{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:28:35Z","timestamp":1789777715834,"version":"4.0.1"},"reference-count":93,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1132524"],"award-info":[{"award-number":["APP1132524"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1154692"],"award-info":[{"award-number":["APP1154692"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.<\/jats:p>","DOI":"10.3390\/ijms222112078","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T08:05:16Z","timestamp":1636358716000},"page":"12078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Senolytics: A Novel Strategy for Neuroprotection in ALS?"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-1076","authenticated-orcid":false,"given":"Alexandra","family":"Maximova","sequence":"first","affiliation":[{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2008, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eryn L.","family":"Werry","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2008, Australia"},{"name":"Faculty of Science, The University of Sydney, Sydney, NSW 2008, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kassiou","sequence":"additional","affiliation":[{"name":"Faculty of Science, The University of Sydney, Sydney, NSW 2008, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1136\/jnnp.2009.183525","article-title":"Incidence of amyotrophic lateral sclerosis in Europe","volume":"81","author":"Logroscino","year":"2010","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fneur.2019.00068","article-title":"Diagnostic Challenge and Neuromuscular Junction Contribution to ALS Pathogenesis","volume":"10","author":"Campanari","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.tins.2003.11.001","article-title":"Excitotoxic and oxidative cross-talk between motor neurons and glia in ALS pathogenesis","volume":"27","author":"Rao","year":"2004","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/ene.14393","article-title":"Amyotrophic lateral sclerosis: A clinical review","volume":"27","author":"Masrori","year":"2020","journal-title":"Eur. J. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1093\/bmb\/ldw026","article-title":"Pathogenesis of amyotrophic lateral sclerosis","volume":"119","author":"Morgan","year":"2016","journal-title":"Br. Med. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a024125","DOI":"10.1101\/cshperspect.a024125","article-title":"Genetics of Amyotrophic Lateral Sclerosis","volume":"8","author":"Ghasemi","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nrl.2015.12.001","article-title":"Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis","volume":"34","author":"Riancho","year":"2019","journal-title":"Neurologia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11588","DOI":"10.1523\/JNEUROSCI.5385-12.2013","article-title":"Small peptides against the mutant SOD1\/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell viability in mutant SOD1-mediated ALS","volume":"33","author":"Tan","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_9","first-page":"325","article-title":"Nuedexta for the treatment of pseudobulbar affect: A condition of involuntary crying or laughing","volume":"38","author":"Cruz","year":"2013","journal-title":"Pharm. Ther."},{"key":"ref_10","first-page":"S175","article-title":"Edaravone in the treatment of amyotrophic lateral sclerosis: Efficacy and access to therapy\u2014A roundtable discussion","volume":"24","author":"Brooks","year":"2018","journal-title":"Am. J. Manag. Care"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pereira, S.M., Ribeiro, R., and Logarinho, E. (2019). Approaches towards Longevity: Reprogramming, Senolysis, and Improved Mitotic Competence as Anti-Aging Therapies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040938"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12844","DOI":"10.18632\/aging.102557","article-title":"Targeting senescent cells: Approaches, opportunities, challenges","volume":"11","year":"2019","journal-title":"Aging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.bbrc.2010.05.011","article-title":"Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons","volume":"396","author":"Geng","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","article-title":"A Biomarker That Identifies Senescent Human-Cells in Culture and in Aging Skin In-Vivo","volume":"92","author":"Dimri","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1016\/j.neurobiolaging.2014.09.020","article-title":"Astrocytes show reduced support of motor neurons with aging that is accelerated in a rodent model of ALS","volume":"36","author":"Das","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"42","DOI":"10.3389\/fnagi.2019.00042","article-title":"Emergence of Microglia Bearing Senescence Markers During Paralysis Progression in a Rat Model of Inherited ALS","volume":"11","author":"Trias","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.ebiom.2019.11.026","article-title":"Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity","volume":"50","author":"Birger","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1111\/acel.12344","article-title":"The Achilles\u2019 heel of senescent cells: From transcriptome to senolytic drugs","volume":"14","author":"Zhu","year":"2015","journal-title":"Aging Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/S0006-291X(03)00402-9","article-title":"Bcl-2 promotes premature senescence induced by oncogenic Ras","volume":"303","author":"Tombor","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1111\/j.1582-4934.2008.00273.x","article-title":"Heat shock proteins: Essential proteins for apoptosis