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. Overall design: C57BL/6NTac female mice at 8 weeks of age were fed a control diet (69.1% kcal carbohydrate, 10.4% kcal fat, 20.5% kcal protein, Envigo®) or an obesogenic diet, which consisted of a combination of a high-fat diet (21.3% kcal carbohydrate, 60.3% kcal fat, 18.4% kcal protein, 5.1 kcal/g, Envigo®) and sweetened condensed milk (55% sugar, 13% fat, 7% protein, 3.25 kcal/g, Nestlé®) for 24 weeks (de Oliveira Silva et al., 2020). To assess the impact of senescent cells removal in obesity-induced metabolic and cardiac dysfunctions, we used a senolytic cocktail. After 16 weeks of obesogenic diet feeding, some obese female mice were treated with a senolytic cocktail containing dasatinib (5mg/kg) and quercetin (50mg/kg) diluted in 10% PEG400, which was administered orally (via gavage) for three consecutive days weekly (Xu et al., 2018) until the 24th week of treatment. Other obese female mice were treated with vehicle (10% PEG400) via oral gavage. Total RNA was isolated from the hearts using the TRIzol protocol (Invitrogen). RNA integrity and quality was assessed using the Qubit RNA. One µg of total RNA per sample was used for the library preparations. The libraries were prepared and sequenced by GENEWIZ (Azenta Life Sciences) using Illumina (2x150bp, at least 60M reads per sample).