Acyl‐CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

The omega-3 fatty acid docosahexaenoic (DHA) inversely relates to neurological impairments with aging. However, limited non-dietary in vivo models specifically depleting brain DHA have direct linkage of aging processes. We discovered that loss long-chain acyl-CoA synthetase 6 (ACSL6) depletes membrane phospholipid levels. Here, the effects depletion on behavioral and outcomes across natural progression control Acsl6 knockout mice (Acsl6-/-) were determined. Across lifespan, Acsl6-/- brains contained lower compared controls. DHA-enriched increased arachidonic acid-enriched phospholipids was visualized by MALDI imaging, predominantly neuronal rich regions where robust gene expression localized smFISH neurons brain, including pyramidal, Purkinje, within cerebellar granular layer. ACSL6 also found astrocytes; however, astrocyte-specific did not regulate DHA, a phenomenon attributed alternative-exon variants do prefer as substrate. Total exhibited hyperlocomotion early-onset working spatial memory, cholesterol biosynthesis genes. In response aging, neuroinflammation gliosis developed. Neuroinflammation accompanied major alterations lipid mediators but preceded decreased synaptic proteins. Together our findings suggest is enriched promote enrichment, important for levels protects against disordered motor function, age-related reflecting importance its metabolism ACSL6, early life neuroprotection.