{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:54:21Z","timestamp":1791377661276,"version":"4.3.2"},"reference-count":203,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease where chronological aging predicts the conversion to progressive MS (PMS), a phase defined by compartmentalized inflammation and accelerated neurodegeneration. While current disease modifying therapies (DMTs) are effective for managing the inflammatory aspect of MS, treatments remain inadequate. It is imperative to understand the biology of aging including an important hallmark of aging, cellular senescence. Cellular senescence is a state of cell cycle arrest where cells remain in their senescent state and produce a distinctive senescence-associated secretory phenotype (SASP), characterized by the release of pro-inflammatory cytokines, chemokines, and growth factors. Growing experimental and clinical evidence suggests that the accumulation of senescent cells and SASP secretion perpetuates a pathological feedback loop linking age-related processes with accelerated neurodegeneration observed in PMS. Whether senescence drives PMS or accompanies it remains unresolved. In this Review, we outline the biology of aging, senescence pathway markers, and SASP components. We evaluate studies of cellular senescence and SASP markers in MS, including immunosenescence, T- and B-cell changes; the contributions of Epstein-Barr virus, cytomegalovirus, and herpes simplex virus-1; and the relationship between senescence burden, brain atrophy, and DMT response. Lastly, we outline the available senotherapeutic approaches aimed at mitigating MS and other neurodegenerative diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1944657","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:57:50Z","timestamp":1791374270000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular senescence in multiple sclerosis: hallmarks, immunosenescence, and therapeutic implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Ala\u2019","family":"Yousef","sequence":"first","affiliation":[{"name":"Department of Medicine (Neurology), Faculty of Medicine and Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Multiple Sclerosis Centre, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Seubert","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Power","sequence":"additional","affiliation":[{"name":"Department of Medicine (Neurology), Faculty of Medicine and Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Multiple Sclerosis Centre, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabeela","family":"Nathoo","sequence":"additional","affiliation":[{"name":"Department of Medicine (Neurology), Faculty of Medicine and Dentistry, University of Alberta","place":["Edmonton, AB, Canada"]},{"name":"Multiple Sclerosis Centre, University of Alberta","place":["Edmonton, AB, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"B1","volume-title":"Atlas of MS 3rd Edition: Mapping Multiple Sclerosis Around the World","author":"King","year":"2020"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000622","article-title":"Multiple sclerosis: clinical aspects","volume":"31","author":"Oh","year":"2018","journal-title":"Curr Opin Neurol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/ana.24747","article-title":"Long-term evolution of multiple sclerosis disability in the treatment era","volume":"80","author":"Cree","year":"2016","journal-title":"Ann Neurol"},{"key":"B4","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":"B5","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":"B6","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":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.07.024","article-title":"Ageing as a risk factor for disease","volume":"22","author":"Niccoli","year":"2012","journal-title":"Curr Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1177\/13524585231204122","article-title":"Biological aging in multiple sclerosis","volume":"29","author":"Zhang","year":"2023","journal-title":"Mult Scler"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Lopez-Otin","year":"2013","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Lopez-Otin","year":"2023","journal-title":"Cell"},{"key":"B11","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":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4000","article-title":"Cellular senescence in aging and age-related disease: from mechanisms to therapy","volume":"21","author":"Childs","year":"2015","journal-title":"Nat Med"},{"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":"10.1016\/j.devcel.2014.11.012","article-title":"An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA","volume":"31","author":"Demaria","year":"2014","journal-title":"Dev Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/s41420-025-02720-5","article-title":"The role of cellular senescence in cardiovascular disease","volume":"11","author":"Xu","year":"2025","journal-title":"Cell Death Discov"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14532","article-title":"Cellular senescence mediates fibrotic pulmonary disease","volume":"8","author":"Schafer","year":"2017","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-025-01814-3","article-title":"Alterations in mitochondria and cellular senescence in aged sEH null female kidneys","volume":"48","author":"Yousef","year":"2026","journal-title":"Geroscience"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045069","article-title":"Astrocyte senescence as a component of Alzheimer's disease","volume":"7","author":"Bhat","year":"2012","journal-title":"PloS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The serial cultivation of human diploid cell strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp Cell Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/345458a0","article-title":"Telomeres shorten during ageing of human fibroblasts","volume":"345","author":"Harley","year":"1990","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.24.11190","article-title":"Telomere