{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:16:39Z","timestamp":1791414999992,"version":"4.3.3"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS). Age is the strongest predictor of disease phenotype, with the majority of older adults transitioning to a progressive form marked by irreversible neurological decline. This clinical progression is associated with smoldering, CNS-compartmentalized inflammation and neurodegeneration, for which there are currently no effective disease-modifying therapies. Cellular senescence, characterized by the secretion of pro-inflammatory mediators collectively known as the senescence-associated secretory phenotype (SASP), increases with age and contributes to tissue injury. In MS, neuroinflammation can further promote cellular senescence, creating a self-reinforcing cycle of damage. Senescent microglia have been identified within MS lesions, where their SASP may impair remyelination and exacerbate neurodegeneration. Senolytic agents selectively target and eliminate senescent cells by disrupting anti-apoptotic pathways. In experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, senolytic treatment reduces senescent microglia burden and attenuates disease severity in an age- and drug-dependent manner. Specifically, here we show that middle-aged mice (40\u201344 weeks) with EAE exhibit improved clinical outcomes and survival following treatment with either dasatinib plus quercetin (D+Q) or navitoclax. Early-phase clinical trials of senolytics in age-related diseases have demonstrated functional benefits, including improved gait speed in idiopathic pulmonary fibrosis and CNS penetrance in Alzheimer\u2019s disease. Translating senolytic therapy to MS will require careful selection of CNS-penetrant and well-tolerated agents, identification of appropriate patient populations, and deployment of responsive biomarkers. Senolytic therapy represents a promising geroscience-based strategy to meet the urgent therapeutic need in progressive MS.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1681724","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T04:13:46Z","timestamp":1759810426000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach"],"prefix":"10.3389","volume":"16","author":[{"given":"Jeffrey","family":"Atkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Dokiburra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley","family":"Groover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Godbout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Segal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007035","article-title":"The prevalence of MS in the United States: A population-based estimate using health claims data","volume":"92","author":"Wallin","year":"2019","journal-title":"Neurology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10147","article-title":"Age-related disability in multiple sclerosis","volume":"51","author":"Trojano","year":"2002","journal-title":"Ann Neurol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1093\/brain\/awh714","article-title":"Age at disability milestones in multiple sclerosis","volume":"129","author":"Confavreux","year":"2006","journal-title":"Brain"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318230a17d","article-title":"Age and disability accumulation in multiple sclerosis","volume":"77","author":"Scalfari","year":"2011","journal-title":"Neurology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/1352458516630396","article-title":"The relationship of age with the clinical phenotype in multiple sclerosis","volume":"22","author":"Scalfari","year":"2016","journal-title":"Mult Scler"},{"key":"B6","doi-asserted-by":"publisher","first-page":"17562864211006499","DOI":"10.1177\/17562864211006499","article-title":"Disease-modifying therapy prescription patterns in people with multiple sclerosis by age","volume":"14","author":"Zhang","year":"2021","journal-title":"Ther Adv Neurol Disord"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/112.1.133","article-title":"The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability","volume":"112","author":"Weinshenker","year":"1989","journal-title":"Brain"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2012.168","article-title":"Progressive multiple sclerosis: pathology and pathogenesis","volume":"8","author":"Lassmann","year":"2012","journal-title":"Nat Rev Neurol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/S1474-4422(24)00027-9","article-title":"Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges","volume":"23","author":"Chataway","year":"2024","journal-title":"Lancet Neurol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.854390","article-title":"Efficacy of disease modifying therapies in progressive MS and how immune senescence may explain their failure","volume":"13","author":"Manouchehri","year":"2022","journal-title":"Front Neurol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41580-020-00314-w","article-title":"Cellular senescence in ageing: from mechanisms to therapeutic opportunities","volume":"22","author":"Di Micco","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nat Cell Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3823","article-title":"Cellular senescence: from physiology to