Aging, Cellular Senescence, and Progressive Multiple Sclerosis

Abstract

Aging is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying aging. Several stressors associated with aging and MS pathology, such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of cellular senescence. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with aging and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

Keywords: cellular senescence; inflammation; multiple sclerosis; neurodegeneration; neuroprotection; remyelination; senolytics.

Figure 1

Schematic representation of the putative impact of the conversion of different cell types to senescence on inflammation, remyelination, neurodegeneration and ultimately on disability progression. OPCs, oligodendrocyte progenitors; MSCs, mesenchymal stem cells; NPCs, neural progenitor cells; EC, endothelial cells.