Brain Endothelial Senescence and Vascular Density in Mid-Life Obesity: Exploring Neurovascular Dysfunction and Cognitive Impairment

Abstract

The obesity epidemic is a major health challenge in the United States, with more than 42% of American adults being obese. Growing evidence shows that mid-life obesity has detrimental effects on cerebrovasculature, and it compromises cerebral blood flow (CBF) regulation and promotes the pathogenesis of vascular cognitive impairment and dementia (VCID). The cerebral microcirculation and the "neurovascular unit" (NVU) play a key role in maintaining healthy brain function. Our previous studies have shown that obesity-induced NVU dysfunction impairs endothelium-mediated neurovascular coupling (NVC) and contributes to VCID. Although great advances have been made in the last decade, the cellular mechanisms underlying NVU dysfunction, CBF dysregulation and NVC impairment remain not clear and there are no available treatments. Cellular senescence is a typical cellular response that occurs in physiological and pathological conditions. In this context, we found that middle-life obesity promotes cellular senescence in the brain and in the vasculature. Moreover, senescence of cells within the NVU has been linked to cognitive impairment and neuro-vascular dysfunction. To provide proof-of-concept for our studies on obesity induced NVU senescence, we used the novel transgenic mouse model (p16-3MR mouse), which allows the visualization and selective elimination of senescent cells. We evaluated senescence through the expression of RFP (senescent marker) with flow cytometry and through the analysis of single cell transcriptomic. NVC and vascular density was measured with functional ultrasound imaging (ICONEUS) and cognitive function was tested with radial arm water maze test (RAWM). We found increased senescence in endothelial cells in high fat diet-fed (HFD; 60% kcal from fat) mice compared to ones fed with standard diet (SD; 10% kcal from fat). Moreover, we demonstrated the functional significance of senescent cells by treating older HFD-fed obese mice with the well-characterized, potent senolytic compound Navitoclax/ABT263, which selectively kills senescent cells. We found that in obese older mice NVC responses were significantly impaired and were rescued by senolytic treatment. HFD-fed mice had impaired learning plasticity in RAWM. Restoration of NVC responses by ABT263 treatment associated with significant cognitive benefit. Overall, our work is novel in that it will be the first to demonstrate that obesity-induced senescence is a critical contributing factor to the pathogenesis of VCID, providing insights into potential therapeutic interventions. NIH R03AG070479, K01AG073614, R21AG080775, American Heart Association, Hevolution/AFAR. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.