Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis

Aging is characterized, amongst other features, by a complex process of cellular senescence(definition) involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging(definition), a low-grade chronic inflammation. Both processes fuel each other and partially explain increasing incidence of cancers, infections, age-related autoimmunity, and vascular disease as well as a reduced response to vaccination. Multiple sclerosis (MS) is a lifelong disease, for which considerable progress in disease-modifying therapies (DMTs) and management has improved long-term survival. However, disability progression, increasing with age and disease duration, remains. Neurologists are now involved in caring for elderly MS patients, with increasing comorbidities. Aging of the immune system therefore has relevant implications for MS pathogenesis, response to DMTs and the risks mediated by these treatments. We propose to review current evidence regarding markers and molecular mechanisms of immunosenescence and their relevance to understanding MS pathogenesis. We will focus on age-related changes in the innate and adaptive immune system in MS and other auto-immune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The consequences of these immune changes on MS pathology, in interaction with the intrinsic aging process of central nervous system resident cells will be discussed. Finally, the impact of immunosenescence on disease evolution and on the safety and efficacy of current DMTs will be presented.