The risk of cardiovascular disease increases with age. In the brain, this dysfunction leads to reduced cerebral blood flow, increased vascular permeability, and impaired cognition. Vascular Dementia (VD) is the second leading cause of cognitive impairment, driven by limits in cerebrovascular function, and lacks effective therapeutics. As endothelial dysfunction frequently precedes cerebrovascular disease, endothelial cells underpin this pathophysiological remodeling linking aging to cerebrovascular health. However, the specific role of the endothelium in the pathogenesis of Vascular Dementia remains insufficiently described. Exercise has shown promise in improving cerebral perfusion, neurovascular function, and cognitive performance. As the primary mediator of exercise-induced cardiometabolic changes, skeletal muscle (SKM) is the primary target for studying the effects of exercise. Prior studies from our lab have demonstrated that deletion of myostatin (MSTN), a potent negative regulator of skeletal muscle growth, can improve endothelial function. Sestrin 1 (SESN1), a mediator of cellular stress responses and exercise adaptability, is a potential mediator of the effects of MSTN deletion. In the current study, 60-week-old C57BL/6 mice showed impaired spatial memory and executive function as well as reduced endothelial SESN1 expression. Deletion of MSTN improved cognition and increased SESN1 expression in aged mice, suggesting that muscle mass is protective against cognitive decline. To assess the contribution of the endothelium to pathophysiological aging in cerebrovascular dysfunction, we use mice floxed for zinc-metallopeptidase STE24 (ZMPSTE24). In the absence of ZMPSTE24, cells rapidly age and produce a progeric-like phenotype. To delete ZMPSTE24 in the cerebrovascular endothelium, we used adeno-associated virus (AAV) with cerebral endothelial cell tropism (AAV X1.1) to deliver a Cre recombinase payload. The results of ZMPSTE24 knockdown in our mice showed decreased spatial memory and executive function, decreased cerebral blood flow, and decreased SESN1 expression, recapitulating results from our 60-week-old mice. These findings support the concept that endothelial cell aging is sufficient to account for aging-induced cerebrovascular dysfunction, potentially mediated through SESN1. Whether targeting SESN1 and skeletal muscle is sufficient protect vascular and cognitive function in endothelial-specific aging remains to be determined. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Bridgewater et al. (Fri,) studied this question.