Targeting senescence as a new promising approach in treatment of metabolic diseases

Introduction: Obesity and type 2 diabetes mellitus (T2DM) represent a major health problems with increasing prevalence worldwide. Limited efficacy of current therapies have prompted a search for novel therapeutic options. Changes induced by long-standing, poorly controlled obesity followed by the development of T2DM are linked to premature senescence in various tissues, contributing to further deterioration of their function and eventually to the development of chronic irreversible complications. Since mitochondria play a key role in development and maintenance of cellular senescence, our goal was to develop new, tamoxifen independent mitochondria-targeted senolytic agents and test their potential to improve metabolic diseases and pathologies related to T2DM. Methods: C57BL/6 male mice (n=8-10) fed with SD (standard diet for 8 month), HFD (high fat diet for 8 month) were treated with MitoTam (MT; 2 mg/kg dissolved in 4 % ethanol in corn oil), compound X (2mg/kg dissolved in 4 % ethanol in corn oil) or the vehicle (CO) given i.p. twice per week for a period of 4 weeks. Results: Our data show, that compared to non-treated mice HFD mice compoud X improved glucose parameters, reduced body weight and adipose tissue mass similarly as previously used MitoTam. Glucose-lowering effect of compound X was linked to improvement of T2DM-related hormones profile and was accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues also resulted in lower level of circulating inflammatory mediators that enhance metabolic dysfunction. Moreover, decreased presence of senescent cells reduced pancreatic fibrosis, a frequently occurring complication of T2DM that worsen its progression. Mice treated with compound X showed lower accumulation of fibrotic cells in pancreas followed by decreased inflammation and improvement of hyperinsulinemia. Compound X also showed direct effect on reduction of pancreatic adenocarcinoma compared to MitoTam. This indicates, that compound X reduces not only risk of development of pancreatitis, but also prevents/reduces risk of development of pancreatic cancer. Conclusions: Mitochondria-targeted senolytic agents represent promising therapy for metabolic diseases and prevention of their chronic complications including cancers development.