Determining the Chronological Onset of Senescence in the Aging Vasculature

National Institute On Aging

Investigators

Abstract

Senescent cells contribute greatly to the development of vascular diseases and vascular aging, making senescent vascular cells important therapeutic targets. While senolytics have demonstrated moderate effectiveness in animal models, the need for increasingly selective and specific therapeutics remains. We hypothesize that by identifying the time at which arterial function begins to decline (Objective 1) and the accompanying changes in gene and protein expression (Objective 2), we can optimize the administration of senotherapeutics to improve aging outcomes (Objective 3). In the preliminary phase of Objective 1, we performed wire myography to measure smooth muscle-dependent vasodilation in HET3 mice ranging from 6-36 months old (Objective 1). From the same mice, we collected sections of aortas for histology to assess structure and sections for total RNA sequencing to determine gene expression changes with age and function (Objective 2). In preliminary studies for Objective 3, we have begun testing senolytic compounds ABT-737 and Fisetin on old mouse aortas. To do so, we have excised the arteries from mice > 21 months old and incubated them with a vehicle, ABT-737, and Fisetin for 24-48h before measuring their smooth muscle-dependent vasodilation potential. Early results suggest as other studies have shown that Fisetin is not effective at improving arterial stiffness mediated by vascular smooth muscle cells.