Nutritional modulation of the glymphatic system: mechanistic insights and clinical implications

The glymphatic system is a brain-wide perivascular clearance pathway mediated by aquaporin-4 (AQP4) water channels at astrocytic endfeet and plays a key role in eliminating neurotoxic proteins, including amyloid-β, tau, and α-synuclein. Impaired glymphatic function has been implicated in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. While sleep and physical activity are established modulators of glymphatic activity, the role of nutrition remains less clearly defined. This review summarizes current evidence on how nutritional factors may influence glymphatic-relevant biology and the underlying molecular and physiological mechanisms. Emerging studies suggest that micronutrients, bioactive lipids, and phytochemicals may influence glymphatic-relevant processes by regulating AQP4 expression and polarization, preserving blood-brain barrier integrity, reducing oxidative stress and neuroinflammation, improving cerebrovascular function, and supporting sleep and circadian regulation. In contrast, high-fat diets, excessive alcohol intake, and iron overload are associated with adverse glymphatic-relevant changes, including altered AQP4 regulation and less favorable clearance-related markers. Although mechanistic and preclinical evidence is increasing, large-scale human studies with standardized imaging approaches are still needed to determine whether targeted nutritional strategies can meaningfully alter glymphatic-related biology and whether such changes are accompanied by favorable neuroimaging or clinical outcomes.