Authors

Celia Oreja-Guevara ^1,2;Sven G. Meuth ³; Nikos Grigoriadis ⁴; Patrick Vermersch ⁵; Hans Peter Hartung ^6,7,8; Per Soelberg Sörensen ^9,10; Letizia Leocani ¹¹; Klaus Schmierer ^12,13; Ralf Gold ¹⁴; Óscar Fernández ^15*

Abstract

Background

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.

Methods

This narrative review integrates clinical, radiological, pathological and therapeutic evidence on the relationship between brain aging and MS. It covers mechanisms of immunosenescence and inflammaging, the impact of age on disability, cognition and comorbidities, and age-related changes in the safety and efficacy of DMT, including de-escalation and discontinuation strategies.

Results

New approaches relevant to this population are described, including Bruton’s tyrosine kinase inhibitors, neuroprotective and remyelinating agents, advanced cellular therapies and lifestyle-based interventions. Key findings include:

1. Immunosenescence appears to start earlier in pwMS, with immune aging biomarkers resembling those of much older reference populations.
2. Older pwMS have fewer relapses but accumulate disability faster, with progression independent of relapse activity (PIRA) becoming dominant.
3. Comorbidities are frequent and are associated with higher disability.
4. DMT efficacy appears to decline with age, and older patients remain under-represented in clinical trials.
5. De-escalation or discontinuation of DMT must be individualized, as risks of disease reactivation differ by drug class and patient profile.

Conclusions

Practical implications for personalized treatment decisions in older pwMS are outlined, together with open questions that future clinical trials and biomarker studies must address. Direct evidence linking inflammaging biomarkers to clinical or radiological outcomes in MS remains scarce, and more inclusive trial designs are needed to support therapeutic approaches that prioritize functional outcomes, autonomy and quality of life in older adults with MS

Keywords:

Aging; Immunosenescence; Inflammaging; Multiple Sclerosis; neuroinflammation.

Publication History:

Received 17 March 2026; Revised 11 May 2026;Accepted 19 May 2026; Published 12 June 2026; Volume 17 – 2026

DOI: 10.3389/fimmu.2026.1832582 External LinkAlso available on Frontiers in Immunology vol.17

© 2026 Oreja-Guevara, Meuth, Grigoriadis, Vermersch, Hartung, Sörensen, Leocani, Schmierer, Gold and Fernández. 

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