length and replicative aging in human vascular tissues","volume":"92","author":"Chang","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.18.6622","article-title":"A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes","volume":"85","author":"Moyzis","year":"1988","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz6876","article-title":"Determinants of telomere length across human tissues","volume":"369","author":"Demanelis","year":"2020","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.10.028","article-title":"Short telomeres are sufficient to cause the degenerative defects associated with aging","volume":"85","author":"Armanios","year":"2009","journal-title":"Am J Hum Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2011.08.003","article-title":"Telomeres and lifestyle factors: roles in cellular aging","volume":"730","author":"Lin","year":"2012","journal-title":"Mutat Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/brv.70152","article-title":"The ageing holobiont: crosstalk between telomere dynamics, oxidative stress and the gut microbiome","volume":"101","author":"Pepke","year":"2026","journal-title":"Biol Rev Camb Philos Soc"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2466","article-title":"Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation","volume":"14","author":"Fumagalli","year":"2012","journal-title":"Nat Cell Biol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"24","DOI":"10.15761\/MRI.1000149","article-title":"Senescence, oxidative stress and mitochondria dysfunction","volume":"21","author":"Zhu","year":"2018","journal-title":"Med Res Innov"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00706.2023","article-title":"Cardioprotective response and senescence in aged sEH null female mice exposed to LPS","volume":"326","author":"Yousef","year":"2024","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2020.151108","article-title":"Aging of the cells: Insight into cellular senescence and detection Methods","volume":"99","author":"Mohamad Kamal","year":"2020","journal-title":"Eur J Cell Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2233","article-title":"Cellular senescence: when bad things happen to good cells","volume":"8","author":"Campisi","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.tins.2019.11.005","article-title":"Fiery cell death: Pyroptosis in the central nervous system","volume":"43","author":"McKenzie","year":"2020","journal-title":"Trends Neurosci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: Gasdermin-mediated programmed necrotic cell death","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2970","article-title":"Molecular mechanisms of necroptosis: an ordered cellular explosion","volume":"11","author":"Vandenabeele","year":"2010","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.arr.2015.04.002","article-title":"Programmed cell death in aging","volume":"23","author":"Tower","year":"2015","journal-title":"Ageing Res Rev"},{"key":"B37","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":"B38","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":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/biom10030420","article-title":"Role of p53 in the regulation of cellular senescence","volume":"10","author":"Mijit","year":"2020","journal-title":"Biomolecules"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/s0955-0674(03)00003-6","article-title":"Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation","volume":"15","author":"Brooks","year":"2003","journal-title":"Curr Opin Cell Biol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(91)90453-2","article-title":"A role for both RB and p53 in the regulation of human cellular senescence","volume":"196","author":"Shay","year":"1991","journal-title":"Exp Cell Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/genes11060593","article-title":"CDK-independent and PCNA-dependent functions of p21 in DNA replication","volume":"11","author":"Mansilla","year":"2020","journal-title":"Genes (Basel)"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27316","article-title":"Cellular senescence and tumor suppressor gene p16","volume":"130","author":"Rayess","year":"2012","journal-title":"Int J Cancer"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95148","article-title":"Mechanisms and functions of cellular senescence","volume":"128","author":"Herranz","year":"2018","journal-title":"J Clin Invest"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/s0047-6374(99)00031-7","article-title":"Does pH 6 \u03b2-galactosidase activity indicate cell senescence","volume":"109","author":"Krishna","year":"1999","journal-title":"Mech Ageing Dev"},{"key":"B46","doi-asserted-by":"publisher","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"},{"key":"B47","doi-asserted-by":"publisher","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":"B48","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cyto.2019.01.013","article-title":"The senescence-associated secretory phenotype and its regulation","volume":"117","author":"Lopes-Paciencia","year":"2019","journal-title":"Cytokine"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa728","article-title":"New horizons: Novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms","volume":"106","author":"Tchkonia","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00586-18","article-title":"Uncoupling the senescence-associated secretory phenotype from cell cycle exit via interleukin-1 inactivation unveils its protumorigenic role","volume":"39","author":"Lau","year":"2019","journal-title":"Mol Cell Biol"},{"key":"B51","doi-asserted-by":"publisher","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's disease","volume":"22","author":"Chinta","year":"2018","journal-title":"Cell Rep"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-019-00100-3","article-title":"Astrocyte senescence may drive alterations in GFAPalpha, CDKN2A p14(ARF), and TAU3 