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.
Highlights
With the aging of the world population, seniors aged over 65 years, that account for 9.3% of the global population in 2020, are predicted to have doubled in absolute number by 2050, representing 15.9% [1]
We aim to review and compare current knowledge on immunosenescence and inflammaging, relative to Multiple sclerosis (MS) and other autoimmune diseases (AIDs), such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), as these AIDs are amongst the most studied in this context [19–21]
In the setting of MS, we will focus on the concomitant senescence of central nervous system (CNS) resident cells in order to answer several questions. (a) What is the evidence or the lack thereof to consider MS a disease of premature immunosenescence? (b) What are the common or different immunosenescence features found in MS and other autoimmune diseases? (c) Are epigenetic changes involved in immunosenescence? (d) Is the age-related evolution of MS toward a progressive phenotype linked to immunosenescence? (e) Does immunosenescence expose aging MS patients to increased risks of infection and cancer, especially when taking disease-modifying therapy (DMT)?
Summary
With the aging of the world population, seniors aged over 65 years, that account for 9.3% of the global population in 2020, are predicted to have doubled in absolute number by 2050, representing 15.9% [1] This increase in life expectancy inevitably has an impact on disease prevalence and incidence, especially of chronic diseases. Senescent cells, accumulating with age, are arrested in their cell cycle, but are still active, functionally dysregulated and affecting their microenvironment by secreting soluble signaling factors (interleukins, chemokines, growth factors), proteases, or insoluble proteins/extracellular components. These constitute the so-called senescence-associated secretory phenotype (SASP) exerting a paracrine pro-inflammatory effect [3, 4]. In the setting of MS, we will focus on the concomitant senescence of central nervous system (CNS) resident cells in order to answer several questions. (a) What is the evidence or the lack thereof to consider MS a disease of premature immunosenescence? (b) What are the common or different immunosenescence features found in MS and other autoimmune diseases? (c) Are epigenetic changes involved in immunosenescence? (d) Is the age-related evolution of MS toward a progressive phenotype linked to immunosenescence? (e) Does immunosenescence expose aging MS patients to increased risks of infection and cancer, especially when taking DMTs?
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