cell. 2005;4:57–64. doi: 10.1111/j.1474-9728.2005.00146.x. PubMed DOI

Yoo D.Y., Kim W., Lee C.H., Shin B.N., Nam S.M., Choi J.H., Won M.H., Yoon Y.S., Hwang I.K. Melatonin Improves D-Galactose-Induced Aging Effects on Behavior, Neurogenesis, and Lipid Peroxidation in the Mouse Dentate Gyrus via Increasing PCREB Expression. J. Pineal Res. 2012;52:21–28. doi: 10.1111/j.1600-079X.2011.00912.x. PubMed DOI

Salehpour F., Ahmadian N., Rasta S.H., Farhoudi M., Karimi P., Sadigh-Eteghad S. Transcranial Low-Level Laser Therapy Improves Brain Mitochondrial Function and Cognitive Impairment in D-Galactose–Induced Aging Mice. Neurobiol. Aging. 2017;58:140–150. doi: 10.1016/j.neurobiolaging.2017.06.025. PubMed DOI

Remigante A., Spinelli S., Trichilo V., Loddo S., Sarikas A., Pusch M., Dossena S., Marino A., Morabito R. D-Galactose Induced Early Aging in Human Erythrocytes: Role of Band 3 Protein. J. Cell. Physiol. 2022;237:1586–1596. doi: 10.1002/jcp.30632. PubMed DOI PMC

Sun K., Yang P., Zhao R., Bai Y., Guo Z. Matrine Attenuates D-Galactose-Induced Aging-Related Behavior in Mice via Inhibition of Cellular Senescence and Oxidative Stress. Oxid. Med. Cell. Longev. 2018;2018:7108604. doi: 10.1155/2018/7108604. PubMed DOI PMC

Liu Y., Liu Y., Guo Y., Xu L., Wang H. Phlorizin Exerts Potent Effects against Aging Induced by D-Galactose in Mice and PC12 Cells. Food Funct. 2021;12:2148–2160. doi: 10.1039/D0FO02707C. PubMed DOI

Li J.-H., Wei T.-T., Guo L., Cao J.-H., Feng Y.-K., Guo S.-N., Liu G.-H., Ding Y., Chai Y.-R. Curcumin Protects Thymus against D-Galactose-Induced Senescence in Mice. Naunyn. Schmiedebergs. Arch. Pharmacol. 2021;394:411–420. doi: 10.1007/s00210-020-01945-8. PubMed DOI

Wang S.H., Liang C.J., Weng Y.W., Chen Y.H., Hsu H.Y., Chien H.F., Tsai J.S., Tseng Y.C., Li C.Y., Chen Y.L. Ganoderma Lucidum Polysaccharides Prevent Platelet-Derived Growth Factor-Stimulated Smooth Muscle Cell Proliferation in vitro and Neointimal Hyperplasia in the Endothelial-Denuded Artery in vivo. J. Cell. Physiol. 2012;227:3063–3071. doi: 10.1002/jcp.23053. PubMed DOI

Lee J., Kim Y.S., Kim E., Kim Y., Kim Y. Curcumin and Hesperetin Attenuate D-Galactose-Induced Brain Senescence in vitro and in vivo. Nutr. Res. Pract. 2020;14:438. doi: 10.4162/nrp.2020.14.5.438. PubMed DOI PMC

Chen X., Li Y., Chen W., Nong Z., Huang J., Chen C. Protective Effect of Hyperbaric Oxygen on Cognitive Impairment Induced by D-Galactose in Mice. Neurochem. Res. 2016;41:3032–3041. doi: 10.1007/s11064-016-2022-x. PubMed DOI

Sarkisian C.J., Keister B.A., Stairs D.B., Boxer R.B., Moody S.E., Chodosh L.A. Dose-Dependent Oncogene-Induced Senescence in vivo and Its Evasion during Mammary Tumorigenesis. Nat. Cell Biol. 2007;9:493–505. doi: 10.1038/ncb1567. PubMed DOI

Baek K.H., Ryeom S. Detection of Oncogene-Induced Senescence in vivo. Methods Mol. Biol. 2017;1534:185–198. doi: 10.1007/978-1-4939-6670-7_18. PubMed DOI PMC

Toogood P.L., Harvey P.J., Repine J.T., Sheehan D.J., VanderWel S.N., Zhou H., Keller P.R., McNamara D.J., Sherry D., Zhu T., et al. Discovery of a Potent and Selective Inhibitor of Cyclin-Dependent Kinase 4/6. J. Med. Chem. 2005;48:2388–2406. doi: 10.1021/jm049354h. PubMed DOI

Fry D.W., Harvey P.J., Keller P.R., Elliott W.L., Meade M., Trachet E., Albassam M., Zheng X., Leopold W.R., Pryer N.K., et al. Specific Inhibition of Cyclin-Dependent Kinase 4/6 by PD 0332991 and Associated Antitumor Activity in Human Tumor Xenografts. Mol. Cancer Ther. 2004;3:1427–1438. doi: 10.1158/1535-7163.1427.3.11. PubMed DOI

