Figure 1.

The impact of aging on microglia function and its systemic regulation. Young microglia (in pink) gradually transition from a ramified morphological state to a deramified, spheroid formation with abnormal processes with chronological age. Several cytoplasmic features are hallmarks of microglial senescence including increased granule formation, autofluorescent pigments such as lipofuscin, and process fragmentation. Age-related neuronal loss (in red) reduces the overall level of immunoinhibitory molecules (e.g., CD200, CX3CL1) required to maintain microglia in a quiescent state. Basal increases in inflammatory signaling are associated with enhanced reactive oxygen species (ROS) production which results in the generation of free radicals, lipid peroxidation, and DNA damage. This positive feedback loop is further compounded by defects in lysosomal digestion and autophagy, resulting in the potentially toxic buildup of indigestible material. Concurrent reductions in process motility and phagocytic activity lead to decreased immune surveillance and debris clearance, resulting in plaque formation (in brown). In turn, microglia activation triggers astrocyte activation (in orange) and promotes the recruitment of T cells (in blue) into the aging brain. These pathological features of microglial aging are highly influenced by the systemic environment. Diminished (↓) levels of circulating anti-aging factors in conjunction with increased (↑) concentrations of pro-aging factors are critical drivers of microglial senescence. For example, diminished estrogen levels in older (menopausal) females are associated with elevated expression of macrophage-associated genes in the brain. Therapeutic interventions intended to increase anti-aging factors and decrease pro-aging factors appear to be able to halt or delay microglia aging, enhance neurogenesis, and improve cognitive function.