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.
Highlights
Multiple sclerosis (MS) is a chronic, immune mediated disease of unknown etiology characterized by inflammatory demyelination, astrogliosis, neuronal and axonal loss involving the brain and spinal cord
Cellular senescence (CS) has been recognized as a key biological process underling normal aging (López-Otín et al, 2013; Gorgoulis et al, 2019) and evidence suggest that the accumulation of senescent cells with time may contribute to the pathogenesis of age-related and neurodegenerative disease (Kritsilis et al, 2018)
CS may be a shared mechanism, which substantially contributes to the pathogenesis and impact of neurodegenerative diseases and thereby may determine disease susceptibility, age at disease presentation and rate of progression
Summary
Multiple sclerosis (MS) is a chronic, immune mediated disease of unknown etiology characterized by inflammatory demyelination, astrogliosis, neuronal and axonal loss involving the brain and spinal cord. Damaged senescent cells remain viable and metabolically active, they accumulate with aging and evidence suggests that their build-up may promote neurodegeneration (Rodier and Campisi, 2011).
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