Cellular senescence in the aging brain: A promising target for neurodegenerative diseases

Aging is inevitable. Along with reduced ability to maintain the homeostasis of various biological processes, aging gradually deteriorates overall health. Extensive research on the aging brain has identified cellular senescence as a critical risk factor of neurodegeneration and cognitive decline. Associations of cellular senescence with neurodegenerative diseases like Alzheimer’s disease, Down syndrome, Parkinson’s disease, and multiple sclerosis are evident in an extensive body of literature generated over decades of research on aging. Cellular senescence triggers neurodegeneration via a complex interplay of mechanisms including neuroinflammation, mitochondrial dysfunction, oxidative stress burden, deranged protein homeostasis, and compromised nuclear and blood-brain-barrier integrity. Thus, cellular senescence can serve as a primary therapeutic target for various neurodegenerative diseases. This review summarizes the concept of cellular senescence, its role in the aging brain, and how it mediates neurodegeneration in several neurodegenerative disorders. Further, we have also highlighted senolytic therapeutics discovered and employed to ameliorate cellular senescence-associated degenerative diseases. This review can aid in providing directions for repurposing senolytic compounds and finding more therapeutic strategies targeting cellular senescence for the management and treatment of neurodegenerative diseases. •Accumulation of senescent cells is the central hallmark event of the aging process.•In the aging brain, senescence is evident in the glia and the post-mitotic neurons.•Glial and neuronal senescence is mediated by p53/p21, p16/RB, and NF-κB pathways.•The senescence of brain cells is a major risk factor for neurodegenerative diseases.•Emerging senolytics have shown promising outcomes in ameliorating neurodegeneration.