Targeting senescence mitigates the deleterious effects of midlife obesity on neurovascular function by partially restoring blood-brain barrier integrity and neurovascular coupling.

Sharon Negri, Madison Milan, Rakesh Rudraboina, Sherwin A Tavakol, Zeke Reyff, Jennifer Ihuoma, Eva Troyano-Rodriguez, Roland Patai, Rafal Gulej, Woncheol Jung, Hassan Abushukair, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar, Priya Balasubramanian, Michael C Rudolph, Elizabeth A Wellberg, Tae Gyu Oh, Mickael Tanter, Stefano Tarantini

Vascular Cognitive Impairment and Neurodegeneration Program, Department of Neurosurgery, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Oklahoma University Health Campus, Oklahoma City, OK, USA.Vascular Cognitive Impairment and Neurodegeneration Program, Department of Neurosurgery, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Oklahoma University Health Campus, Oklahoma City, OK, USA. · pubmed

Paper

Abstract

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

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Research summary

The paper claims that targeting cellular senescence can restore blood-brain barrier integrity and neurovascular function impaired by midlife obesity. This research is relevant as it addresses the underlying mechanisms of aging-related cognitive decline and explores potential interventions that could mitigate age-related vascular dysfunction.

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