The study investigates the impairment of paravascular clearance pathways in the aging brain, which may contribute to cognitive decline and neurodegenerative diseases. Using in vivo and ex vivo techniques, the researchers evaluated CSF-ISF exchange and interstitial solute clearance in young, middle-aged, and old mice. They found that aging significantly reduced the efficiency of CSF-ISF exchange and interstitial solute clearance, with a 40% decrease in amyloid β clearance in old mice. This decline was accompanied by reduced vessel wall pulsatility and widespread loss of perivascular AQP4 polarization. AQP4, an astroglial water channel, is crucial for glymphatic pathway function, and its loss in the aging brain is associated with impaired clearance of interstitial solutes. The study also shows that age-related changes in AQP4 expression and GFAP expression are linked to impaired glymphatic pathway function. These findings suggest that impaired glymphatic clearance may be a novel therapeutic target for neurodegenerative diseases associated with protein aggregation. The study highlights the importance of paravascular pathways in brain waste removal and their decline with age, which may contribute to the vulnerability of the aging brain to neurodegenerative diseases.The study investigates the impairment of paravascular clearance pathways in the aging brain, which may contribute to cognitive decline and neurodegenerative diseases. Using in vivo and ex vivo techniques, the researchers evaluated CSF-ISF exchange and interstitial solute clearance in young, middle-aged, and old mice. They found that aging significantly reduced the efficiency of CSF-ISF exchange and interstitial solute clearance, with a 40% decrease in amyloid β clearance in old mice. This decline was accompanied by reduced vessel wall pulsatility and widespread loss of perivascular AQP4 polarization. AQP4, an astroglial water channel, is crucial for glymphatic pathway function, and its loss in the aging brain is associated with impaired clearance of interstitial solutes. The study also shows that age-related changes in AQP4 expression and GFAP expression are linked to impaired glymphatic pathway function. These findings suggest that impaired glymphatic clearance may be a novel therapeutic target for neurodegenerative diseases associated with protein aggregation. The study highlights the importance of paravascular pathways in brain waste removal and their decline with age, which may contribute to the vulnerability of the aging brain to neurodegenerative diseases.