Gelbert L.M., Cai S., Lin X., Sanchez-Martinez C., Del Prado M., Lallena M.J., Torres R., Ajamie R.T., Wishart G.N., Flack R.S., et al. Preclinical Characterization of the CDK4/6 Inhibitor LY2835219: In-Vivo Cell Cycle-Dependent/Independent Anti-Tumor Activities Alone/in Combination with Gemcitabine. Investig. New Drugs. 2014;32:825–837. doi: 10.1007/s10637-014-0120-7. PubMed DOI PMC

Kim S., Loo A., Chopra R., Caponigro G., Huang A., Vora S., Parasuraman S., Howard S., Keen N., Sellers W., et al. Abstract PR02: LEE011: An Orally Bioavailable, Selective Small Molecule Inhibitor of CDK4/6– Reactivating Rb in Cancer. Mol. Cancer Ther. 2013;12:PR02. doi: 10.1158/1535-7163.TARG-13-PR02. DOI

Vijayaraghavan S., Karakas C., Doostan I., Chen X., Bui T., Yi M., Raghavendra A.S., Zhao Y., Bashour S.I., Ibrahim N.K., et al. CDK4/6 and Autophagy Inhibitors Synergistically Induce Senescence in Rb Positive Cytoplasmic Cyclin E Negative Cancers. Nat. Commun. 2017;8:15916. doi: 10.1038/ncomms15916. PubMed DOI PMC

Goel S., Decristo M.J., Watt A.C., Brinjones H., Sceneay J., Li B.B., Khan N., Ubellacker J.M., Xie S., Metzger-Filho O., et al. CDK4/6 Inhibition Triggers Anti-Tumour Immunity. Nature. 2017;548:471–475. doi: 10.1038/nature23465. PubMed DOI PMC

Anders L., Ke N., Hydbring P., Choi Y.J., Widlund H.R., Chick J.M., Zhai H., Vidal M., Gygi S.P., Braun P., et al. A Systematic Screen for CDK4/6 Substrates Links FOXM1 Phosphorylation to Senescence Suppression in Cancer Cells. Cancer Cell. 2011;20:620–634. doi: 10.1016/j.ccr.2011.10.001. PubMed DOI PMC

Yoshida A., Lee E.K., Diehl J.A. Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. Cancer Res. 2016;76:2990–3002. doi: 10.1158/0008-5472.CAN-15-2931. PubMed DOI PMC

Bollard J., Miguela V., Ruiz De Galarreta M., Venkatesh A., Bian C.B., Roberto M.P., Tovar V., Sia D., Molina-Sánchez P., Nguyen C.B., et al. Palbociclib (PD-0332991), a Selective CDK4/6 Inhibitor, Restricts Tumour Growth in Preclinical Models of Hepatocellular Carcinoma. Gut. 2017;66:1286–1296. doi: 10.1136/gutjnl-2016-312268. PubMed DOI PMC

Rader J., Russell M.R., Hart L.S., Nakazawa M.S., Belcastro L.T., Martinez D., Li Y., Carpenter E.L., Attiyeh E.F., Diskin S.J., et al. Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma. Clin. Cancer Res. 2013;19:6173–6182. doi: 10.1158/1078-0432.CCR-13-1675. PubMed DOI PMC

Valenzuela C.A., Vargas L., Martinez V., Bravo S., Brown N.E. Palbociclib-Induced Autophagy and Senescence in Gastric Cancer Cells. Exp. Cell Res. 2017;360:390–396. doi: 10.1016/j.yexcr.2017.09.031. PubMed DOI

Kovatcheva M., Liao W., Klein M.E., Robine N., Geiger H., Crago A.M., Dickson M.A., Tap W.D., Singer S., Koff A. ATRX Is a Regulator of Therapy Induced Senescence in Human Cells. Nat. Commun. 2017;8:386. doi: 10.1038/s41467-017-00540-5. PubMed DOI PMC

Zhuang C., Miao Z., Wu Y., Guo Z., Li J., Yao J., Xing C., Sheng C., Zhang W. Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit P53-MDM2 Interaction and the NF-ΚB Pathway. J. Med. Chem. 2014;57:567–577. doi: 10.1021/jm401800k. PubMed DOI

Kovatcheva M., Liu D.D., Dickson M.A., Klein M.E., O’Connor R., Wilder F.O., Socci N.D., Tap W.D., Schwartz G.K., Singer S., et al. MDM2 Turnover and Expression of ATRX Determine the Choice between Quiescence and Senescence in Response to CDK4 Inhibition. Oncotarget. 2015;6:8226–8243. doi: 10.18632/oncotarget.3364. PubMed DOI PMC

Wang B., Varela-Eirin M., Brandenburg S.M., Hernandez-Segura A., van Vliet T., Jongbloed E.M., Wilting S.M., Ohtani N., Jager A., Demaria M. Pharmacological CDK4/6 Inhibition Reveals a P53-Dependent Senescent State with Restricted Toxicity. EMBO J. 2022;41:e108946. doi: 10.15252/embj.2021108946. PubMed DOI PMC

