Abstract 11782: Senolytic Therapy Improves Diastolic Cardiac Function in Aged Mice

Abstract

Introduction: Cellular senescence, an irreversible arrest of the cell cycle, is a recognized hallmark of aging that contributes to age-related multi-organ dysfunction and diseases. Evidence suggests that cardiomyocyte senescence plays a critical role in the development of age-related cardiac dysfunction. We tested the hypothesis that targeting senescent cells via intermittent administration of the senolytic drugs dasatinib and quercetin (D&Q) will improve cardiac dysfunction in old mice. Methods: 21-month-old C57Bl/6 mice were treated with D&Q or vehicle via oral gavage on a bi-monthly basis for three months. Systolic and diastolic cardiac function were assessed using echocardiography. Expression of inflammatory and matrix metalloproteinase genes was assessed using quantitative polymerase chain reactions. Cardiac tissue morphology was assessed by histological analysis. Results: D&Q treatment improved ejection fraction (EF) in old mice (60.3% vs. 64.5%, con vs. D&Q, p = 0.0207, n=18). Global longitudinal strain was improved by D&Q treatment (-13.99% vs. -17.03%, con vs. D&Q, p=.0005, n=18). Measures of diastolic function were improved after D&Q treatment (n=18 for all): E/E’ (27.60 vs. 20.08, con vs. D&Q, p<.0001), isovolumetric relaxation time (IVRT, 22.74ms vs. 14.99ms, con vs. D&Q, p<.0001), and reverse longitudinal strain rate (rLSR, 4.64 1/s vs. 13.41 1/s, con vs. D&Q, p<.0001). Expression of inflammatory and matrix metalloproteinase genes ( cd3e, foxp3, tnf- α, mcp-1, mmp9 ) was lower in hearts from D&Q treated compared to control mice (p≤0.05). Extracellular matrix collagen expression was lower in cardiac tissue from D&Q treated compared to control (p<0.01). Conclusions: For the first time we report a significant improvement in diastolic function in aged mice when treated long term with the senolytic therapy dasatinib and quercetin. Measurements of systolic function also improved, but not to the same degree as observed for diastolic function. Overall, senolytic therapy with D&Q represents an attractive option to explore for the treatment of diastolic heart failure in humans.