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

Abstract

Aging is characterized, amongst other features, by a complex process of cellular senescence involving both innate and adaptive immunity, called immunosenescence and associated to inflammaging, 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.

Selective Upregulation of SIRT1 Expression in Retinal Ganglion Cells by AAV-Mediated Gene Delivery Increases Neuronal Cell Survival and Alleviates Axon Demyelination Associated with Optic Neuritis

“…Up to 75% of patients with ON convert to full-blown MS between 10 years and 15 years after clinical onset [ 4 ]. Although disease causes have not completely been identified, the underlying mechanism is suggested to likely involve infiltration of inflammatory cells (e.g., CD4 + T cells (known as T helper 17 cells) and CD8+ T cells) into and demyelination of optic nerve, axonal damage, and death of retinal ganglion cells (RGCs) [ 5 ], the projection neurons that convey visual signals from other retinal neurons to the brain. This neurodegenerative process leads to irreversible loss of vision.…”

Immunosenescence and multiple sclerosis

“…Patients over the age of 55 are usually excluded from clinical trials. Therefore, the safety and efficacy of DMTs in this group of patients is not confirmed [49]. Schweitzer et al [17] suggested that the benefits of high efficacy DMTs could decrease with age.…”

“…One possible explanation is the impact of immunosenescence which is associated with the accumulation of unusual immune cell subsets that may play a role in the development of an early ageing process in autoimmunity [48]. Some features of immunosenescence found in aged healthy controls have already been observed in MS patients at a younger age [49].…”

“…The process of autophagy becomes less efficient with age, which leads to cellular senescence. In active RRMS patients, this capacity is increased [49]. In progressive MS, the signs of neurodegeneration are present despite increased autophagy in the brain tissue [50].…”

“…In progressive MS, the signs of neurodegeneration are present despite increased autophagy in the brain tissue [50]. It seems that sustained autophagy related to damage could lead to the dysregulation of this process, and paradoxical inflammasome activation and apoptosis [49].…”