Wong C.H., Ma B.B.Y., Hui C.W.C., Lo K.W., Hui E.P., Chan A.T.C. Preclinical Evaluation of Ribociclib and Its Synergistic Effect in Combination with Alpelisib in Non-Keratinizing Nasopharyngeal Carcinoma. Sci. Rep. 2018;8:8010. doi: 10.1038/s41598-018-26201-1. PubMed DOI PMC

Kirkland J.L., Tchkonia T. Senolytic Drugs: From Discovery to Translation. J. Intern. Med. 2020;288:518–536. doi: 10.1111/joim.13141. PubMed DOI PMC

Van Deursen J.M. The Role of Senescent Cells in Ageing. Nature. 2014;509:439–446. doi: 10.1038/nature13193. PubMed DOI PMC

Sikora E., Bielak-Zmijewska A., Mosieniak G. Targeting Normal and Cancer Senescent Cells as a Strategy of Senotherapy. Ageing Res. Rev. 2019;55:100941. doi: 10.1016/j.arr.2019.100941. PubMed DOI

Childs B.G., Durik M., Baker D.J., Van Deursen J.M. Cellular Senescence in Aging and Age-Related Disease: From Mechanisms to Therapy HHS Public Access. Nat. Med. 2015;21:1424–1435. doi: 10.1038/nm.4000. PubMed DOI PMC

Dolgin E. Send in the Senolytics. Nat. Biotechnol. 2020;38:1371–1377. doi: 10.1038/s41587-020-00750-1. PubMed DOI

Childs B.G., Baker D.J., Kirkland J.L., Campisi J., Deursen J.M. Senescence and Apoptosis: Dueling or Complementary Cell Fates? EMBO Rep. 2014;15:1139–1153. doi: 10.15252/embr.201439245. PubMed DOI PMC

Coppé J.P., Rodier F., Patil C.K., Freund A., Desprez P.Y., Campisi J. Tumor Suppressor and Aging Biomarker P16(INK4a) Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype. J. Biol. Chem. 2011;286:36396–36403. doi: 10.1074/jbc.M111.257071. PubMed DOI PMC

Burton D.G.A., Stolzing A. Cellular Senescence: Immunosurveillance and Future Immunotherapy. Ageing Res. Rev. 2018;43:17–25. doi: 10.1016/j.arr.2018.02.001. PubMed DOI

Pellegrini G., Dellambra E., Paterna P., Golisano O., Traverso C.E., Rama P., Lacal P., De Luca M. Telomerase Activity Is Sufficient to Bypass Replicative Senescence in Human Limbal and Conjunctival but Not Corneal Keratinocytes. Eur. J. Cell Biol. 2004;83:691–700. doi: 10.1078/0171-9335-00424. PubMed DOI

Galanos P., Vougas K., Walter D., Polyzos A., Maya-Mendoza A., Haagensen E.J., Kokkalis A., Roumelioti F.M., Gagos S., Tzetis M., et al. Chronic P53-Independent P21 Expression Causes Genomic Instability by Deregulating Replication Licensing. Nat. Cell Biol. 2016;18:777–789. doi: 10.1038/ncb3378. PubMed DOI PMC

Lapasset L., Milhavet O., Prieur A., Besnard E., Babled A., Ät-Hamou N., Leschik J., Pellestor F., Ramirez J.M., De Vos J., et al. Rejuvenating Senescent and Centenarian Human Cells by Reprogramming through the Pluripotent State. Genes Dev. 2011;25:2248–2253. doi: 10.1101/gad.173922.111. PubMed DOI PMC

Patel P.L., Suram A., Mirani N., Bischof O., Herbig U. Derepression of HTERT Gene Expression Promotes Escape from Oncogene-Induced Cellular Senescence. Proc. Natl. Acad. Sci. USA. 2016;113:E5024–E5033. doi: 10.1073/pnas.1602379113. PubMed DOI PMC

Saleh T., Tyutyunyk-Massey L., Gewirtz D.A. Tumor Cell Escape from Therapy-Induced Senescence as a Model of Disease Recurrence after Dormancy. Cancer Res. 2019;79:1044–1046. doi: 10.1158/0008-5472.CAN-18-3437. PubMed DOI

Milanovic M., Fan D.N.Y., Belenki D., Däbritz J.H.M., Zhao Z., Yu Y., Dörr J.R., Dimitrova L., Lenze D., Monteiro Barbosa I.A., et al. Senescence-Associated Reprogramming Promotes Cancer Stemness. Nature. 2017;553:96–100. doi: 10.1038/nature25167. PubMed DOI

Short S., Fielder E., Miwa S., von Zglinicki T. Senolytics and Senostatics as Adjuvant Tumour Therapy. EBioMedicine. 2019;41:683–692. doi: 10.1016/j.ebiom.2019.01.056. PubMed DOI PMC

Carpenter V.J., Saleh T., Gewirtz D.A. Senolytics for Cancer Therapy: Is All That Glitters Really Gold? Cancers. 2021;13:723. doi: 10.3390/cancers13040723. PubMed DOI PMC