transcript expression and contribute to cognitive decline","volume":"41","author":"Lye","year":"2019","journal-title":"Geroscience"},{"key":"B53","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1038\/s41467-025-68118-0","article-title":"Brain and neural cell type proteomics reveal extracellular matrix proteins enriched in progressive multiple sclerosis","volume":"17","author":"Wang","year":"2026","journal-title":"Nat Commun"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/61.10.914","article-title":"Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats","volume":"61","author":"Proescholdt","year":"2002","journal-title":"J Neuropathol Exp Neurol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000675","article-title":"Growth differentiation factor 15 is increased in stable MS","volume":"7","author":"Amstad","year":"2020","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201747442","article-title":"Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment","volume":"48","author":"Grist","year":"2018","journal-title":"Eur J Immunol"},{"key":"B57","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":"B58","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1040885","article-title":"Multiple sclerosis: lessons from neuropathology","volume":"18","author":"Lucchinetti","year":"1998","journal-title":"Semin Neurol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1177\/1352458518814117","article-title":"Slowly expanding\/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions","volume":"25","author":"Elliott","year":"2019","journal-title":"Mult Scler"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24497","article-title":"Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque","volume":"78","author":"Frischer","year":"2015","journal-title":"Ann Neurol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa158","article-title":"Molecular signature of slowly expanding lesions in progressive multiple sclerosis","volume":"143","author":"Jackle","year":"2020","journal-title":"Brain"},{"key":"B62","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/s41582-021-00581-x","article-title":"Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis","volume":"18","author":"Yong","year":"2022","journal-title":"Nat Rev Neurol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000001139","article-title":"Slowly expanding lesions predict 9-year multiple sclerosis disease progression","volume":"9","author":"Preziosa","year":"2022","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1177\/17562864211066751","article-title":"Smouldering multiple sclerosis: the 'real MS'","volume":"15","author":"Giovannoni","year":"2022","journal-title":"Ther Adv Neurol Disord"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23137273","article-title":"Oxidative stress in ageing and chronic degenerative pathologies: molecular mechanisms involved in counteracting oxidative stress and chronic inflammation","volume":"23","author":"Leyane","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B66","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":"B67","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 USA"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.2775","article-title":"Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF) and blood reveals new candidate genes for multiple sclerosis","volume":"4","author":"Safari-Alighiarloo","year":"2016","journal-title":"PeerJ"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1242\/bio.059845","article-title":"Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect","volume":"12","author":"Daviaud","year":"2023","journal-title":"Biol Open"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.18632\/aging.103612","article-title":"Signatures of cell stress and altered bioenergetics in skin fibroblasts from patients with multiple sclerosis","volume":"12","author":"Wilkins","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.09.022","article-title":"Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis","volume":"113","author":"Park","year":"2025","journal-title":"Neuron"},{"key":"B72","doi-asserted-by":"publisher","first-page":"8477","DOI":"10.1038\/s41467-025-63371-9","article-title":"Spatially-restricted inflammation-induced senescent-like glia in multiple sclerosis and patient-derived organoids","volume":"16","author":"Fagiani","year":"2025","journal-title":"Nat Commun"},{"key":"B73","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/s12883-025-04145-0","article-title":"Intrathecal interleukin-6 levels are associated with progressive disease and clinical severity in multiple sclerosis","volume":"25","author":"Itorralba","year":"2025","journal-title":"BMC Neurol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25137399","article-title":"Cytokine profiling in cerebrospinal fluid of patients with newly diagnosed relapsing-remitting multiple sclerosis (RRMS): associations between inflammatory biomarkers and disease activity","volume":"25","author":"Gebka-Kepinska","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.633167","article-title":"Immune soluble factors in the cerebrospinal fluid of progressive multiple sclerosis patients segregate into two groups","volume":"12","author":"Donninelli","year":"2021","journal-title":"Front Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.06.012","article-title":"A meta-analysis of cytokines in Alzheimer's disease","volume":"68","author":"Swardfager","year":"2010","journal-title":"Biol Psychiatry"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02122","article-title":"Cerebrospinal fluid inflammatory cytokine aberrations in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis: a systematic review and meta-analysis","volume":"9","author":"Chen","year":"2018","journal-title":"Front Immunol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1104393","article-title":"Serum inflammatory cytokines levels and the correlation analyses in Parkinson's