Aging-dependent immunological changes in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease in which immune dysregulation plays a central role. As the life expectancy of people with MS (pwMS) increases, understanding how aging affects their immune system-collectively referred to as immunosenescence-has become crucial. In this study, we characterized immunosenescence in pwMS by analyzing age-related changes in the immune system. To fulfill this, blood samples were collected from pwMS and healthy controls (HCs) of independent cohorts: i) immune cell populations were assessed in PBMCs (n= 110), ii) thymic involution and telomere attrition were measured in DNA samples (n=150), and iii) inflammatory and neurodegeneration markers were evaluated in plasma (n=146).Our results revealed distinct age-associated alterations in immune cell subsets between pwMS and HCs, including B and NK cells. Notably, pwMS showed an age-related increase in CD28-CD57+ and CD28+CD57+ cells in CD4+ and CD8+ T cells. Thymic involution was reported with age in both groups and, importantly, we found a more pronounced thymic involution in younger pwMS. A positive correlation was found between age and the levels of IL-6, TNF-α, and CRP in pwMS, results consistent with the inflammaging phenomenon. Similarly, NFL levels were elevated in pwMS and correlated positively with age in both groups., Remarkably, we found a positive correlation between NFL levels and IL-6, and between NFL levels and TNF-α only in pwMS. Telomere shortening occurred with age in both groups, without significant differences. Notably, our study provides an integrative and multi-biomarker characterization of immune aging process in pwMS, revealing new insights into this complex relationship. These findings highlight specific age-related immune alterations in MS and underscore the importance of incorporating age and immunosenescence monitoring into MS clinical management and therapeutic strategies.