Zhu Y., Tchkonia T., Fuhrmann-Stroissnigg H., Dai H.M., Ling Y.Y., Stout M.B., Pirtskhalava T., Giorgadze N., Johnson K.O., Giles C.B., et al. Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors. Aging Cell. 2016;15:428–435. doi: 10.1111/acel.12445. PubMed DOI PMC

Chang J., Wang Y., Shao L., Laberge R.M., Demaria M., Campisi J., Janakiraman K., Sharpless N.E., Ding S., Feng W., et al. Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice. Nat. Med. 2016;22:78–83. doi: 10.1038/nm.4010. PubMed DOI PMC

Kim H.N., Chang J., Shao L., Han L., Iyer S., Manolagas S.C., O’Brien C.A., Jilka R.L., Zhou D., Almeida M. DNA Damage and Senescence in Osteoprogenitors Expressing Osx1 May Cause Their Decrease with Age. Aging Cell. 2017;16:693–703. doi: 10.1111/acel.12597. PubMed DOI PMC

Cang S., Iragavarapu C., Savooji J., Song Y., Liu D. ABT-199 (Venetoclax) and BCL-2 Inhibitors in Clinical Development. J. Hematol. Oncol. 2015;8:129. doi: 10.1186/s13045-015-0224-3. PubMed DOI PMC

Zhu Y., Doornebal E.J., Pirtskhalava T., Giorgadze N., Wentworth M., Fuhrmann-Stroissnigg H., Niedernhofer L.J., Robbins P.D., Tchkonia T., Kirkland J.L. New Agents That Target Senescent Cells: The Flavone, Fisetin, and the BCL-XL Inhibitors, A1331852 and A1155463. Aging. 2017;9:955–963. doi: 10.18632/aging.101202. PubMed DOI PMC

Liu Z., Wild C., Ding Y., Ye N., Chen H., Wold E.A., Zhou J. BH4 Domain of Bcl-2 as a Novel Target for Cancer Therapy. Drug Discov. Today. 2016;21:989–996. doi: 10.1016/j.drudis.2015.11.008. PubMed DOI PMC

Baar M.P., Brandt R.M.C., Putavet D.A., Klein J.D.D., Derks K.W.J., Bourgeois B.R.M., Stryeck S., Rijksen Y., van Willigenburg H., Feijtel D.A., et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017;169:132–147.e16. doi: 10.1016/j.cell.2017.02.031. PubMed DOI PMC

Liu X., Wang Y., Zhang X., Gao Z., Zhang S., Shi P., Zhang X., Song L., Hendrickson H., Zhou D., et al. Senolytic Activity of Piperlongumine Analogues: Synthesis and Biological Evaluation. Bioorg. Med. Chem. 2018;26:3925–3938. doi: 10.1016/j.bmc.2018.06.013. PubMed DOI PMC

Wang Y., Chang J., Liu X., Zhang X., Zhang S., Zhang X., Zhou D., Zheng G. Discovery of Piperlongumine as a Potential Novel Lead for the Development of Senolytic Agents. Aging. 2016;8:2915. doi: 10.18632/aging.101100. PubMed DOI PMC

Zhang X., Zhang S., Liu X., Wang Y., Chang J., Zhang X., Mackintosh S.G., Tackett A.J., He Y., Lv D., et al. Oxidation Resistance 1 Is a Novel Senolytic Target. Aging Cell. 2018;17:12780. doi: 10.1111/acel.12780. PubMed DOI PMC

Samaraweera L., Adomako A., Rodriguez-Gabin A., McDaid H.M. A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC. Sci. Rep. 2017;7:1900. doi: 10.1038/s41598-017-01964-1. PubMed DOI PMC

Zhu Y., Tchkonia T., Pirtskhalava T., Gower A.C., Ding H., Giorgadze N., Palmer A.K., Ikeno Y., Hubbard G.B., Lenburg M., et al. The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. 2015;14:644–658. doi: 10.1111/acel.12344. PubMed DOI PMC

Yousefzadeh M.J., Zhu Y., McGowan S.J., Angelini L., Fuhrmann-Stroissnigg H., Xu M., Ling Y.Y., Melos K.I., Pirtskhalava T., Inman C.L., et al. Fisetin Is a Senotherapeutic That Extends Health and Lifespan. EBioMedicine. 2018;36:18–28. doi: 10.1016/j.ebiom.2018.09.015. PubMed DOI PMC

Tia N., Singh A.K., Pandey P., Azad C.S., Chaudhary P., Gambhir I.S. Role of Forkhead Box O (FOXO) Transcription Factor in Aging and Diseases. Gene. 2018;648:97–105. doi: 10.1016/j.gene.2018.01.051. PubMed DOI

Triana-Martínez F., Picallos-Rabina P., Da Silva-Álvarez S., Pietrocola F., Llanos S., Rodilla V., Soprano E., Pedrosa P., Ferreirós A., Barradas M., et al. Identification and Characterization of Cardiac Glycosides as Senolytic Compounds. Nat. Commun. 2019;10:4731. doi: 10.1038/s41467-019-12888-x. PubMed DOI PMC