disease","volume":"11","author":"Fu","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnha.2025.100561","article-title":"Plasma senescence associated secretory proteins: a new link to mild cognitive impairment","volume":"29","author":"Banarjee","year":"2025","journal-title":"J Nutr Health Aging"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-024-03768-5","article-title":"The role of cellular senescence in neurodegenerative diseases","volume":"98","author":"Wang","year":"2024","journal-title":"Arch Toxicol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.10.3742-3751.2000","article-title":"Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury","volume":"20","author":"Hsiao","year":"2000","journal-title":"Mol Cell Biol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1080\/10408363.2019.1615034","article-title":"Growth differentiation factor 15: a novel biomarker with high clinical potential","volume":"56","author":"Desmedt","year":"2019","journal-title":"Crit Rev Clin Lab Sci"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148709","article-title":"GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction","volume":"11","author":"Montero","year":"2016","journal-title":"PloS One"},{"key":"B84","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/ggi.12724","article-title":"Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders","volume":"16","author":"Fujita","year":"2016","journal-title":"Geriatr Gerontol Int"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24506","article-title":"Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders","volume":"78","author":"Yatsuga","year":"2015","journal-title":"Ann Neurol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2023.578268","article-title":"Biomarkers of disability worsening in inactive primary progressive multiple sclerosis","volume":"387","author":"Baeva","year":"2024","journal-title":"J Neuroimmunol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2019.116429","article-title":"GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis","volume":"405","author":"Nohara","year":"2019","journal-title":"J Neurol Sci"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000001094","article-title":"Evaluation of age-dependent immune signatures in patients with multiple sclerosis","volume":"8","author":"Eschborn","year":"2021","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-021-08899-6","article-title":"Immunology of aging: the birth of inflammaging","volume":"64","author":"Fulop","year":"2023","journal-title":"Clin Rev Allergy Immunol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2023.1234572","article-title":"Immunosenescence and multiple sclerosis: inflammaging for prognosis and therapeutic consideration","volume":"4","author":"Thakolwiboon","year":"2023","journal-title":"Front Aging"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006","article-title":"Molecular signature of CD8+ T cell exhaustion during chronic viral infection","volume":"27","author":"Wherry","year":"2007","journal-title":"Immunity"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2019.100998","article-title":"Activation of immunosuppressive network in the aging process","volume":"57","author":"Salminen","year":"2020","journal-title":"Ageing Res Rev"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.11.7446","article-title":"The influence of age on T cell generation and TCR diversity","volume":"174","author":"Naylor","year":"2005","journal-title":"J Immunol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/s0047-6374(97)00161-9","article-title":"Functional properties of CD4+ CD28- T cells in the aging immune system","volume":"102","author":"Weyand","year":"1998","journal-title":"Mech Ageing Dev"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12675","article-title":"Human CD8(+) EMRA T cells display a senescence-associated secretory phenotype regulated by p38 MAPK","volume":"17","author":"Callender","year":"2018","journal-title":"Aging Cell"},{"key":"B97","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1146\/annurev.immunol.23.021704.115707","article-title":"Immunology of multiple sclerosis","volume":"23","author":"Sospedra","year":"2005","journal-title":"Annu Rev Immunol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1361.066","article-title":"Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients","volume":"1051","author":"Thewissen","year":"2005","journal-title":"Ann N Y Acad Sci"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2014.07.013","article-title":"IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: current and future developments","volume":"25","author":"Luchtman","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"key":"B100","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/jnr.20522","article-title":"Decreased FOXP3 levels in multiple sclerosis patients","volume":"81","author":"Huan","year":"2005","journal-title":"J Neurosci Res"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502448","article-title":"Age-associated B cells with proinflammatory characteristics are expanded in a proportion of multiple sclerosis patients","volume":"197","author":"Claes","year":"2016","journal-title":"J Immunol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2010.12.007","article-title":"Reduced thymic output and peripheral naive CD4 T-cell alterations in primary progressive multiple sclerosis (PPMS)","volume":"233","author":"Haegert","year":"2011","journal-title":"J Neuroimmunol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3390\/cells12030439","article-title":"People with primary progressive multiple sclerosis have a lower number of central memory T cells and HLA-DR(+) Tregs","volume":"12","author":"Canto-Gomes","year":"2023","journal-title":"Cells"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-016-0441-0","article-title":"Activated CD4+ and CD8+ T cell proportions in multiple sclerosis patients","volume":"39","author":"Arneth","year":"2016","journal-title":"Inflammation"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801236","article-title":"Phenotypic