Abstract 13452: Age-Related Increases in Arterial Stiffness is Attenuated With Long-Term Senolytic Therapy in Mice

Abstract

Introduction: It has been established that with advancing age, large elastic arteries (i.e. aorta) demonstrate increased stiffening resulting in detrimental CV health outcomes. Cellular senescence, the permanent arrest of the cell cycle, within the vasculature is characterized by a population of cells that are profibrotic and proinflammatory. Profibrotic and proinflammatory environments have been shown to directly lead to increased large artery stiffness (LAS) with aging. We tested the hypothesis that treatment with the senolytic cocktail dasatinib and quercetin (D&Q) will attenuate LAS in aging 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. LAS was measured pre, mid and post treatment by quantifying the aortic pulse wave velocity (aPWV) using a combined Doppler and EKG recording system. Expression of inflammatory genes was assessed by quantitative polymerase chain reaction. Aortic tissue histology was assessed by standard histological methods. Results: D&Q treatment attenuated the age-associated increase in LAS in mice. In the vehicle group, we observed that aPWV increased steadily with age in the vehicle group at 21, 22.5 and 24 months of age (338.9 ± 10.84 cm/s, 351.6 ± 11.53 cm/s, and 369.5 ± 18.57 cm/s respectively, intragroup p=0.004). However, in the D&Q group, we observed a blunted response with corresponding aPWVs (339.5 ± 12.96 cm/s, 322.9 ± 13.9 cm/s, and 342.1 ± 5.67 cm/s; intragroup p=0.7729). Intergroup analysis confirms a significant difference with a p<0.001. Inflammatory markers (TGF-β and TNF-α) were significantly reduced in the D&Q compared to the vehicle group (p<0.05). Extracellular matrix collagen content was lower in aortic tissue from D&Q treated compared to vehicle mice (p<0.01). Conclusions: Chronic, intermittent administration of D&Q prevented the progression of aortic stiffening with advancing age as measured in a longitudinal preclinical mouse study. Aortic inflammatory markers were reduced in the treatment group and similarly the treatment group had attenuated fibrosis vs. vehicle controls. Overall, senolytic therapy represents a potential therapy for aortic fibrosis and age-related increases in large artery stiffness.