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Background: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption and vascular dementia, are emerging as potential risks for many neurodegenerative diseases. Therefore, the endothelial cells that constitute the cerebrovasculature may play key roles in preventing brain injury. Our previous study showed that CU06-1004, an endothelial cell dysfunction blocker, prevented vascular leakage, enhanced vascular integrity in ischemic reperfusion injury, and promoted the normalization of tumor vasculature. Here, we evaluated the effects of CU06-1004 on age-related cerebrovascular functional decline in the aged mouse brain., Results: In this study, we investigated the protective effects of CU06-1004 against oxidative stress-induced damage in human brain microvascular endothelial cells (HBMECs). HBMECs were treated with hydrogen peroxide (H 2 O 2 ) to establish an oxidative stress-induced model of cellular injury. Compared with H 2 O 2 treatment alone, pretreatment of HBMECs with CU06-1004 considerably reduced oxidative stress-induced cytotoxicity, reactive oxygen species generation, senescence-associated β-galactosidase activity, senescence marker expression, and the expression levels of inflammatory proteins. Based on the observed cytoprotective effects of CU06-1004 in HBMECs, we examined whether CU06-1004 displayed protective effects against cerebrovascular aging in mice. Long-term administration of CU06-1004 alleviated age-associated cerebral microvascular rarefaction and cerebrovascular senescence in the aged mouse brain. CU06-1004 supplementation also reduced the extravasation of plasma IgG by improving BBB integrity in the aged mouse brain, associated with reductions in neuronal injury. A series of behavioral tests also revealed improved motor and cognitive functions in aged mice that received long-term CU06-1004 administration., Conclusions: These findings suggest that CU06-1004 may represent a promising therapeutic approach for delaying age-related cerebrovascular impairment and improving cognitive function in old age., (© 2023. The Author(s).)