Glial lipid reprogramming in brain aging: Lipid identity, organelle stress, and redox vulnerability

Brain aging is accompanied by progressive glial dysfunction, impaired metabolic adaptation, oxidative stress, and increased susceptibility to neurodegenerative disease. Although many studies of lipid metabolism in aging and neurodegeneration emphasize lipid abundance, lipid amount alone cannot explain why glia become redox-vulnerable. This review advances a chemistry-resolved integrative framework in which glial lipid reprogramming is understood through aging- and disease-associated changes in lipid identity, composition, oxidation state, storage form, subcellular localization, and lipid-mediated signaling. We discuss evidence from aged brain tissue, human neurodegenerative disease, iPSC-derived glial systems, and mouse models showing that altered lipid handling in microglia, astrocytes, and oligodendrocyte-lineage cells reshapes phagocytosis, inflammatory signaling, myelin processing, astrocytic metabolic support, and neuronal injury. We emphasize that acyl-chain saturation, head-group structure, oxidized lipid species, neutral lipid storage, plasmalogen-dependent redox buffering, peroxisomal lipid metabolism, and compartmental distribution determine how lipids regulate receptor engagement, lipid-droplet dynamics, lysosomal stress, mitochondrial function, ferroptotic susceptibility, and inflammatory redox signaling. Importantly, glial lipid reprogramming is further shaped by extracellular vesicle-mediated neuron-glia communication, regional lipid heterogeneity, and sex-dependent modifiers of glial metabolism. Oxidative stress therefore reflects the convergence of polyunsaturated fatty acid (PUFA)-enriched membranes, oxidized phospholipids, oxysterols, ceramide accumulation, plasmalogen loss, mitochondrial reactive oxygen species (ROS) production, lysosomal iron release, peroxisomal dysfunction, and declining glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), GTP cyclohydrolase 1-tetrahydrobiopterin (GCH1-BH4), and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent protective systems. Finally, we discuss lipid-centered therapeutic opportunities targeting cholesterol efflux, apolipoprotein E (APOE) lipidation, lipid-droplet metabolism, sphingolipid pathways, lipid peroxide defense, plasmalogen support, extracellular vesicle biology, and lipid-based delivery systems. By shifting the focus from lipid accumulation to lipid identity, compartmental handling, and biological context, this review synthesizes glial lipid reprogramming as an integrative framework linking brain aging to redox-sensitive neurodegeneration.