regulation","volume":"12","author":"Lanneau","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"10761","DOI":"10.1074\/jbc.275.15.10761","article-title":"Akt\/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein","volume":"275","author":"Pugazhenthi","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1038\/sj.cdd.4402166","article-title":"The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis","volume":"14","author":"Hetz","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1016\/j.mcn.2007.01.003","article-title":"Lack of changes in the PI3K\/AKT survival pathway in the spinal cord motor neurons of a mouse model of familial amyotrophic lateral sclerosis","volume":"34","author":"Peviani","year":"2007","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/366704a0","article-title":"A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D\/CDK4","volume":"366","author":"Serrano","year":"1993","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1073\/pnas.1818313116","article-title":"Cells exhibiting strong p16 (INK4a) promoter activation in vivo display features of senescence","volume":"116","author":"Liu","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/nan.12559","article-title":"Expression of p16 and p21 in the frontal association cortex of ALS\/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease","volume":"46","author":"Garwood","year":"2020","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"13742","DOI":"10.1073\/pnas.93.24.13742","article-title":"Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts","volume":"93","author":"Alcorta","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1006\/nbdi.2000.0314","article-title":"p53 is abnormally elevated and active in the CNS of patients with amyotrophic lateral sclerosis","volume":"7","author":"Martin","year":"2000","journal-title":"Neurobiol. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1038\/sj.cdd.4400741","article-title":"The role of p53 in neuronal cell death","volume":"7","author":"Morrison","year":"2000","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.dnarep.2016.04.008","article-title":"Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage","volume":"42","author":"Karimian","year":"2016","journal-title":"DNA Repair"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9660","DOI":"10.1073\/pnas.1002298107","article-title":"Paradoxical suppression of cellular senescence by p53","volume":"107","author":"Demidenko","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.molmed.2010.03.003","article-title":"Inflammatory networks during cellular senescence: Causes and consequences","volume":"16","author":"Freund","year":"2010","journal-title":"Trends Mol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Limbad, C., Oron, T.R., Alimirah, F., Davalos, A.R., Tracy, T.E., Gan, L., Desprez, P.Y., and Campisi, J. (2020). Astrocyte senescence promotes glutamate toxicity in cortical neurons. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227887"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/glia.23298","article-title":"Astrocytes expressing ALS-linked mutant FUS induce motor neuron death through release of tumor necrosis factor-alpha","volume":"66","author":"Kia","year":"2018","journal-title":"Glia"},{"key":"ref_35","first-page":"93","article-title":"Astrocytes in Pathogenesis of ALS Disease and Potential Translation into Clinic","volume":"2018","author":"Michal","year":"2017","journal-title":"Astrocyte Physiol. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1038\/s41467-020-17514-9","article-title":"Knockout of reactive astrocyte activating factors slows disease progression in an ALS mouse model","volume":"11","author":"Guttenplan","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1742-2094-3-2","article-title":"Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation","volume":"3","author":"Hensley","year":"2006","journal-title":"J. Neuroinflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/glia.21167","article-title":"Activation of interferon signaling pathways in spinal cord astrocytes from an ALS mouse model","volume":"59","author":"Wang","year":"2011","journal-title":"Glia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0969-9961(03)00087-1","article-title":"Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis","volume":"14","author":"Hensley","year":"2003","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12974-015-0350-4","article-title":"Humoral factors in ALS patients during disease progression","volume":"12","author":"Ehrhart","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"552295","DOI":"10.3389\/fneur.2020.552295","article-title":"Plasma Inflammatory Cytokines Are Elevated in ALS","volume":"11","author":"Tortelli","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26115","DOI":"10.1074\/jbc.M313509200","article-title":"p53 induces NF-kappaB activation by an IkappaB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1","volume":"279","author":"Bohuslav","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3290","DOI":"10.18632\/aging.202640","article-title":"Suppression of p16 alleviates the senescence-associated secretory phenotype","volume":"13","author":"Buj","year":"2021","journal-title":"Aging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"645593","DOI":"10.3389\/fcell.2021.645593","article-title":"Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype","volume":"9","author":"Kumari","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1096\/fasebj.2020.34.s1.06566","article-title":"Oxidative Stress-Induced Senescence Alters Glutamate Transporter Expression in Human Brainstem Astrocytes","volume":"34","author":"Sivasubramanian","year":"2020","journal-title":"FASEB J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1111\/j.1471-4159.2006.04369.x","article-title":"Astrocytes aged in vitro show a decreased neuroprotective capacity","volume":"101","author":"Pertusa","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neures.2017.09.011","article-title":"The multi-dimensional roles of astrocytes in ALS","volume":"126","author":"Yamanaka","year":"2018","journal-title":"Neurosci. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.bbadis.2012.11.013","article-title":"Role of the N-methyl-D-aspartate receptors complex in amyotrophic lateral sclerosis","volume":"1832","author":"Spalloni","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14825","DOI":"10.1073\/pnas.0705046104","article-title":"Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity","volume":"104","author":"Bogaert","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41586-018-0543-y","article-title":"Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline","volume":"562","author":"Bussian","year":"2018","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e12840","DOI":"10.1111\/acel.12840","article-title":"Tau protein aggregation is associated with cellular senescence in the brain","volume":"17","author":"Musi","year":"2018","journal-title":"Aging Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/s41593-019-0372-9","article-title":"Senolytic therapy alleviates Abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer\u2019s disease model","volume":"22","author":"Zhang","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.celrep.2017.12.092","article-title":"Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson\u2019s Disease","volume":"22","author":"Chinta","year":"2018","journal-title":"Cell Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"14170","DOI":"10.1038\/s41598-020-71042-6","article-title":"Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice","volume":"10","author":"Acklin","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e13296","DOI":"10.1111\/acel.13296","article-title":"Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice","volume":"20","author":"Ogrodnik","year":"2021","journal-title":"Aging Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nature16932","article-title":"Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan","volume":"530","author":"Baker","year":"2016","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1016\/j.cmet.2019.01.013","article-title":"Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis","volume":"29","author":"Ogrodnik","year":"2019","journal-title":"Cell Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10571-015-0242-2","article-title":"Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase","volume":"36","author":"Oh","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"17728","DOI":"10.1038\/s41598-019-53982-w","article-title":"Cromolyn sodium delays disease onset and is neuroprotective in the SOD1(G93A) Mouse Model of amyotrophic lateral sclerosis","volume":"9","author":"Granucci","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cell.2017.05.015","article-title":"Senescence in Health and Disease","volume":"169","author":"He","year":"2017","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/356215a0","article-title":"Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours","volume":"356","author":"Donehower","year":"1992","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1080\/15384101.2018.1475828","article-title":"Hsp90 inhibitors as senolytic drugs to extend healthy aging","volume":"17","author":"Niedernhofer","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10832","DOI":"10.1073\/pnas.170276797","article-title":"Modulation of Akt kinase activity by binding to Hsp90","volume":"97","author":"Sato","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1093\/hmg\/ddn419","article-title":"17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse","volume":"18","author":"Tokui","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1007\/s10072-016-2582-1","article-title":"Elevation of serum heat-shock protein levels in amyotrophic lateral sclerosis","volume":"37","author":"Miyazaki","year":"2016","journal-title":"Neurol. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3389\/fnmol.2017.00123","article-title":"Protein Homeostasis in Amyotrophic Lateral Sclerosis: Therapeutic Opportunities?","volume":"10","author":"Webster","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e21594","DOI":"10.1096\/fj.202002645R","article-title":"Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity","volume":"35","author":"Lin","year":"2021","journal-title":"FASEB J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1750-1326-5-33","article-title":"Phosphorylation regulates proteasomal-mediated degradation and solubility of TAR DNA binding protein-43 C-terminal fragments","volume":"5","author":"Zhang","year":"2010","journal-title":"Mol. Neurodegener."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0898-6568(01)00271-6","article-title":"The protein kinase B\/Akt signaling pathway in human malignancy","volume":"14","author":"Nicholson","year":"2002","journal-title":"Cell. Signal."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1101\/gad.284851.116","article-title":"A senescence secretory switch mediated by PI3K\/AKT\/mTOR activation controls chemoprotective endothelial secretory responses","volume":"30","author":"Bent","year":"2016","journal-title":"Genes Dev."