Fuhrmann-Stroissnigg H., Ling Y.Y., Zhao J., McGowan S.J., Zhu Y., Brooks R.W., Grassi D., Gregg S.Q., Stripay J.L., Dorronsoro A., et al. Identification of HSP90 Inhibitors as a Novel Class of Senolytics. Nat. Commun. 2017;8:422. doi: 10.1038/s41467-017-00314-z. PubMed DOI PMC

Kang H.T., Park J.T., Choi K., Kim Y., Choi H.J.C., Jung C.W., Lee Y.S., Park S.C. Chemical Screening Identifies ATM as a Target for Alleviating Senescence. Nat. Chem. Biol. 2017;13:616–623. doi: 10.1038/nchembio.2342. PubMed DOI

Salminen A., Kauppinen A., Kaarniranta K. Emerging Role of NF-ΚB Signaling in the Induction of Senescence-Associated Secretory Phenotype (SASP) Cell. Signal. 2012;24:835–845. doi: 10.1016/j.cellsig.2011.12.006. PubMed DOI

Herranz N., Gallage S., Mellone M., Wuestefeld T., Klotz S., Hanley C.J., Raguz S., Acosta J.C., Innes A.J., Banito A., et al. MTOR Regulates MAPKAPK2 Translation to Control the Senescence-Associated Secretory Phenotype. Nat. Cell Biol. 2015;17:1205–1217. doi: 10.1038/ncb3225. PubMed DOI PMC

Laberge R.M., Sun Y., Orjalo A.V., Patil C.K., Freund A., Zhou L., Curran S.C., Davalos A.R., Wilson-Edell K.A., Liu S., et al. MTOR Regulates the Pro-Tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation. Nat. Cell Biol. 2015;17:1049–1061. doi: 10.1038/ncb3195. PubMed DOI PMC

Alimbetov D., Davis T., Brook A.J.C., Cox L.S., Faragher R.G.A., Nurgozhin T., Zhumadilov Z., Kipling D. Suppression of the Senescence-Associated Secretory Phenotype (SASP) in Human Fibroblasts Using Small Molecule Inhibitors of P38 MAP Kinase and MK2. Biogerontology. 2016;17:305. doi: 10.1007/s10522-015-9610-z. PubMed DOI PMC

Wiley C.D., Schaum N., Alimirah F., Lopez-Dominguez J.A., Orjalo A.V., Scott G., Desprez P.Y., Benz C., Davalos A.R., Campisi J. Small-Molecule MDM2 Antagonists Attenuate the Senescence-Associated Secretory Phenotype. Sci. Rep. 2018;8:2410. doi: 10.1038/s41598-018-20000-4. PubMed DOI PMC

Jeon O.H., Kim C., Laberge R.M., Demaria M., Rathod S., Vasserot A.P., Chung J.W., Kim D.H., Poon Y., David N., et al. Local Clearance of Senescent Cells Attenuates the Development of Post-Traumatic Osteoarthritis and Creates a pro-Regenerative Environment. Nat. Med. 2017;23:775–781. doi: 10.1038/nm.4324. PubMed DOI PMC

Moiseeva O., Deschênes-Simard X., St-Germain E., Igelmann S., Huot G., Cadar A.E., Bourdeau V., Pollak M.N., Ferbeyre G. Metformin Inhibits the Senescence-Associated Secretory Phenotype by Interfering with IKK/NF-ΚB Activation. Aging Cell. 2013;12:489–498. doi: 10.1111/acel.12075. PubMed DOI

Pitozzi V., Mocali A., Laurenzana A., Giannoni E., Cifola I., Battaglia C., Chiarugi P., Dolara P., Giovannelli L. Chronic Resveratrol Treatment Ameliorates Cell Adhesion and Mitigates the Inflammatory Phenotype in Senescent Human Fibroblasts. J. Gerontol. A. Biol. Sci. Med. Sci. 2013;68:371–381. doi: 10.1093/gerona/gls183. PubMed DOI

Faget D.V., Ren Q., Stewart S.A. Unmasking Senescence: Context-Dependent Effects of SASP in Cancer. Nat. Rev. Cancer. 2019;19:439–453. doi: 10.1038/s41568-019-0156-2. PubMed DOI

Xu M., Tchkonia T., Ding H., Ogrodnik M., Lubbers E.R., Pirtskhalava T., White T.A., Johnson K.O., Stout M.B., Mezera V., et al. JAK Inhibition Alleviates the Cellular Senescence-Associated Secretory Phenotype and Frailty in Old Age. Proc. Natl. Acad. Sci. USA. 2015;112:E6301–E6310. doi: 10.1073/pnas.1515386112. PubMed DOI PMC

Van Rhee F., Wong R.S., Munshi N., Rossi J.F., Ke X.Y., Fosså A., Simpson D., Capra M., Liu T., Hsieh R.K., et al. Siltuximab for Multicentric Castleman’s Disease: A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Oncol. 2014;15:966–974. doi: 10.1016/S1470-2045(14)70319-5. PubMed DOI

