Emerging role of senescent microglia in brain aging-related neurodegenerative diseases

Abstract

Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.

Keywords: Brain aging; Neurodegenerative diseases; Rejuvenation; Senescent microglia.

Fig. 1

Proposed mechanism of the TREM2-APOE axis-mediated microglial senescence among previously reported microglial phenotypes. Accumulated DNA damage can dysregulate RNA metabolism and proteostasis, leading to accumulation of cytoplasmic aggregates and disruption of nucleocytoplasmic transport. Furthermore, chronic exposure to extracellular protein aggregates induces autophagy, mitochondrial dysfunction, and secretion of SASPs, with a primary focus on the TREM2-APOE axis. Created with Biorender.com

Fig. 2

Previously reported microglial subpopulations may share features with senescent microglia. Microglia in the neurodegenerative brain can be classified into distinct phenotypes: disease-associated microglia (DAM) and neurodegenerative microglia (MGnD). In the aged brain, microglia exhibit senescent features and accumulate lipid droplets (LDAM). Previous studies suggest that senescent microglia contribute to the pathophysiology of neurodegeneration, as the gene expression patterns of previously reported microglia overlap with those of senescent microglia. Created with Biorender.com

Fig. 3

Driving forces and phenotypes of senescent microglia. (1) Genomic instability: Accumulating DNA damage arrests the cell cycle and regulates gene expression through epigenetic modifications. As a result, secretion of a senescence-associated secretory phenotype is increased, leading to a primed microglial response. (2) Cytoplasmic aggregates: Autophagy or lysosomal dysfunction can lead to abnormal protein degradation or inability to degrade excess lipids, resulting in impaired phagocytosis. These defects can lead to intracellular iron accumulation and either microglial senescence or ferroptosis-resistance. (3) Bioenergetics: Chronic phagocytic challenges due to either disease-associated protein aggregates or excessive myelin debris can lead to alterations in mitochondrial metabolism and energy sources, as well as alterations in the TREM2-ApoE axis. Created with Biorender.com

Fig. 4

Promising strategies for microglia-targeted senotherapy. a Senolysis: Healthy and senescent microglia coexist in the aging brain, and senolysis targets and removes only the senescent microglia. b Infusion of youthful factor: To restore cognitive function in old mice, cerebrospinal fluid or plasma from young mice was administered. Further research is needed to determine which factors in the young mice reverse aging. c Restoration of microglial function: Microglial rejuvenation can be achieved by restoring the function of senescent microglia, revitalizing metabolism, and inhibiting inflammaging. Further research is needed. Created with Biorender.com