Modulation of the immunological and neuroinflammatory microenvironment in older people with multiple sclerosis

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 55-60 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 "inflammaging", including changes in adaptive and innate immunity, gut microbiota dysbiosis, mitochondrial dysfunction and blood-brain 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's 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.