Cellular senescence in multiple sclerosis: hallmarks, immunosenescence, and therapeutic implications

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease where chronological aging predicts the conversion to progressive MS (PMS), a phase defined by compartmentalized inflammation and accelerated neurodegeneration. While current disease modifying therapies (DMTs) are effective for managing the inflammatory aspect of MS, treatments remain inadequate. It is imperative to understand the biology of aging including an important hallmark of aging, cellular senescence. Cellular senescence is a state of cell cycle arrest where cells remain in their senescent state and produce a distinctive senescence-associated secretory phenotype (SASP), characterized by the release of pro-inflammatory cytokines, chemokines, and growth factors. Growing experimental and clinical evidence suggests that the accumulation of senescent cells and SASP secretion perpetuates a pathological feedback loop linking age-related processes with accelerated neurodegeneration observed in PMS. Whether senescence drives PMS or accompanies it remains unresolved. In this Review, we outline the biology of aging, senescence pathway markers, and SASP components. We evaluate studies of cellular senescence and SASP markers in MS, including immunosenescence, T- and B-cell changes; the contributions of Epstein-Barr virus, cytomegalovirus, and herpes simplex virus-1; and the relationship between senescence burden, brain atrophy, and DMT response. Lastly, we outline the available senotherapeutic approaches aimed at mitigating MS and other neurodegenerative diseases.