and Ig repertoire analyses indicate a common origin of IgD(-)CD27(-) double negative B cells in healthy individuals and multiple sclerosis patients","volume":"203","author":"Fraussen","year":"2019","journal-title":"J Immunol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2024.1337339","article-title":"Peripheral memory B cells in multiple sclerosis vs. double negative B cells in neuromyelitis optica spectrum disorder: disease driving B cell subsets during CNS inflammation","volume":"18","author":"Tieck","year":"2024","journal-title":"Front Cell Neurosci"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21939","article-title":"Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS","volume":"67","author":"Bar-Or","year":"2010","journal-title":"Ann Neurol"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1002\/path.4437","article-title":"The pathogenesis of human cytomegalovirus","volume":"235","author":"Griffiths","year":"2015","journal-title":"J Pathol"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.24.3083","article-title":"Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study","volume":"286","author":"Ascherio","year":"2001","journal-title":"JAMA"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181aa29fe","article-title":"Humoral immune response to EBV in multiple sclerosis is associated with disease activity on MRI","volume":"73","author":"Farrell","year":"2009","journal-title":"Neurology"},{"key":"B111","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1126\/science.abj8222","article-title":"Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis","volume":"375","author":"Bjornevik","year":"2022","journal-title":"Science"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.70501","article-title":"EBV latency programs: molecular and epigenetic regulation and its role in disease pathogenesis","volume":"97","author":"Lyu","year":"2025","journal-title":"J Med Virol"},{"key":"B113","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/s1074-7613(00)00049-2","article-title":"The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell","volume":"13","author":"Babcock","year":"2000","journal-title":"Immunity"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/cti.2016.87","article-title":"Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis","volume":"6","author":"Pender","year":"2017","journal-title":"Clin Transl Immunol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939761","article-title":"Intrathecal immune responses to EBV in early MS","volume":"40","author":"Jaquiery","year":"2010","journal-title":"Eur J Immunol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201444662","article-title":"High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells","volume":"44","author":"Lossius","year":"2014","journal-title":"Eur J Immunol"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003220","article-title":"Increased CD8+ T cell response to Epstein-Barr virus lytic antigens in the active phase of multiple sclerosis","volume":"9","author":"Angelini","year":"2013","journal-title":"PloS Pathog"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2007.11.005","article-title":"Telomere and adaptive immunity","volume":"129","author":"Weng","year":"2008","journal-title":"Mech Ageing Dev"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.3390\/v9100289","article-title":"Telomere dynamics in immune senescence and exhaustion triggered by chronic viral infection","volume":"9","author":"Bellon","year":"2017","journal-title":"Viruses"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1086\/592170","article-title":"Progressive telomere shortening of Epstein-Barr virus-specific memory T cells during HIV infection: contributor to exhaustion","volume":"198","author":"van Baarle","year":"2008","journal-title":"J Infect Dis"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25020753","article-title":"Immunosenescence and cytomegalovirus: exploring their connection in the context of aging, health, and disease","volume":"25","author":"Muller","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6675353","article-title":"Cytomegalovirus infection and its relationship with leukocyte telomere length: a cross-sectional study","volume":"2021","author":"Lin","year":"2021","journal-title":"Mediators Inflammation"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903442","article-title":"Cytomegalovirus infection reduces telomere length of the circulating T cell pool","volume":"184","author":"van de Berg","year":"2010","journal-title":"J Immunol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-018-1686-x","article-title":"Targeting senescence to delay progression of multiple sclerosis","volume":"96","author":"Oost","year":"2018","journal-title":"J Mol Med (Berl)"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2025.105559","article-title":"Peripheral blood age-sensitive immune markers in multiple sclerosis: relation to sex, cytomegalovirus status, and treatment","volume":"112","author":"Desu","year":"2025","journal-title":"EBioMedicine"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2022.105084","article-title":"Is there a role for herpes simplex virus type 1 in multiple sclerosis","volume":"25","author":"Duarte","year":"2023","journal-title":"Microbes Infect"},{"key":"B127","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/s1074-7613(03)00112-2","article-title":"Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia","volume":"18","author":"Khanna","year":"2003","journal-title":"Immunity"},{"key":"B128","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0014-4886(64)90008-1","article-title":"Virus isolated from the brain of a patient with multiple sclerosis","volume":"9","author":"Gudnadottir","year":"1964","journal-title":"Exp Neurol"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410260218","article-title":"Isolation of herpes simplex virus type 1 during