Long-term Omega-3 Polyunsaturated Fatty Acid Supplementation Improves Meningeal Lymphatic Function During Brain Aging in Mice.

Abstract

Emerging evidence implicates that meningeal lymphatic dysfunction may contribute to the pathogenesis of brain age-related diseases, suggesting its potential as a therapeutic target for brain aging. This study investigated whether long-term Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) supplementation could delay brain aging through meningeal lymphatic modulation. We randomly assigned C57BL/6J mice into control, low-dose, and high-dose Omega-3 PUFAs groups, and administered dietary supplementation for 12 months until reaching 24 months of age. We then assessed the anti-aging effects on brain function and further examined meningeal lymphatic performance in clearance capacity and immune regulation. Our findings demonstrate that long-term Omega-3 PUFAs supplementation increases docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels in the brain, reduces age-related neuronal loss, and improves motor and cognitive behaviors in aged mice. Additionally, it reduces accumulation of toxic proteins (phosphorylated tau and amyloid-β) and metabolites (NADPH, succinyl-CoA, and cAMP) in the brain and decreases immune cell infiltration (CD68+ microglia and CD3+ T cells) in the central nervous system of aged mice. Furthermore, we demonstrate that these protective effects may be mediated through preservation of the meningeal lymphatic system during aging. In conclusion, this study elucidates a novel understanding of the anti-brain-aging mechanisms of Omega-3 PUFAs.