Abstract 13075: A Novel Senolytic Drug, Seno-7284 Ameliorates Aging and Age-related Cardiometabolic Disorders

Abstract

Introduction: Recent studies have shown elimination of senescent cells, so-called "senolysis" has the potential to become a novel therapy for aging and age-related disorders. However, there is no senolytic drug available in clinical settings currently. Purpose: The present study was aimed to identify a novel senolytic reagent effective for cardiometabolic disease among compounds already available in clinical settings. Here we identified a compound called "seno-7284" which exhibits senolytic effect in murine models of aging and age-related cardiometabolic disorders. Methods: We generated diet-induced obese(DIO) mice model by imposing high-fat diet, atherosclerotic mice model by imposing western diet to ApoE knockout mice. We administered seno-7284 mixed in the diet (0.03% w/w) to each mouse model for 1, 2 or 4 weeks. We harvested tissue samples for molecular biological analysis after measuring glucose/insulin tolerance. We also administered seno-7284 to Zmpste24 homozygous knockout mice as a progeroid mice model from 12-week-old to measure lifespan and to wild-type mice from 1-year-old for 20 weeks to measure physical function. Results: Seno-7284 reduced accumulation of senescent cells in visceral adipose tissue of DIO mice as senescence-associated beta-galactosidase (SA-beta-gal) staining exhibits (figure(fig) a), resulting in improvement of glucose metabolism (fig b). We also found seno-7284 reduced accumulation of senescent cells in the aorta of atherosclerotic mice model (fig c) and inhibited advancing atherosclerosis (fig d). Furthermore, Seno-7284 improved lifespan of progeroid mice (fig e) and physical function of aged mice (fig f). Further analysis including RNA-seq speculated seno-7284 stimulates endogenous senolytic function of immune cells. Conclusion: Our results indicate that seno-7284 would become a promising senolytic drug that exhibits novel therapeutic machinery for aging and age-related cardiometabolic diseases.