The effect of senescent cells depletion in obese hearts

Obesity is a major contributor to metabolic and cardiovascular diseases. Senescence is a highly dynamic process activated by diverse stimuli and increased cellular senescence has been associated with age-related disorders. Here, we investigated the impact of cellular senescence in obesogenic diet-related metabolic and cardiac dysfunctions. An obesogenic diet induced an increase on body weight gain and adiposity, glucose intolerance, insulin resistance, dyslipidemia, and hepatic disorders in mice; however, these alterations were prevented by a senolytic cocktail (dasatinib and quercetin), which leads to removal of senescent cells. In addition, the elimination of senescent cells counteracted the activation of the senescent program and DNA damage in the white adipose tissue (WAT) induced by an obesogenic diet. Obese mice had an increase of the senescence-associated secretory phenotype (SASP) and DNA damage in the heart, cardiac hypertrophy, and diastolic dysfunction; however, the use of a senolytic combination abolished these myocardial alterations caused by an obesogenic diet. Transcriptomic analysis of the hearts revealed that obese mice exhibited a downregulation of genes associated with fatty acid metabolism, oxidative phosphorylation, PI3K AKT MTOR signaling, P53 pathway, and DNA repair; however, the treatment with senolytic cocktail induced an increase of these pathways in the heart. Collectively, these data suggest that obesogenic diet elicits WAT and cardiac senescence program in mice, and that targeting senescent cells may be a novel therapeutic strategy for attenuating obesity-related metabolic and cardiac disorders.