{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:28:56Z","timestamp":1793158136528,"version":"4.5.0"},"reference-count":272,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"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>Life expectancy and the age at onset of multiple sclerosis (MS) are increasing, and a growing proportion of people with MS (pwMS) are now older than 55\u201360 years. Aging modifies MS pathobiology, with the dominant disease mechanisms moving from focal, relapse-driven inflammation to chronic, compartmentalized neuroinflammation and neurodegeneration. In this narrative review, we summarize current knowledge on the relationship between brain aging and MS, integrating clinical, radiological, pathological and therapeutic evidence. We first discuss mechanisms of immunosenescence and \u201cinflammaging\u201d, including changes in adaptive and innate immunity, gut microbiota dysbiosis, mitochondrial dysfunction and blood\u2013brain barrier dysfunction, and how these processes favor microglial activation, slowly expanding lesions, smouldering MS and progression independent of relapse activity. We then examine the impact of age on disability trajectories, cognitive decline and comorbidities, and the role of vascular and neurodegenerative mechanisms. The review also addresses age-related changes in safety and efficacy of disease-modifying therapies (DMT), with a focus on high-efficacy DMT, de-escalation and discontinuation strategies, and the management of infections, malignancies and polypharmacy in older pwMS. Finally, we describe new approaches relevant to this population, including Bruton\u2019s tyrosine kinase inhibitors, neuroprotective and remyelinating agents, advanced cellular therapies and lifestyle-based interventions. We conclude by outlining practical implications for personalized treatment decisions in older pwMS and open questions that future clinical trials and biomarker studies must address.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1832582","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:40:29Z","timestamp":1781239229000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulation of the immunological and neuroinflammatory microenvironment in older people with multiple sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Celia","family":"Oreja-Guevara","sequence":"first","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico Universitario San Carlos, Instituto de Investigaci\u00f3n Sanitaria del Hospital Cl\u00ednico San Carlos (IdISSC)","place":["Madrid, Spain"]},{"name":"Department of Medicine, Faculty of Medicine, Complutense University of Madrid","place":["Madrid, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven G.","family":"Meuth","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Hospital M\u00fcnster","place":["M\u00fcnster, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikos","family":"Grigoriadis","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki","place":["Thessaloniki, Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Vermersch","sequence":"additional","affiliation":[{"name":"Univ. Lille, Inserm U1172 LilNCog, Centre Hospitalier Universitaire (CHU) Lille, F\u00e9d\u00e9ration Hospitalo-Universitaire (FHU) Precise","place":["Lille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans Peter","family":"Hartung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, Heinrich-Heine-University","place":["D\u00fcsseldorf, Germany"]},{"name":"Brain and Mind Center, University of Sydney","place":["Sydney, NSW, Australia"]},{"name":"Department of Neurology, Palacky University Olomouc","place":["Olomouc, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per Soelberg","family":"S\u00f6rensen","sequence":"additional","affiliation":[{"name":"Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet","place":["Copenhagen, Denmark"]},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen","place":["Copenhagen, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Leocani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vita-Salute San Raffaele University","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Schmierer","sequence":"additional","affiliation":[{"name":"Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London","place":["London, United Kingdom"]},{"name":"Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Gold","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital","place":["Bochum, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d3scar","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Institute of Biomedical Research of Malaga (IBIMA), Regional University Hospital of Malaga, University of Malaga","place":["Malaga, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458520970841","article-title":"Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition","volume":"26","author":"Walton","year":"2020","journal-title":"Mult Scler"},{"key":"B2","unstructured":"Number of people with multiple sclerosis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.nrleng.2025.04.010","article-title":"Prevalence of multiple sclerosis in Spain. 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