PROJECT SUMMARY/ ABSTRACT Aging-induced cerebromicrovascular endothelial dysfunction is the primary factor in impairment of neurovascular coupling (NVC) responses and dysregulation of cerebral blood flow (CBF), contributing to the genesis of vascular cognitive impairment and dementia (VCID). Heterochronic blood exchange (HBE) in mice as well as bioassay experiments in cultured endothelial cells treated with sera from human patients, non-human primates and rodent models of aging provide compelling evidence that implicates non-cell autonomous mechanisms as key drivers of endothelial aging processes. Guided by analysis of vascular transcriptomic changes in heterochronic parabiont mice the objective of the proposal is to elucidate the mechanism of cerebromicrovascular rejuvenation activated by specific circulating anti-geronic factors present in young blood. The central hypothesis is that young blood rescues the age-related decline in signaling via the NAD+/SIRT1 axis and reverses circulating IGF-1 deficiency, each of which can result in vascular mitochondrial rejuvenation, attenuation of endothelial oxidative stress, improved endothelial vasodilator function and restoration of endothelial angiogenic processes. The resulting increases in CBF and NVC responses reduce ischemic loci, promoting brain health. The following aims are proposed: 1) Determine the role of the cerebromicrovascular NAD+ /SIRT1 axis in rejuvenation by HBE. The working hypothesis is that HBE rescues the age-related decline in NAD+, which rejuvenates cerebromicrovascular endothelial cells via a SIRT1-dependent pathway. It is predicted that disruption of the NAD+ /SIRT1 axis will prevent cerebrovascular rejuvenation by HBE in aged mice. 2) Determine the role of circulating IGF-1 in cerebromicrovascular rejuvenation by HBE. The working hypothesis is that HBE reverses age-related IGF-1 deficiency, which exerts multifaceted endothelial protective effects contributing to cerebromicrovascular rejuvenation by young blood. It is predicted that HBE-mediated endothelial functional and transcriptomic changes are partially prevented by disruption of IGF-1/IGFR1 signaling. 3) Determine how circulating NAD precursors and IGF-1 in young and old humans determine cerebromicrovascular endothelial function and phenotype. This will be tested by bioassaying the effects of circulating factors and integrating the results with existing endothelial function, NVC and CBF data from the serum donors. To optimize cognitive status prediction with automated machine learning we will perform association analyses of endothelial signatures with cerebrovascular and cognitive measures using linear mixed effect models. Together, the proposed studies will elucidate the involvement of two key mechanisms in the protective effects of HBE against cerebromicrovascular aging and the pathogenesis of VCID.

RF1AG072295

2021-06-01

2024-05-31