Raffaele M., Kovacovicova K., Biagini T., Lo Re O., Frohlich J., Giallongo S., Nhan J.D., Giannone A.G., Cabibi D., Ivanov M., et al. Nociceptin/Orphanin FQ Opioid Receptor (NOP) Selective Ligand MCOPPB Links Anxiolytic and Senolytic Effects. GeroScience. 2022;44:463–483. doi: 10.1007/s11357-021-00487-y. PubMed DOI PMC

Cochemé H.M., Murphy M.P. Can Antioxidants Be Effective Therapeutics? [(accessed on 20 March 2022)];Curr. Opin. Investig. Drugs. 2010 11:426–431. Available online: https://pubmed.ncbi.nlm.nih.gov/20336590/ PubMed

Firuzi O., Miri R., Tavakkoli M., Saso L. Antioxidant Therapy: Current Status and Future Prospects. Curr. Med. Chem. 2011;18:3871–3888. doi: 10.2174/092986711803414368. PubMed DOI

Bjelakovic G., Nikolova D., Gluud L.L., Simonetti R.G., Gluud C. Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-Analysis. JAMA. 2007;297:842–857. doi: 10.1001/jama.297.8.842. PubMed DOI

Dallner G., Sindelar P.J. Regulation of Ubiquinone Metabolism. Free Radic. Biol. Med. 2000;29:285–294. doi: 10.1016/S0891-5849(00)00307-5. PubMed DOI

Garrido-Maraver J., Cordero M.D., Oropesa-Ávila M., Fernández Vega A., De La Mata M., Delgado Pavón A., De Miguel M., Pérez Calero C., Villanueva Paz M., Cotán D., et al. Coenzyme Q10 Therapy. Mol. Syndromol. 2014;5:187–197. doi: 10.1159/000360101. PubMed DOI PMC

Reeves M.A., Hoffmann P.R. The Human Selenoproteome: Recent Insights into Functions and Regulation. Cell. Mol. Life Sci. 2009;66:2457–2478. doi: 10.1007/s00018-009-0032-4. PubMed DOI PMC

Vinceti M., Bonvicini F., Bergomi M., Malagoli C. Possible Involvement of Overexposure to Environmental Selenium in the Etiology of Amyotrophic Lateral Sclerosis: A Short Review. Ann. Dell’istituto Super. Sanità. 2010;46:279–283. doi: 10.4415/ANN_10_03_09. PubMed DOI

Sanmartin C., Plano D., Font M., Palop J.A. Selenium and Clinical Trials: New Therapeutic Evidence for Multiple Diseases. Curr. Med. Chem. 2011;18:4635–4650. doi: 10.2174/092986711797379249. PubMed DOI

Artero A., Artero A., Tarín J.J., Cano A. The Impact of Moderate Wine Consumption on Health. Maturitas. 2015;80:3–13. doi: 10.1016/j.maturitas.2014.09.007. PubMed DOI

Bouzid M.A., Filaire E., McCall A., Fabre C. Radical Oxygen Species, Exercise and Aging: An Update. Sports Med. 2015;45:1245–1261. doi: 10.1007/s40279-015-0348-1. PubMed DOI

Radak Z., Zhao Z., Koltai E., Ohno H., Atalay M. Oxygen Consumption and Usage during Physical Exercise: The Balance between Oxidative Stress and ROS-Dependent Adaptive Signaling. Antioxid. Redox Signal. 2013;18:1208–1246. doi: 10.1089/ars.2011.4498. PubMed DOI PMC

Battram A.M., Bachiller M., Martín-Antonio B. Senescence in the Development and Response to Cancer with Immunotherapy: A Double-Edged Sword. Int. J. Mol. Sci. 2020;21:4346. doi: 10.3390/ijms21124346. PubMed DOI PMC

Krizhanovsky V., Yon M., Dickins R.A., Hearn S., Simon J., Miething C., Yee H., Zender L., Lowe S.W. Senescence of Activated Stellate Cells Limits Liver Fibrosis. Cell. 2008;134:657–667. doi: 10.1016/j.cell.2008.06.049. PubMed DOI PMC

Sagiv A., Burton D.G.A., Moshayev Z., Vadai E., Wensveen F., Ben-Dor S., Golani O., Polic B., Krizhanovsky V. NKG2D Ligands Mediate Immunosurveillance of Senescent Cells. Aging. 2016;8:328–344. doi: 10.18632/aging.100897. PubMed DOI PMC

Kale A., Sharma A., Stolzing A., Stolzing A., Desprez P.Y., Desprez P.Y., Campisi J., Campisi J. Role of Immune Cells in the Removal of Deleterious Senescent Cells. Immun. Ageing. 2020;17:16. doi: 10.1186/s12979-020-00187-9. PubMed DOI PMC

Ovadya Y., Landsberger T., Leins H., Vadai E., Gal H., Biran A., Yosef R., Sagiv A., Agrawal A., Shapira A., et al. Impaired Immune Surveillance Accelerates Accumulation of Senescent Cells and Aging. Nat. Commun. 2018;9:5435. doi: 10.1038/s41467-018-07825-3. PubMed DOI PMC

