Anti-aging effects of chlorpropamide depend on mitochondrial complex-Ⅱ and the production of mitochondrial reactive oxygen species  

作　　者：Zhifan Mao Wenwen Liu Yunyuan Huang Tianyue Sun Keting Bao Jiali Feng Alexey Moskalev Zelan Hu Jian Li 

机构地区：[1]State Key Laboratory of Bioreactor Engineering,Frontiers Science Center for Materiobiology and Dynamic Chemistry,Shanghai Key Laboratory of New Drug Design,East China University of Science and Technology,Shanghai 200237,China [2]Laboratory of Geroprotective and Radioprotective Technologies,Institute of Biology,Komi Science Centre,Ural Branch,Russian Academy of Sciences,Syktyvkar 167982,Russia [3]Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan,College of Pharmacy,Dali University,Dali 671000,China [4]Clinical Medicine Scientific and Technical Innovation Center,Shanghai Tenth People’s Hospital,Tongji University School of Medicine,Shanghai 200092,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第2期665-677,共13页药学学报（英文版）

基　　金：Financial support for this research provided by the National Natural Science Foundation of China(22037002 and 81772689);the Program for Professor of Special Appointment(Eastern Scholar TP2018025,China)at Shanghai Institutions of Higher Learning;the Innovative Research Team of High-level Local Universities in Shanghai;the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering(2060204,China);Strains of Caenorhabditis elegans were provided by the CGC,which is funded by NIH Office of Research Infrastructure Programs(P40 OD010440)。

摘　　要：Sulfonylureas are widely used oral anti-diabetic drugs.However,its long-term usage effects on patients’lifespan remain controversial,with no reports of influence on animal longevity.Hence,the anti-aging effects of chlorpropamide along with glimepiride,glibenclamide,and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+(mito K-ATP)channels and mitochondrial complex II.Chlorpropamide delayed aging in Caenorhabditis elegans,human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice.In addition,the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms,which is consistent with the function of its reported targets,mito K-ATP channels.Increased levels of mitochondrial reactive oxygen species(mt ROS)were observed in chlorpropamide-treated worms.Moreover,the lifespan extension by chlorpropamide required complex II and increased mt ROS levels,indicating that chlorpropamide acts on complex II directly or indirectly via mito K-ATP to increase the production of mt ROS as a pro-longevity signal.This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C.elegans.

关 键 词：SULFONYLUREAS CHLORPROPAMIDE ANTI-AGING Mitochondrial complexⅡ Mitochondrial reactive oxygen species ATP sensitive potassium channels SENESCENCE Succinate dehydrogenase 

分 类 号：R96[医药卫生—药理学]