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1038\/onc.2011.394","article-title":"AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: Implications for targeting mTOR during malignancy","volume":"31","author":"Astle","year":"2012","journal-title":"Oncogene"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11010-016-2796-9","article-title":"The PI3K\/Akt\/mTOR pathway regulates the replicative senescence of human VSMCs","volume":"422","author":"Tan","year":"2016","journal-title":"Mol. Cell. Biochem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep24049","article-title":"Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis","volume":"6","author":"Srivastava","year":"2016","journal-title":"Sci Rep."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Liu, J., Zhang, Y., Liu, A., Wang, J., Li, L., Chen, X., Gao, X., Xue, Y., Zhang, X., and Liu, Y. (2016). Distinct Dasatinib-Induced Mechanisms of Apoptotic Response and Exosome Release in Imatinib-Resistant Human Chronic Myeloid Leukemia Cells. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17040531"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.neuropharm.2015.01.027","article-title":"The flavonoid quercetin ameliorates Alzheimer\u2019s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer\u2019s disease model mice","volume":"93","author":"Osorio","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"131","DOI":"10.5581\/1516-8484.20110034","article-title":"Dasatinib: Clinical trials and management of adverse events in imatinib resistant\/intolerant chronic myeloid leukemia","volume":"33","author":"Conchon","year":"2011","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e000392","DOI":"10.1136\/bmjresp-2018-000392","article-title":"Randomised clinical trial to determine the safety of quercetin supplementation in patients with chronic obstructive pulmonary disease","volume":"7","author":"Han","year":"2020","journal-title":"BMJ Open Respir. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.mcn.2015.08.009","article-title":"Downregulated AEG-1 together with inhibited PI3K\/Akt pathway is associated with reduced viability of motor neurons in an ALS model","volume":"68","author":"Yin","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s12035-013-8507-6","article-title":"Specific induction of Akt3 in spinal cord motor neurons is neuroprotective in a mouse model of familial amyotrophic lateral sclerosis","volume":"49","author":"Peviani","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2016.06.043","article-title":"scAAV9-VEGF prolongs the survival of transgenic ALS mice by promoting activation of M2 microglia and the PI3K\/Akt pathway","volume":"1648","author":"Wang","year":"2016","journal-title":"Brain Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jnr.21503","article-title":"Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation","volume":"86","author":"Bureau","year":"2008","journal-title":"J. Neurosci. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.brainresbull.2007.01.016","article-title":"Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: Implications in neuroprotection","volume":"73","author":"Sharma","year":"2007","journal-title":"Brain Res. Bull."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.cellbi.2007.04.009","article-title":"Antioxidative and prooxidative effects of quercetin on A549 cells","volume":"31","author":"Robaszkiewicz","year":"2007","journal-title":"Cell Biol. Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6819","DOI":"10.1021\/jm060727j","article-title":"2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor","volume":"49","author":"Das","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.biopha.2016.10.011","article-title":"Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions","volume":"84","author":"Suganthy","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1182\/blood-2008-02-140665","article-title":"Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia","volume":"112","author":"Porkka","year":"2008","journal-title":"Blood"},{"key":"ref_87","unstructured":"(2021, September 01). Clinical Trials, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04063124."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1111\/acel.12445","article-title":"Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors","volume":"15","author":"Zhu","year":"2016","journal-title":"Aging Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"955","DOI":"10.18632\/aging.101202","article-title":"New agents that target senescent cells: The flavone, fisetin, and the BCL-X-L inhibitors, A1331852 and A1155463","volume":"9","author":"Zhu","year":"2017","journal-title":"Aging"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"564108","DOI":"10.3389\/fphar.2020.564108","article-title":"Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent","volume":"11","author":"Anuar","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.3109\/10428194.2015.1030638","article-title":"A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia","volume":"56","author":"Kipps","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"11190","DOI":"10.1038\/ncomms11190","article-title":"Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL","volume":"7","author":"Yosef","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.1093\/hmg\/ddq202","article-title":"ALS-linked mutant SOD1 damages mitochondria by promoting conformational changes in Bcl-2","volume":"19","author":"Pedrini","year":"2010","journal-title":"Hum. Mol. Genet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/12078\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:27:36Z","timestamp":1760167656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/21\/12078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,8]]},"references-count":93,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222112078"],"URL":"https:\/\/doi.org\/10.3390\/ijms222112078","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,8]]}}}