Aging and Disease · 2026
The Microglial Lipid-Immune Axis in Brain Aging: Adaptive Lipid Handling and Metabolic Dysfunction in Lipid-Droplet-Accumulating Microglia
Microglia in the aging brain process lipids released during membrane and myelin turnover. Lipid droplets can buffer this demand, but lipid retention also accompanies defective phagocytosis and inflammatory responses. This review critically compares the substrates, perturbations, and functional endpoints underlying these observations. We examine cholesterol esterification and export, fatty-acid activation and triacylglycerol synthesis, and lipid mobilization through lipolysis and lipophagy in relation to TREM2-TYROBP/DAP12-SYK signaling, APOE genotype, and local substrate supply. Physiological-aging studies are distinguished from demyelination, Alzheimer’s disease, and Parkinson’s disease models. Quantitative comparisons show why inhibiting storage can improve selected amyloid-associated phenotypes while impaired storage can compromise myelin repair. We use the established distinction between lipid pools and metabolic flux to assess what each experiment demonstrates: altered droplet abundance, a specific processing defect, or recovery of a cellular task. We propose a reporting framework covering droplet burden, transcriptional state, metabolic function, and cellular performance, with missing measurements retained explicitly and no claim of validated diagnostic thresholds. Intervention evidence is assessed by the reaction perturbed, dose and duration, target validation, delivery route, and measured benefit. The resulting synthesis identifies supported mechanisms and unresolved causal steps, providing a practical basis for selecting and evaluating interventions without treating droplet reduction as a universal therapeutic endpoint.