Midlife obesity is a major risk factor for vascular cognitive impairment (VCI) and dementia, but the cellular mechanisms linking obesity to brain microvascular dysfunction remain unclear. Here, we show that high-fat diet (HFD)-induced obesity accelerates cellular senescence within the neurovascular unit (NVU), resulting in structural and functional microcirculatory deficits. Combining multimodal in vivo longitudinal imaging with single-cell RNA sequencing, we identify a senescence-associated transcriptional program in endothelial cells and neurons, coinciding with reduced brain microvascular density, impaired neurovascular coupling (NVC), and disruption of blood-brain barrier (BBB) integrity. These vascular abnormalities associate with cognitive decline in behavioral assays. Transcriptomic profiling further revealed cell-type-specific senescence signatures, including dysregulation of angiogenic, mitochondrial, and inflammatory pathways, which were alleviated by senescent-cell clearance. Notably, clearing p16+ senescent cells partially restored BBB integrity, improved NVC responses, and reduced neuroinflammation. Together, these findings identify cellular senescence as a mechanistic driver of midlife obesity-induced cerebrovascular and cognitive dysfunction and provide proof-of-concept that senescence-targeted therapies may preserve brain health in individuals with midlife obesity who are at risk for dementia.
Keywords: Neurovascular coupling; blood–brain barrier (BBB); cerebral blood flow; endothelial senescence; obesity; senolytics.