The study investigates the impairment of paravascular clearance pathways in the aging brain, which is crucial for the removal of protein waste. The glymphatic system, driven by cerebrovascular pulsation and dependent on astroglial water channels (AQP4), facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the brain. The researchers used in vivo and ex vivo fluorescence microscopy and radio-tracer clearance assays to evaluate CSF-ISF exchange and interstitial solute clearance in young, middle-aged, and old mice. They found that aging was associated with a significant decline in the efficiency of CSF-ISF exchange, with a 40% reduction in Aβ clearance in old mice compared to young mice. Additionally, there was a 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along penetrating arteries. These findings suggest that impaired glymphatic clearance contributes to cognitive decline and may represent a novel therapeutic target for neurodegenerative diseases associated with protein aggregation.The study investigates the impairment of paravascular clearance pathways in the aging brain, which is crucial for the removal of protein waste. The glymphatic system, driven by cerebrovascular pulsation and dependent on astroglial water channels (AQP4), facilitates the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in the brain. The researchers used in vivo and ex vivo fluorescence microscopy and radio-tracer clearance assays to evaluate CSF-ISF exchange and interstitial solute clearance in young, middle-aged, and old mice. They found that aging was associated with a significant decline in the efficiency of CSF-ISF exchange, with a 40% reduction in Aβ clearance in old mice compared to young mice. Additionally, there was a 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along penetrating arteries. These findings suggest that impaired glymphatic clearance contributes to cognitive decline and may represent a novel therapeutic target for neurodegenerative diseases associated with protein aggregation.