pathology","volume":"15","author":"Munoz-Espin","year":"2014","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afad127","article-title":"New Horizons in cellular senescence for clinicians","volume":"52","author":"Witham","year":"2023","journal-title":"Age Ageing"},{"key":"B15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/S1474-4422(22)00184-3","article-title":"Ageing and multiple sclerosis","volume":"22","author":"Graves","year":"2023","journal-title":"Lancet Neurol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"111366","DOI":"10.1016\/j.mad.2020.111366","article-title":"Cellular senescence and failure of myelin repair in multiple sclerosis","volume":"192","author":"Koutsoudaki","year":"2020","journal-title":"Mech Ageing Dev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19102937","article-title":"Ageing, cellular senescence and neurodegenerative disease","volume":"19","author":"Kritsilis","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2020.00178","article-title":"Aging, cellular senescence, and progressive multiple sclerosis","volume":"14","author":"Papadopoulos","year":"2020","journal-title":"Front Cell Neurosci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818348116","article-title":"Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis","volume":"116","author":"Nicaise","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/ana.27195","article-title":"Accelerated cellular senescence in progressive multiple sclerosis: A histopathological study","volume":"97","author":"Papadopoulos","year":"2025","journal-title":"Ann Neurol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-13-0350","article-title":"The molecular balancing act of p16(INK4a) in cancer and aging","volume":"12","author":"LaPak","year":"2014","journal-title":"Mol Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2009.00489.x","article-title":"Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging","volume":"8","author":"Liu","year":"2009","journal-title":"Aging Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03892-7","article-title":"A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis","volume":"597","author":"Absinta","year":"2021","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s42003-023-05027-2","article-title":"Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype","volume":"6","author":"Matsudaira","year":"2023","journal-title":"Commun Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.158153","article-title":"Biological aging of CNS-resident cells alters the clinical course and immunopathology of autoimmune demyelinating disease","volume":"7","author":"Atkinson","year":"2022","journal-title":"JCI Insight"},{"key":"B26","doi-asserted-by":"publisher","first-page":"2283","DOI":"10.1038\/s41467-025-57632-w","article-title":"Senescent-like microglia limit remyelination through the senescence associated secretory phenotype","volume":"16","author":"Gross","year":"2025","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.clim.2016.09.010","article-title":"An emerging role for eotaxins in neurodegenerative disease","volume":"189","author":"Huber","year":"2018","journal-title":"Clin Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1124\/jpet.114.213074","article-title":"Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells","volume":"349","author":"Erickson","year":"2014","journal-title":"J Pharmacol Exp Ther"},{"key":"B29","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/s42003-024-06263-w","article-title":"Replication stress as a driver of cellular senescence and aging","volume":"7","author":"Herr","year":"2024","journal-title":"Commun Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13080","article-title":"Measuring biological aging in humans: A quest","volume":"19","author":"Ferrucci","year":"2020","journal-title":"Aging Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1177\/1352458512451510","article-title":"Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis","volume":"19","author":"Tutuncu","year":"2013","journal-title":"Mult Scler"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01923-y","article-title":"Cellular senescence and senolytics: the path to the clinic","volume":"28","author":"Chaib","year":"2022","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.12440","article-title":"Aging, cell senescence, and chronic disease: emerging therapeutic strategies","volume":"320","author":"Tchkonia","year":"2018","journal-title":"JAMA"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdm223","article-title":"Dasatinib: a new step in molecular target therapy","author":"Olivieri","year":"2007","journal-title":"Ann Oncol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-3-642-54490-3_2","article-title":"Dasatinib","volume":"201","author":"Lindauer","year":"2014","journal-title":"Recent Results Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"115071","DOI":"10.1016\/j.biopha.2023.115071","article-title":"Quercetin inhibits DNA damage responses to induce apoptosis via SIRT5\/PI3K\/AKT pathway in non-small cell lung cancer","volume":"165","author":"Zhou","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B37","doi-asserted-by":"publisher","first-page":"69","DOI":"10.4196\/kjpp.2020.24.1.69","article-title":"Quercetin-induced apoptosis ameliorates vascular smooth muscle cell senescence through AMP-activated protein kinase signaling