Senolytics to Improve Cognition and Mobility in Older Adults at Risk of Alzheimer’s Disease

抽象/项目总结

Abstract/Project Summary Abnormalities in cognition and mobility are common accompaniments of aging that often precede the development of Alzheimer’s disease. Among their many etiologies, these abnormalities are associated with alterations in the regulation of cerebral blood flow to frontal regions of the brain that subserve executive functions and gait speed. We have previously shown that treatment with cocoa flavanols can improve blood flow in response to a cognitive task (neurovascular coupling [NVC]), as well as executive function in older people with impaired NVC. These compounds can also reduce the number of senescent cells and their toxic secretory products (SASP) in a variety of tissues. In mice, “senolytic” compounds such as flavanols and tyrosine kinase inhibitors, have been shown to reduce neurofibrillary tangle density, neuron loss, and ventricular enlargement, and in humans with idiopathic pulmonary fibrosis, improve gait speed and other functional abilities. Based on these findings, we hypothesize that the flavanol, Quercetin, and tyrosine kinase inhibitor, Dasatinib, (Q+D) will improve NVC in response to an executive task, reduce circulating SASP components, and in so doing, improve cognition and mobility in older adults who are at risk of Alzheimer’s disease. Our specific aims are: 1) To conduct a 12-week single arm, open label, pre-post pilot study to determine the feasibility and recruitment challenges of studying intermittent doses of Quercetin and Dasatinib (Q+D) in 12 older adults aged 70 to 90 years with slow gait speed (<1.0 m/sec) and Mild Cognitive Impairment; 2) To obtain preliminary data on the effect of this Q+D regimen on: a) resting cerebral blood flow (CBF) and neurovascular coupling (NVC) during an executive task, b) gait speed and executive function, and c) other secondary measures of physical and cognitive performance; and 3) To develop preliminary evidence concerning whether Q+D is associated with a) a reduction in biomarkers of senescence in serum and urine and senescent cells in blood, and b) whether reductions in these biomarkers are associated with improvements in NVC, gait speed, and executive function. This research will leverage the expertise and resources of the Boston Pepper Center and Mayo Clinic-based Translational Geroscience Network. Its results may identify a novel approach for improving cerebral blood flow regulation, mobility, and cognition in older adults, and preventing their progression to Alzheimer’s disease. The study may also help establish proof-of-concept that the cognitive and functional disabilities of older age may arise, in part, from the secretory products of senescent cells and be alleviated by senolytic agents.