Novel miR-senotherapeutics in age-related atherosclerosis

Aged (senescent) cells that accumulate during the course of a lifetime exert deleterious effects on the surrounding tissue through the secretion of substances that potentiate inflammation but also reinforce the aging of the surrounding tissue. Through such mechanisms, senescent cells contribute to aging and age- related diseases. Elimination of senescent cells using pharmacological agents termed senolytics has been a huge success in the treatment of age-related diseases in preclinical models. However, in the treatment of age-related atherosclerosis, despite the initial success, current senolytics were associated with some side effects. Thus, there is a huge demand to decipher the role of different senescent cell types in disease progression in order to develop more effective strategies to combat atherosclerosis in aging. In this project, we will utilize our previously in vitro-developed microRNA-based approach, termed miR- senotherapeutics, to target senescent cells in order to combat atherosclerosis disease progression. The efficacy of these agents will be tested on our newly developed progeria mouse model with selective premature aging of the endothelial tissue genetically manipulated to develop human-related atherosclerosis. In addition, we will use atheroprone premature (progeria) and physiological ubiquitous aging mouse models to discern endothelial from non-endothelial effects. We will assess the ability of these microRNA agents to reduce atherosclerosis burden, improve cardiac function, and combat associated bone defects in correlation to the reduction of senescent cell burden. This strategy will be complemented with different in vitro approaches to deep dive into the mechanisms of miR-senotherapeutic mode of action. Using a new approach to introduce selective endothelial aging in the in vivo context of atherosclerosis, we expect in this study to gain in vivo insights into how aging affects vasculature and how this in turn affects the surrounding microenvironment in the course of atherosclerosis progression. Importantly, by using novel senomorphic-like miR-based therapies to target senescence and preserve endothelial fitness, we expect to develop more effective strategies to combat age-linked atherogenesis.