pathway","volume":"24","author":"Kim","year":"2020","journal-title":"Korean J Physiol Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","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":"B40","doi-asserted-by":"publisher","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":"B41","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12974-025-03425-3","article-title":"Senescent cell reduction does not improve recovery in mice under experimental autoimmune encephalomyelitis (EAE) induced demyelination","volume":"22","author":"Manavi","year":"2025","journal-title":"J Neuroinflammation"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-023-00843-0","article-title":"Sexual dimorphic metabolic and cognitive responses of C57BL\/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment","volume":"45","author":"Fang","year":"2023","journal-title":"Geroscience"},{"key":"B43","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.immuni.2018.02.014","article-title":"High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease","volume":"48","author":"Mrdjen","year":"2018","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-024-01620-8","article-title":"Identification of senescent, TREM2-expressing microglia in aging and Alzheimer\u2019s disease model mouse brain","volume":"27","author":"Rachmian","year":"2024","journal-title":"Nat Neurosci"},{"key":"B45","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1186\/s12974-024-03278-2","article-title":"Senolytic treatment diminishes microglia and decreases severity of experimental autoimmune encephalomyelitis","volume":"21","author":"Drake","year":"2024","journal-title":"J Neuroinflammation"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.12.052","article-title":"Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study","volume":"40","author":"Justice","year":"2019","journal-title":"EBioMedicine"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02543-w","article-title":"Senolytic therapy in mild Alzheimer\u2019s disease: a phase 1 feasibility trial","volume":"29","author":"Gonzales","year":"2023","journal-title":"Nat Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03096-2","article-title":"Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial","volume":"30","author":"Farr","year":"2024","journal-title":"Nat Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13141","article-title":"Senolytic drugs: from discovery to translation","volume":"288","author":"Kirkland","year":"2020","journal-title":"J Intern Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.04.013","article-title":"Cellular senescence: A translational perspective","volume":"21","author":"Kirkland","year":"2017","journal-title":"EBioMedicine"},{"key":"B51","doi-asserted-by":"publisher","first-page":"14532","DOI":"10.1038\/ncomms14532","article-title":"Cellular senescence mediates fibrotic pulmonary disease","volume":"8","author":"Schafer","year":"2017","journal-title":"Nat Commun"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.08.069","article-title":"Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus Quercetin in individuals with diabetic kidney disease","volume":"47","author":"Hickson","year":"2019","journal-title":"EBioMedicine"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14489","article-title":"Characterization of human senescent cell biomarkers for clinical trials","volume":"2025","author":"Farr","year":"2025","journal-title":"Aging Cell"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64098","article-title":"Cellular senescence and the senescent secretory phenotype: therapeutic opportunities","volume":"123","author":"Tchkonia","year":"2013","journal-title":"J Clin Invest"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00738-8","article-title":"SenNet recommendations for detecting senescent cells in different tissues","volume":"25","author":"Suryadevara","year":"2024","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100991","article-title":"Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells","volume":"8","author":"Hall","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"B57","doi-asserted-by":"publisher","first-page":"104179","DOI":"10.1016\/j.ebiom.2022.104179","article-title":"Immune aging in multiple sclerosis is characterized by abnormal CD4 T cell activation and increased frequencies of cytotoxic CD4 T cells with advancing age","volume":"82","author":"Zuroff","year":"2022","journal-title":"EBioMedicine"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-804766-8.00032-7","article-title":"The evolution of geriatric neurology","volume":"167","author":"DeKosky","year":"2019","journal-title":"Handb Clin Neurol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.16056","article-title":"Translational geroscience: challenges and opportunities for geriatric medicine","volume":"67","author":"Gill","year":"2019","journal-title":"J Am Geriatr Soc"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681724\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T04:13:46Z","timestamp":1759810426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681724\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2025.1681724"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1681724","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"article-number":"1681724"}}