- Cellular senescence has emerged as a significant contributor to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and others.
- Traditionally viewed as a protective mechanism that halts the proliferation of damaged or stressed cells, senescence becomes pathological when senescent cells accumulate in tissues, especially in the central nervous system (CNS), where cell turnover is limited and regenerative capacity is low. In this context, senescent cells drive inflammation, tissue dysfunction, and neuronal decline, which are central features of neurodegeneration.
- In the brain, neurons, astrocytes, microglia, oligodendrocyte precursor cells, and even endothelial cells can undergo senescence in response to various stressors such as oxidative stress, mitochondrial dysfunction, DNA damage, protein aggregation, and chronic inflammation—all of which are prominent in neurodegenerative conditions. Although mature neurons are post-mitotic and do not divide, they can display senescence-like phenotypes, including expression of senescence-associated secretory phenotype (SASP) factors, increased DNA damage markers, and impaired cellular functions.
- A key feature of senescent cells in neurodegenerative diseases is the SASP, a pro-inflammatory secretome that includes cytokines (e.g., IL-6, IL-1β, TNF-α), chemokines, matrix metalloproteinases, and growth factors. These factors can alter the brain microenvironment, amplify neuroinflammation, disrupt the blood-brain barrier, and negatively affect neighboring neurons and glial cells. This creates a vicious cycle in which senescent cells promote further cellular stress and senescence, contributing to progressive neurodegeneration.
- In Alzheimer’s disease, for instance, astrocytes and microglia have been shown to adopt a senescent phenotype, and their SASP can exacerbate amyloid-β pathology and tau hyperphosphorylation. Similarly, in Parkinson’s disease, senescent glial cells have been associated with the accumulation of α-synuclein and degeneration of dopaminergic neurons. In both cases, senescence-associated pathways, such as p16^INK4a, p21^CIP1, and p53, are upregulated in affected brain regions.
- Emerging evidence also suggests that the accumulation of senescent cells in the CNS is not merely a consequence but may be a driving factor in disease progression. Animal models of neurodegeneration have demonstrated that the selective clearance of senescent cells using senolytic drugs—agents that target and eliminate senescent cells—can improve cognitive function, reduce neuroinflammation, and preserve neuronal integrity. These findings support the concept of senescence as a therapeutic target in neurodegenerative diseases.
