Multiple Sclerosis Accelerates Immune Aging Across Multiple Biological Markers
A multi-biomarker study finds pwMS show accelerated thymic involution, senescent T cell expansion, and neuroinflammation linked to aging.
Summary
Researchers from Spain and Australia conducted a comprehensive multi-cohort study examining how aging affects the immune system in people with multiple sclerosis (pwMS). Across 110 participants assessed for immune cell populations, 150 for thymic involution and telomere length, and 146 for inflammatory and neurodegeneration biomarkers, they found that pwMS display distinct and sometimes accelerated immunosenescence compared to healthy controls. Key findings included increased senescent T cell populations, more pronounced thymic involution in younger pwMS, rising inflammatory markers with age, and a unique correlation between neurodegeneration marker neurofilament light chain (NFL) and pro-inflammatory cytokines IL-6 and TNF-α exclusively in pwMS. These results suggest that MS and biological aging interact to worsen immune dysfunction, with significant implications for clinical monitoring and treatment decisions.
Detailed Summary
Multiple sclerosis (MS) is increasingly recognized as a disease of long duration — nearly 25% of people with MS worldwide are now over 60 years old. As this population ages, the convergence of disease-driven immune dysregulation and normal biological aging (immunosenescence) becomes clinically critical. This 2025 study by Iribarren-López and colleagues offers one of the most comprehensive multi-biomarker characterizations of immunosenescence in MS to date, drawing on three independent cohorts and five distinct biological domains.
The study enrolled participants across a wide age range (13–100 years) divided into three cohorts: a PBMCs cohort (n=110; 42 healthy controls, 68 pwMS), a DNA cohort (n=150; 75 HC, 75 pwMS), and a plasma cohort (n=146; 66 HC, 76 pwMS). Three multicolor flow cytometry panels characterized immune cell subsets including T cells, B cells, NK cells, and monocytes. Thymic involution was estimated via signal joint T-cell receptor excision circles (sjTRECs) using quantitative PCR. Telomere length was measured in leukocyte DNA. Plasma inflammatory markers (IL-6, TNF-α, CRP) and neurofilament light chain (NFL) were quantified by ELISA and Simoa, respectively.
In immune cell populations, pwMS showed age-related increases in CD28−CD57+ and CD28+CD57+ subsets within both CD4+ and CD8+ T cells — hallmarks of cellular senescence. These expansions were more pronounced in pwMS than in healthy controls. B cell and NK cell proportions also showed distinct age-associated patterns between groups. Notably, the CD4+/CD8+ ratio, a classic immunosenescence marker, declined with age in both groups but the trajectory differed in pwMS. NK cells, which are known to be reduced in MS and play immunoregulatory roles, showed further age-related decreases specifically in pwMS.
Thymic involution, assessed by sjTREC levels, declined significantly with age in both groups (p<0.001), but crucially, younger pwMS showed significantly lower sjTREC levels than age-matched healthy controls — indicating premature thymic involution in MS. This is a particularly important finding because thymic output of naïve T cells is essential for maintaining adaptive immune diversity; its premature decline in MS could accelerate immune aging and reduce the efficacy of disease-modifying therapies.
On the inflammatory front, consistent with the concept of 'inflammaging,' plasma levels of IL-6, TNF-α, and CRP all showed significant positive correlations with age in pwMS. NFL levels — a key marker of axonal damage and neurodegeneration — were elevated in pwMS compared to HC and correlated positively with age in both groups. Strikingly, only in pwMS did NFL levels correlate significantly with both IL-6 and TNF-α, suggesting a unique neuro-inflammatory coupling in MS that intensifies with age. Telomere length shortened with age in both groups, but no significant differences were found between pwMS and HC, contrasting with some earlier reports.
The study's integrative design is its greatest strength, linking cellular, molecular, and soluble biomarker evidence of aging across the same disease population. Clinically, the findings argue for routine immunosenescence monitoring in older pwMS and raise questions about whether standard disease-modifying therapies remain optimally calibrated for aging patients whose immune landscape is fundamentally different from younger patients at diagnosis.
Key Findings
- Younger pwMS showed significantly lower sjTREC levels than age-matched healthy controls, indicating premature thymic involution — a key immunosenescence marker — earlier in the disease course
- Age-related expansion of CD28−CD57+ (terminally senescent) and CD28+CD57+ T cells was observed in both CD4+ and CD8+ compartments in pwMS, at greater magnitudes than in healthy controls
- Plasma IL-6, TNF-α, and CRP all correlated positively with age in pwMS, consistent with inflammaging and worsening chronic low-grade inflammation over the disease course
- NFL (neurofilament light chain) levels were elevated in pwMS versus HC and correlated with age in both groups; critically, NFL correlated with IL-6 and TNF-α exclusively in pwMS, linking neurodegeneration to inflammation in an age-dependent manner
- NK cell proportions showed distinct age-associated declines in pwMS compared to healthy controls, consistent with MS-specific immunoregulatory dysfunction compounded by aging
- Telomere length shortened with age in both pwMS (n=75) and HC (n=75), but without statistically significant differences between the two groups — contrasting with hypotheses of accelerated telomere attrition in MS
- Three independent cohorts (PBMCs n=110, DNA n=150, plasma n=146) spanning ages 13–100 years provided multi-layered, convergent evidence of accelerated and altered immunosenescence in MS
Methodology
Three independent cohorts (total N=406 samples across cohorts) were studied cross-sectionally, including healthy controls and pwMS with no exclusion criteria based on EDSS score, MS subtype, or disease-modifying treatment. Immune cell populations were characterized by three multicolor flow cytometry panels; thymic involution was assessed via quantitative PCR for sjTRECs; telomere length was measured in leukocyte DNA; and plasma biomarkers (IL-6, TNF-α, CRP, NFL) were quantified by ELISA and Simoa. Statistical analyses included Spearman correlations for age-biomarker associations and group comparisons corrected for multiple testing.
Study Limitations
This is a cross-sectional study, precluding causal inference about whether MS drives accelerated immunosenescence or whether immunosenescence worsens MS progression over time. The inclusion of pwMS on diverse disease-modifying therapies without stratification by treatment type is a significant confounder, as many DMTs directly alter immune cell populations. The authors did not report conflicts of interest, and the PBMCs cohort's healthy control age range (22–64 years) was narrower than that of pwMS (18–82 years), potentially limiting direct age-matched comparisons.
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