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Our previous research established a causal link between vascular senescence induced cerebromicrovascular dysfunction and cognitive decline in accelerated aging models. The present study examines whether chronological aging promotes endothelial senescence, adversely affecting neurovascular health, and whether senolytic therapies can enhance neurovascular function and cognitive performance in aged mice. We used transgenic p16\u20103MR mice to identify and eliminate senescent cells and employed genetic (ganciclovir) and pharmacological (ABT263\/Navitoclax) senolytic approaches. Evaluations included spatial memory performance, NVC responses, cortical microvascular density, BBB permeability, and detection of senescent endothelial cells via flow cytometry. Brain endothelial cells exhibited heightened sensitivity to aging\u2010induced senescence, undergoing senescence at a greater rate and earlier than other brain cell types, particularly during middle age. This microvascular endothelial cell senescence was associated with NVC dysfunction, microvascular rarefaction, BBB disruption, and deteriorating cognitive performance. On the other hand, senolytic treatments in aged mice improved NVC responses, BBB integrity, microvascular density, and learning capabilities. Notably, these findings suggest that the most effective time window for senolytic treatment is in middle\u2010aged mice, where early intervention could better prevent neurovascular dysfunction and mitigate age\u2010related cognitive impairment.<\/jats:p>","DOI":"10.1111\/acel.70048","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T07:45:29Z","timestamp":1743579929000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Senescent Endothelial Cells in Cerebral Microcirculation Are Key Drivers of Age\u2010Related Blood\u2013Brain Barrier Disruption, Microvascular Rarefaction, and Neurovascular Coupling Impairment in Mice"],"prefix":"10.1111","volume":"24","author":[{"given":"Boglarka","family":"Csik","sequence":"first","affiliation":[{"name":"Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery University of Oklahoma Health 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