Polar lipids, omega-3 polyunsaturated fatty acids homeostasis, and brain aging: Mechanisms, dietary sources, and neuroprotection.

Abstract

The relationship between lipid metabolism and neurodegeneration is a critical determinant of brain aging with therapeutic implications. This review focuses on how polar lipids and omega-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), contribute to membrane organization, signaling, neuroinflammation resolution, and cognitive resilience during aging. The mammalian brain, containing over 50% lipids by dry weight, is exceptionally enriched in DHA, which preferentially accumulates in cognitive-critical regions including the hippocampus and prefrontal cortex. Age-related decline in brain PUFA content is a consistent finding across species and is linked to lower synaptic density, neuronal loss, and cognitive impairment. This decline results from converging mechanisms including impaired transport across the blood-brain barrier, oxidative damage, altered lipid remodeling, and reduced inflammatory resolution. We also discuss how dietary intake, endogenous PUFA biosynthesis, sex, obesity, and hepatic metabolic dysfunction may modify brain PUFA availability. Clinical evidence suggests that omega-3 interventions may provide selective cognitive benefits, particularly for executive function and in genetically susceptible populations such as APOE4 carriers, although effects differ according to dose, formulation, and baseline status. Complex lipid sources including milk fat globule membrane may offer advantages beyond simple fatty acid supplementation by improving the delivery of bioactive polar lipids. Overall, the field is moving toward mechanism-informed and precision nutrition strategies to preserve brain health across the lifespan.