first attack of multiple sclerosis","volume":"26","author":"Bergstrom","year":"1989","journal-title":"Ann Neurol"},{"key":"B130","article-title":"Molecular evidences for a role of HSV-1 in multiple sclerosis clinical acute attack","author":"Ferrante","year":"2000","journal-title":"J Neurovirol"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1996.00550020029012","article-title":"Herpes simplex virus in postmortem multiple sclerosis brain tissue","volume":"53","author":"Sanders","year":"1996","journal-title":"Arch Neurol"},{"key":"B132","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/s42003-024-06486-x","article-title":"Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease","volume":"7","author":"Duarte","year":"2024","journal-title":"Commun Biol"},{"key":"B133","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":"B134","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16301","article-title":"Cellular senescence in glial cells: implications for multiple sclerosis","volume":"169","author":"Maupin","year":"2025","journal-title":"J Neurochem"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00511-7","article-title":"Measuring biological age using omics data","volume":"23","author":"Rutledge","year":"2022","journal-title":"Nat Rev Genet"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.60.7.989","article-title":"A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging","volume":"60","author":"Scahill","year":"2003","journal-title":"Arch Neurol"},{"key":"B137","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.jns.2005.03.016","article-title":"Reduction of brain volume in MS. MRI and pathology findings","volume":"233","author":"Lycklama a Nijeholt","year":"2005","journal-title":"J Neurol Sci"},{"key":"B138","doi-asserted-by":"publisher","first-page":"S5","DOI":"10.1016\/j.msard.2016.07.003","article-title":"Brain health: time matters in multiple sclerosis","author":"Giovannoni","year":"2016","journal-title":"Mult Scler Relat Disord"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000616","article-title":"Contribution of normal aging to brain atrophy in MS","volume":"6","author":"Azevedo","year":"2019","journal-title":"Neurol Neuroimmunol Neuroinflamm"},{"key":"B140","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.jns.2015.07.014","article-title":"The natural history of brain volume loss among patients with multiple sclerosis: a systematic literature review and meta-analysis","volume":"357","author":"Vollmer","year":"2015","journal-title":"J Neurol Sci"},{"key":"B141","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/ana.23882","article-title":"The changing clinical course of multiple sclerosis: a matter of gray matter","volume":"74","author":"Calabrese","year":"2013","journal-title":"Ann Neurol"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-306906","article-title":"Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study","volume":"85","author":"Jacobsen","year":"2014","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.1038\/nature10600","article-title":"Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders","volume":"479","author":"Baker","year":"2011","journal-title":"Nature"},{"key":"B144","doi-asserted-by":"publisher","first-page":"5671","DOI":"10.1038\/s41467-022-33226-8","article-title":"Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat Commun"},{"key":"B145","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2010.06.021","article-title":"Stress-induced senescence in human and rodent astrocytes","volume":"316","author":"Bitto","year":"2010","journal-title":"Exp Cell Res"},{"key":"B146","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/j.1460-9568.2011.07738.x","article-title":"Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype","volume":"34","author":"Salminen","year":"2011","journal-title":"Eur J Neurosci"},{"key":"B147","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00616-5","article-title":"NF-kappaB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss","volume":"18","author":"Schlett","year":"2023","journal-title":"Mol Neurodegener"},{"key":"B148","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25592","article-title":"Telomere length is associated with disability progression in multiple sclerosis","volume":"86","author":"Krysko","year":"2019","journal-title":"Ann Neurol"},{"key":"B149","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13215","article-title":"Current and emerging disease-modulatory therapies and treatment targets for multiple sclerosis","volume":"289","author":"Piehl","year":"2021","journal-title":"J Intern Med"},{"key":"B150","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1606468","article-title":"Ocrelizumab versus placebo in primary progressive multiple sclerosis","volume":"376","author":"Montalban","year":"2017","journal-title":"N Engl J Med"},{"key":"B151","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30475-6","article-title":"Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study","volume":"391","author":"Kappos","year":"2018","journal-title":"Lancet"},{"key":"B152","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(26)00617-3","article-title":"Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study","volume":"407","author":"Giovannoni","year":"2026","journal-title":"Lancet"},{"key":"B153","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2017.00577","article-title":"Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments","volume":"8","author":"Weideman","year":"2017","journal-title":"Front Neurol"},{"key":"B154","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12690","article-title":"Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials","volume":"22","author":"Signori","year":"2015","journal-title":"Eur J Neurol"},{"key":"B155","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.799138","article-title":"Evolution of disease modifying therapy benefits and risks: an argument for de-escalation as a treatment