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