Moutsatsou P., Ochs J., Schmitt R.H., Hewitt C.J., Hanga M.P. Automation in Cell and Gene Therapy Manufacturing: From Past to Future. Biotechnol. Lett. 2019;41:1245–1253. doi: 10.1007/s10529-019-02732-z. PubMed DOI PMC

Kang T.W., Yevsa T., Woller N., Hoenicke L., Wuestefeld T., Dauch D., Hohmeyer A., Gereke M., Rudalska R., Potapova A., et al. Senescence Surveillance of Pre-Malignant Hepatocytes Limits Liver Cancer Development. Nature. 2011;479:547–551. doi: 10.1038/nature10599. PubMed DOI

Iannello A., Thompson T.W., Ardolino M., Lowe S.W., Raulet D.H. P53-Dependent Chemokine Production by Senescent Tumor Cells Supports NKG2D-Dependent Tumor Elimination by Natural Killer Cells. J. Exp. Med. 2013;210:2057–2069. doi: 10.1084/jem.20130783. PubMed DOI PMC

Eggert T., Wolter K., Ji J., Ma C., Yevsa T., Klotz S., Medina-Echeverz J., Longerich T., Forgues M., Reisinger F., et al. Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression. Cancer Cell. 2016;30:533–547. doi: 10.1016/j.ccell.2016.09.003. PubMed DOI PMC

Hanahan D., Weinberg R.A. Hallmarks of Cancer: The next Generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. PubMed DOI

Kuilman T., Michaloglou C., Vredeveld L.C.W., Douma S., van Doorn R., Desmet C.J., Aarden L.A., Mooi W.J., Peeper D.S. Oncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network. Cell. 2008;133:1019–1031. doi: 10.1016/j.cell.2008.03.039. PubMed DOI

Acosta J.C., O’Loghlen A., Banito A., Guijarro M.V., Augert A., Raguz S., Fumagalli M., Da Costa M., Brown C., Popov N., et al. Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence. Cell. 2008;133:1006–1018. doi: 10.1016/j.cell.2008.03.038. PubMed DOI

Birch J., Passos J.F. Targeting the SASP to Combat Ageing: Mitochondria as Possible Intracellular Allies? Bioessays. 2017;39:1600235. doi: 10.1002/bies.201600235. PubMed DOI

Sieben C.J., Sturmlechner I., van de Sluis B., van Deursen J.M. Two-Step Senescence-Focused Cancer Therapies. Trends Cell Biol. 2018;28:723–737. doi: 10.1016/j.tcb.2018.04.006. PubMed DOI PMC

Wang L., Leite de Oliveira R., Wang C., Fernandes Neto J.M., Mainardi S., Evers B., Lieftink C., Morris B., Jochems F., Willemsen L., et al. High-Throughput Functional Genetic and Compound Screens Identify Targets for Senescence Induction in Cancer. Cell Rep. 2017;21:773–783. doi: 10.1016/j.celrep.2017.09.085. PubMed DOI

Jochems F., Thijssen B., De Conti G., Jansen R., Pogacar Z., Groot K., Wang L., Schepers A., Wang C., Jin H., et al. The Cancer SENESCopedia: A Delineation of Cancer Cell Senescence. Cell Rep. 2021;36:109441. doi: 10.1016/j.celrep.2021.109441. PubMed DOI PMC

Saleh T., Carpenter V.J., Tyutyunyk-Massey L., Murray G., Leverson J.D., Souers A.J., Alotaibi M.R., Faber A.C., Reed J., Harada H., et al. Clearance of Therapy-Induced Senescent Tumor Cells by the Senolytic ABT-263 via Interference with BCL-X L -BAX Interaction. Mol. Oncol. 2020;14:2504–2519. doi: 10.1002/1878-0261.12761. PubMed DOI PMC

Demaria M., O’Leary M.N., Chang J., Shao L., Liu S., Alimirah F., Koenig K., Le C., Mitin N., Deal A.M., et al. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017;7:165–176. doi: 10.1158/2159-8290.CD-16-0241. PubMed DOI PMC

Wu H., Schiff D.S., Lin Y., Neboori H.J.R., Goyal S., Feng Z., Haffty B.G. Ionizing Radiation Sensitizes Breast Cancer Cells to Bcl-2 Inhibitor, ABT-737, through Regulating Mcl-1. Radiat. Res. 2014;182:618–625. doi: 10.1667/RR13856.1. PubMed DOI PMC

Hann C.L., Daniel V.C., Sugar E.A., Dobromilskaya I., Murphy S.C., Cope L., Lin X., Hierman J.S., Wilburn D.L., Watkins D.N., et al. Therapeutic Efficacy of ABT-737, a Selective Inhibitor of BCL-2, in Small Cell Lung Cancer. Cancer Res. 2008;68:2321–2328. doi: 10.1158/0008-5472.CAN-07-5031. PubMed DOI PMC

González-Gualda E., Pàez-Ribes M., Lozano-Torres B., Macias D., Wilson J.R., González-López C., Ou H.L., Mirón-Barroso S., Zhang Z., Lérida-Viso A., et al. Galacto-Conjugation of Navitoclax as an Efficient Strategy to Increase Senolytic Specificity and Reduce Platelet Toxicity. Aging Cell. 2020;19:e13142. doi: 10.1111/acel.13142. PubMed DOI PMC

