Senescent Microglia are Likely Important in Age-Related Neurodegeneration
Evidence from animal studies strongly suggests an important role for cellular senescence in supporting cell populations in the brain in driving the onset and progression of age-related neurodegenerative conditions. Senescent cells accumulate with age in tissues throughout the body, the result of growing cell stress resulting from the molecular damage and disarray of aging on the one hand, but on the other hand also the problem of inefficient clearance, resulting from the growing inability of the immune system to destroy senescent cells in a timely fashion. Senescent cells energetically secrete a pro-inflammatory mix of signals, disruptive to tissue structure and function when sustained over the long term.
The existing literature on neurodegenerative diseases (NDDs) reveals a common pathological feature: the accumulation of misfolded proteins. However, the heterogeneity in disease onset mechanisms and the specific brain regions affected complicates the understanding of the diverse clinical manifestations of individual NDDs. Dementia, a hallmark symptom across various NDDs, serves as a multifaceted denominator, contributing to the clinical manifestations of these disorders. There is a compelling hypothesis that therapeutic strategies capable of mitigating misfolded protein accumulation and disrupting ongoing pathogenic processes may slow or even halt disease progression.
Recent research has linked disease-associated microglia to their transition into a senescent state - characterized by irreversible cell cycle arrest - in aging populations and NDDs. Although senescent microglia are consistently observed in NDDs, few studies have utilized animal models to explore their role in disease pathology. Emerging evidence from experimental rat models suggests that disease-associated microglia exhibit characteristics of senescence, indicating that deeper exploration of microglial senescence could enhance our understanding of NDD pathogenesis and reveal novel therapeutic targets.
This review underscores the importance of investigating microglial senescence and its potential contributions to the pathophysiology of NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Additionally, it highlights the potential of targeting microglial senescence through iron chelation and senolytic therapies as innovative approaches for treating age-related NDDs.