The sweet gatekeeper: Mucin-type O-glycans in brain endothelial glycocalyx and aging

The blood-brain barrier (BBB) is crucial for brain homeostasis, and its dysfunction is associated with aging and neurodegenerative diseases. A recent seminal study by Shi et al. (2025) published in Nature illuminates a previously underappreciated component, the brain endothelial glycocalyx, as a key player in age-related BBB breakdown. They demonstrated that aging and neurodegenerative disease can lead to significant structural and compositional dysregulation of the brain endothelial glycocalyx, specifically involving mucin-domain glycoproteins, which ultimately contribute significantly to BBB thinning. Restoring core 1 mucin-type O-glycans can improve BBB function, reduce neuroinflammation, and ameliorate cognitive deficits in aged mice. We contextualize these findings within the broader landscape of glycobiology, neurovascular research, and the concepts of inflammaging and immunosenescence, highlighting recent related discoveries and discussing the limitations and future challenges in translating these insights into therapeutic strategies for healthy brain aging.