Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?

As primary immune cells of the central nervous system (CNS), microglia maintain immune surveillance, inflammation regulation, cell interactions and debris clearance. These dynamic and adaptive effector functions are reciprocally sustained by microglial metabolism. Lipids are emerging as a key programmer of microglial metabolic and functional flexibility in conditions of homeostasis, cellular stress, and pathology. The delicate equilibrium in microglial lipid homeostasis is dependent on the integrated activity of all cellular components, including the lysosome-lipophagy pathway. Continuous adaptations in microglial metabolism contribute to a cumulative imbalance between lysosomal network capacity and the efficacy of lipid turnover in aged microglia. The disequilibrium contributes to microglial fatigue and detrimental homeostatic activity associated with aging. Lipid droplet-accumulating microglia (LDAM) emerged as an age-associated example of these lysosome-lipid flux alterations. While characterized by dysregulated phagocytosis and pro-inflammatory intercellular signaling, the role of LDAM in the contexts of neuroplasticity, aging-related cognitive decline and frailty remains undetermined. This review discusses the immunometabolic profile of aging LDAM and their interactions with neurons and synapses, highlighting the impact of intercellular lipid signaling route.