Guerrero A., Herranz N., Sun B., Wagner V., Gallage S., Guiho R., Wolter K., Pombo J., Irvine E.E., Innes A.J., et al. Cardiac Glycosides Are Broad-Spectrum Senolytics. Nat. Metab. 2019;1:1074–1088. doi: 10.1038/s42255-019-0122-z. PubMed DOI PMC

Fung A.S., Wu L., Tannock I.F. Concurrent and Sequential Administration of Chemotherapy and the Mammalian Target of Rapamycin Inhibitor Temsirolimus in Human Cancer Cells and Xenografts. Clin. Cancer Res. 2009;15:5389–5395. doi: 10.1158/1078-0432.CCR-08-3007. PubMed DOI

Wang C., Vegna S., Jin H., Benedict B., Lieftink C., Ramirez C., de Oliveira R.L., Morris B., Gadiot J., Wang W., et al. Inducing and Exploiting Vulnerabilities for the Treatment of Liver Cancer. Nature. 2019;574:268–272. doi: 10.1038/s41586-019-1607-3. PubMed DOI PMC

Deng J., Wang E.S., Jenkins R.W., Li S., Dries R., Yates K., Chhabra S., Huang W., Liu H., Aref A.R., et al. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-Cell Activation. Cancer Discov. 2018;8:216–233. doi: 10.1158/2159-8290.CD-17-0915. PubMed DOI PMC

Knudsen E.S., Kumarasamy V., Chung S., Ruiz A., Vail P., Tzetzo S., Wu J., Nambiar R., Sivinski J., Chauhan S.S., et al. Targeting Dual Signalling Pathways in Concert with Immune Checkpoints for the Treatment of Pancreatic Cancer. Gut. 2021;70:127–138. doi: 10.1136/gutjnl-2020-321000. PubMed DOI PMC

Brenner E., Schörg B.F., Ahmetlić F., Wieder T., Hilke F.J., Simon N., Schroeder C., Demidov G., Riedel T., Fehrenbacher B., et al. Cancer Immune Control Needs Senescence Induction by Interferon-Dependent Cell Cycle Regulator Pathways in Tumours. Nat. Commun. 2020;11:1335. doi: 10.1038/s41467-020-14987-6. PubMed DOI PMC

Amor C., Feucht J., Leibold J., Ho Y.J., Zhu C., Alonso-Curbelo D., Mansilla-Soto J., Boyer J.A., Li X., Giavridis T., et al. Senolytic CAR T Cells Reverse Senescence-Associated Pathologies. Nature. 2020;583:127–132. doi: 10.1038/s41586-020-2403-9. PubMed DOI PMC

Agostini A., Mondragõn L., Bernardos A., Martínez-Máñez R., Dolores Marcos M., Sancenõn F., Soto J., Costero A., Manguan-García C., Perona R., et al. Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles. Angew. Chem. Int. Ed. 2012;51:10556–10560. doi: 10.1002/anie.201204663. PubMed DOI

Muñoz-Espín D., Rovira M., Galiana I., Giménez C., Lozano-Torres B., Paez-Ribes M., Llanos S., Chaib S., Muñoz-Martín M., Ucero A.C., et al. A Versatile Drug Delivery System Targeting Senescent Cells. EMBO Mol. Med. 2018;10:e9355. doi: 10.15252/emmm.201809355. PubMed DOI PMC

Thapa R.K., Nguyen H.T., Jeong J.H., Kim J.R., Choi H.G., Yong C.S., Kim J.O. Progressive Slowdown/Prevention of Cellular Senescence by CD9-Targeted Delivery of Rapamycin Using Lactose-Wrapped Calcium Carbonate Nanoparticles. Sci. Rep. 2017;7:43299. doi: 10.1038/srep43299. PubMed DOI PMC

Ke S., Lai Y., Zhou T., Li L., Wang Y., Ren L., Ye S. Molybdenum Disulfide Nanoparticles Resist Oxidative Stress-Mediated Impairment of Autophagic Flux and Mitigate Endothelial Cell Senescence and Angiogenic Dysfunctions. ACS Biomater. Sci. Eng. 2018;4:663–674. doi: 10.1021/acsbiomaterials.7b00714. PubMed DOI

Thoppil H., Riabowol K. Senolytics: A Translational Bridge between Cellular Senescence and Organismal Aging. Front. Cell Dev. Biol. 2020;7:367. doi: 10.3389/fcell.2019.00367. PubMed DOI PMC

Wissler Gerdes E.O., Misra A., Netto J.M.E., Tchkonia T., Kirkland J.L. Strategies for Late Phase Preclinical and Early Clinical Trials of Senolytics. Mech. Ageing Dev. 2021;200:111591. doi: 10.1016/j.mad.2021.111591. PubMed DOI PMC

Najít záznam

Citační ukazatele

Nahrávání dat ...

Možnosti archivace

Nahrávání dat ...