paradigm for patients with multiple sclerosis","volume":"12","author":"Vollmer","year":"2021","journal-title":"Front Neurol"},{"key":"B156","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(23)00154-0","article-title":"Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial","volume":"22","author":"Corboy","year":"2023","journal-title":"Lancet Neurol"},{"key":"B157","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2024.4164","article-title":"Discontinuation of first-line disease-modifying therapy in patients with stable multiple sclerosis: the DOT-MS randomized clinical trial","volume":"82","author":"Coerver","year":"2025","journal-title":"JAMA Neurol"},{"key":"B158","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2016.10.001","article-title":"B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses","volume":"173","author":"Fraussen","year":"2016","journal-title":"Clin Immunol"},{"key":"B159","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2588","article-title":"Understanding immunosenescence to improve responses to vaccines","volume":"14","author":"Goronzy","year":"2013","journal-title":"Nat Immunol"},{"key":"B160","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065x.1997.tb01032.x","article-title":"Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development","volume":"160","author":"LeMaoult","year":"1997","journal-title":"Immunol Rev"},{"key":"B161","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41582-023-00800-7","article-title":"Bruton tyrosine kinase inhibitors for multiple sclerosis","volume":"19","author":"Kramer","year":"2023","journal-title":"Nat Rev Neurol"},{"key":"B162","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(26)00141-9","article-title":"Bruton's tyrosine kinase inhibitors: a new class of multiple sclerosis therapeutics","volume":"25","author":"Oh","year":"2026","journal-title":"Lancet Neurol"},{"key":"B163","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1681724","article-title":"Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach","volume":"16","author":"Atkinson","year":"2025","journal-title":"Front Immunol"},{"key":"B164","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12997","article-title":"Targeting senescent cells enhances adipogenesis and metabolic function in old age","volume":"4","author":"Xu","year":"2015","journal-title":"Elife"},{"key":"B165","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12458","article-title":"Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice","volume":"15","author":"Roos","year":"2016","journal-title":"Aging Cell"},{"key":"B166","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4385","article-title":"Targeting cellular senescence prevents age-related bone loss in mice","volume":"23","author":"Farr","year":"2017","journal-title":"Nat Med"},{"key":"B167","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0092-9","article-title":"Senolytics improve physical function and increase lifespan in old age","volume":"24","author":"Xu","year":"2018","journal-title":"Nat Med"},{"key":"B168","doi-asserted-by":"publisher","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":"B169","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":"B170","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":"B171","doi-asserted-by":"publisher","DOI":"10.3390\/neurolint17120204","article-title":"Senotherapeutics for brain aging management","volume":"17","author":"Saliev","year":"2025","journal-title":"Neurol Int"},{"key":"B172","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2008.03.008","article-title":"Health effects of quercetin: from antioxidant to nutraceutical","volume":"585","author":"Boots","year":"2008","journal-title":"Eur J Pharmacol"},{"key":"B173","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/978-3-642-01222-8_7","article-title":"Dasatinib","volume":"184","author":"Lindauer","year":"2010","journal-title":"Recent Results Cancer Res"},{"key":"B174","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02543-w","article-title":"Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial","volume":"29","author":"Gonzales","year":"2023","journal-title":"Nat Med"},{"key":"B175","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 Neuroinflamm"},{"key":"B176","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2524897123","article-title":"Senolytic treatment induces oligodendrocyte dysfunction and demyelination in the corpus callosum","volume":"123","author":"Lombardo","year":"2026","journal-title":"Proc Natl Acad Sci USA"},{"key":"B177","doi-asserted-by":"publisher","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":"B178","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1146\/annurev-pharmtox-050120-105018","article-title":"Senolytic drugs: reducing senescent cell viability to extend health span","volume":"61","author":"Robbins","year":"2021","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B179","doi-asserted-by":"publisher","DOI":"10.1016\/j.tma.2023.10.004","article-title":"Rationale and design of STAMINA: Senolytics to alleviate mobility issues and neurological impairments in aging, a geroscience feasibility study","volume":"7","author":"Millar","year":"2023","journal-title":"Transl Med Aging"},{"key":"B180","doi-asserted-by":"publisher","first-page":"47","DOI":"10.5483\/BMBRep.2019.52.1.293","article-title":"Senotherapeutics: emerging strategy for healthy aging and age-related disease","volume":"52","author":"Kim","year":"2019","journal-title":"BMB Rep"},{"key":"B181","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12075","article-title":"Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK\/NF-kappaB activation","volume":"12","author":"Moiseeva","year":"2013","journal-title":"Aging Cell"},{"key":"B182","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.08.021","article-title":"Metformin decelerates aging clock in male monkeys","volume":"187","author":"Yang","year":"2024","journal-title":"Cell"},{"key":"B183","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2022.e11196","article-title":"Age