Shorter Leukocyte Telomere Length as a Marker of Biological Aging in Relapsing-Remitting Multiple Sclerosis

<title>Abstract</title> <p> Background Multiple sclerosis (MS) is increasingly recognized not only as an immune-mediated demyelinating disease but also as a disorder characterized by accelerated biological aging. Leukocyte telomere(definition) length (LTL) serves as a hallmark biomarker of cellular senescence(definition), yet its predictive role in early-stage MS and its modulation by shelterin complex genetics remain to be fully elucidated. Methods In this case-control study, relative LTL was measured via qPCR in a highly characterized, young cohort of patients with relapsing-remitting MS (RRMS; n = 40, age ≤ 40) and age- and sex-matched healthy controls (n = 39). High-Resolution Melting (HRM) analysis was utilized to genotype key shelterin complex polymorphisms: <italic>TERF1</italic> (rs10107605, rs1545827) and <italic>TERF2</italic> (rs251796). Comprehensive genetic association testing across codominant, dominant, recessive, and additive models was conducted alongside clinical/imaging phenotype correlations. Results LTL was significantly shorter in RRMS patients than in healthy controls (p = 0.005), suggesting evidence of accelerated biological aging even in this relatively young cohort. ROC analysis demonstrated modest discriminatory performance (AUC = 0.698 (95% CI: 0.60–0.79)). Notably, across all inheritance models, <italic>TERF1</italic> and <italic>TERF2</italic> SNPs exhibited no significant association with LTL. Furthermore, subgroup analyses revealed that LTL attrition was independent of chronological age, sex, smoking status, or disease duration, indicating that telomere erosion is driven primarily by intrinsic disease-related systemic stress rather than host shelterin genetic predisposition. Conclusions Our findings demonstrate that leukocyte telomere shortening represents a distinct molecular signature of premature biological aging in young MS patients. By decoupling telomere depletion from primary shelterin genetic variability, this work highlights disease-driven immunosenescence as a key pathophysiological feature of MS. In long-standing, heterogeneous disorders like MS, LTL emerges as a promising prognostic biomarker for capturing biological decline prior to irreversible neurodegeneration. This study provides a foundational framework and strategic catalyst for future longitudinal multi-omics investigations exploring telomere dynamics in chronic neuroinflammation. </p>