Frontiers in Aging Neuroscience · Oct 30, 2026
Microglial Lipid Handling in White Matter Aging: Mechanistic Evidence, Context Dependence, and Implications for Repair
By Tianxiang Lan, Hongyan Li
White matter aging increases the supply of cholesterol-rich myelin debris while reducing the capacity for tissue repair. Demyelination experiments show that phagocytes can engulf myelin yet retain cholesteryl esters when lysosomal processing or cholesterol efflux is inadequate. Lipid droplets can buffer acute lipid stress, but persistent droplets can accompany impaired turnover, oxidative injury, and defective remyelination. This Review evaluates evidence across uptake, storage, lysosomal degradation, intracellular trafficking, lipid export, and tissue repair, while keeping microglia-specific, mixed-myeloid, and whole-tissue findings separate. A candidate lipid-processing bottleneck requires persistent lipid burden plus a measured limitation at one handling stage. Evidence for a processing-repair coupling failure is stronger when temporal precedence is combined with perturbation, rescue, or mediation evidence linking that limitation to oligodendrocyte differentiation, remyelination, axonal integrity, or function. We reserve lipid recycling for tracer-supported redistribution or productive reuse; current evidence rarely demonstrates that lipid exported by microglia enters new myelin. Human tissue supports regional microglial heterogeneity and the coexistence of lipid, iron, and glial abnormalities, but it does not establish the complete temporal sequence. Demyelination and vascular models most directly test clearance and repair, whereas Alzheimer and Parkinson disease studies test disease-specific lipid, lysosomal, or iron-redox segments. The resulting framework is a bounded interpretation and research strategy rather than a fully established linear mechanism.