Abstract 13311: A Novel Senolytic Drug, Seno-7284 Ameliorates Age-Related Cardiometabolic Diseases

Abstract

Cellular senescence plays a pivotal role in aging and age-related disorders. Recently, it was shown that elimination of senescent cells, so-called "senolysis" has the potential to become a next generation therapy for age-related disorders including cardio-metabolic diseases. However, currently there is no senolytic drug available in clinical settings. The present study was aimed to identify a novel senolytic reagent effective for cardiometabolic diseases in compounds already available in clinical settings. We demonstrate a compound called "Seno-7284" exhibits senolytic effect in murine models of type 2 diabetes, atherosclerosis, progeroid and chronological aged mice. Seno-7284 reduced the accumulation of senescent cells in visceral adipose tissue of diabetic mice as senescence-associated-beta-galactosidase (SA-beta-gal) staining exhibits. This associated with the suppression in systemic glucose intolerance, and adipose tissue inflammation in four weeks after the administration of Seno-7284. Administrating Seno-7284 for two weeks also suppressed the progression of atherosclerosis in ApoE-KO mice. This drug significantly improved the lifespan of Zm-KO mice by administering it from 12 weeks old. Administration of Seno-7284 from 50 week-old for 20 weeks improves physical function in chronological aged mice. Further analysis including single cell RNA-seq suggested that Seno-7284 stimulates endogenous senolytic function of NK cells and CD8+ T cells. Our results indicate Seno-7284 mediates its biological effects by inducing senolysis in murine aging models. Seno-7284 would become promising therapies for age-related disorders.