and sex differences on anti-hyperglycemic medication exposure and risk of newly diagnosed multiple sclerosis in propensity score matched type 2 diabetics","volume":"8","author":"Branigan","year":"2022","journal-title":"Heliyon"},{"key":"B184","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1362629","article-title":"A metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration (MACSiMiSE-BRAIN): study protocol for a multi-center randomized placebo controlled clinical trial","volume":"15","author":"De Keersmaecker","year":"2024","journal-title":"Front Immunol"},{"key":"B185","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3195","article-title":"MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation","volume":"17","author":"Laberge","year":"2015","journal-title":"Nat Cell Biol"},{"key":"B186","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2018.08.009","article-title":"Promising effect of rapamycin on multiple sclerosis","volume":"26","author":"Bagherpour","year":"2018","journal-title":"Mult Scler Relat Disord"},{"key":"B187","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.590884","article-title":"Rapamycin alleviates the symptoms of multiple sclerosis in experimental autoimmune encephalomyelitis (EAE) through mediating the TAM-TLRs-SOCS pathway","volume":"11","author":"Li","year":"2020","journal-title":"Front Neurol"},{"key":"B188","doi-asserted-by":"publisher","DOI":"10.1038\/nature08221","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume":"460","author":"Harrison","year":"2009","journal-title":"Nature"},{"key":"B189","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glt056","article-title":"Rapamycin extends life and health in C57BL\/6 mice","volume":"69","author":"Zhang","year":"2014","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"B190","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2020.03.005","article-title":"Reducing senescent cell burden in aging and disease","volume":"26","author":"Pignolo","year":"2020","journal-title":"Trends Mol Med"},{"key":"B191","doi-asserted-by":"publisher","DOI":"10.1177\/13524585251398381","article-title":"Toward a global research agenda for preventing multiple sclerosis","volume":"32","author":"Marrie","year":"2026","journal-title":"Mult Scler"},{"key":"B192","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-2274-1","article-title":"Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening","volume":"400","author":"Guan","year":"2015","journal-title":"Mol Cell Biochem"},{"key":"B193","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2018-0246","article-title":"Vitamin E administration erases an enhanced oxidation in multiple sclerosis","volume":"96","author":"Guan","year":"2018","journal-title":"Can J Physiol Pharmacol"},{"key":"B194","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24020916","article-title":"Leukocyte telomere length predicts severe disability in relapsing-remitting multiple sclerosis and correlates with mitochondrial DNA copy number","volume":"24","author":"Lopez-Armas","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B195","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2024.105498","article-title":"Senescence marker p16INK4a expression in patients with multiple sclerosis","volume":"84","author":"Yang","year":"2024","journal-title":"Mult Scler Relat Disord"},{"key":"B196","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147968","article-title":"Analysis of lymphocytic DNA damage in early multiple sclerosis by automated Gamma-H2AX and 53BP1 foci detection: a case control study","volume":"11","author":"Rasche","year":"2016","journal-title":"PloS One"},{"key":"B197","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.1.432","article-title":"Thymic export function and T cell homeostasis in patients with relapsing remitting multiple sclerosis","volume":"171","author":"Hug","year":"2003","journal-title":"J Immunol"},{"key":"B198","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2020.577187","article-title":"Association between shorter leukocyte telomeres and multiple sclerosis","volume":"341","author":"Habib","year":"2020","journal-title":"J Neuroimmunol"},{"key":"B199","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-021-02315-y","article-title":"Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes","volume":"58","author":"Hecker","year":"2021","journal-title":"Mol Neurobiol"},{"key":"B200","doi-asserted-by":"publisher","DOI":"10.1177\/13524585241273054","article-title":"Telomere length as a biomarker in multiple sclerosis","volume":"30","author":"Piedrabuena","year":"2024","journal-title":"Mult Scler"},{"key":"B201","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/1606125","article-title":"Stemness characteristics of periodontal ligament stem cells from donors and multiple sclerosis patients: A comparative study","volume":"2017","author":"Diomede","year":"2017","journal-title":"Stem Cells Int"},{"key":"B202","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517711276","article-title":"Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro","volume":"24","author":"Redondo","year":"2018","journal-title":"Mult Scler"},{"key":"B203","doi-asserted-by":"publisher","DOI":"10.1080\/00207454.2022.2098737","article-title":"Telomere length and multiple sclerosis: A Mendelian randomization study","volume":"134","author":"Ma","year":"2024","journal-title":"Int J Neurosci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1944657\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:57:54Z","timestamp":1791374274000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1944657\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,7]]},"references-count":203,"alternative-id":["10.3389\/fimmu.2026.1944657"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1944657","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,7]]},"article-number":"1944657"}}