Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases

The phenomenon of an aging population is advancing at a precipitous rate. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common age-associated neurodegenerative diseases, both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures. Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles, including the clearance of macromolecular waste and the trafficking of immune cells. Notably, aquaporin 4-mediated glymphatic transport, crucial for maintaining neural homeostasis, becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD. Functional meningeal lymphatic vessels, which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes, are integral in bridging the central nervous system with peripheral immune responses. Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease. This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders. It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions.