miR-146a impedes the anti-aging effect of AMPK via NAMPT suppression and NAD^(+)/SIRT inactivation

作     者：Hui Gong Honghan Chen Peng Xiao Ning Huang Xiaojuan Han Jian Zhang Yu Yang Tiepeng Li Tingting Zhao Haoran Tai Weitong Xu Gongchang Zhang Chuhui Gong Ming Yang Xiaoqiang Tang Hengyi Xiao 

作者机构：The Lab of Aging ResearchNational Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China HospitalSichuan University1 Keyuan 4 RoadGaopeng AvenueChengdu 610093China Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOEState Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu 610041China 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2022年第7卷第4期

页      面：1181-1193页

核心收录：

学科分类：0710[理学-生物学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：the National Natural Science Foundation of China(Grant Nos.81771511,82071589,81800273,81970426,and 82101629) Post-Doctor Research Project,West China Hospital,Sichuan University(Grant No.2021HXBH003) National Key Research and Development Program of China(Grant No.2018YFC2000400). 

主　　题：miR NAMPT prevention 

摘      要：Nicotinamide adenine dinucleotide(NAD^(+))is indispensable for the anti-aging activity of the sirtuin(SIRT)family enzymes.AMPactivated protein kinase(AMPK)upregulates NAD^(+)synthesis and SIRT activity in a nicotinamide phosphoribosyltransferase(NAMPT)-dependent manner.However,the molecular mechanisms that affect AMPK-driven NAMPT expression and NAD^(+)/SIRT activation remain unclear.In this study,we tried to identify senescence-associated microRNAs(miRNAs)that negatively regulate the cascade linking AMPK and NAMPT expression.miRNA-screening experiments showed that the expression of miR-146a increased in senescent cells but decreased following AMPK activation.Additionally,miR-146a overexpression weakened the metforminmediated upregulation of NAMPT expression,NAD^(+)synthesis,SIRT activity,and senescence protection,whereas treatment with the miR-146a inhibitor reversed this effect.Importantly,these findings were observed both in vitro and in vivo.Mechanistically,miR146a directly targeted the 3′-UTR of Nampt mRNA to reduce the expression of NAMPT.AMPK activators metformin and 5-aminoimidazole-4-carboxamide(AICAR)hindered miR-146a expression at the transcriptional level by promoting IκB kinase(IKK)phosphorylation to attenuate nuclear factor-kappaB(NF-κB)activity.These findings identified a novel cascade that negatively regulates the NAD^(+)/SIRT pathway by suppressing miR-146a-mediated NAMPT downregulation.Furthermore,our results showed that miR-146a impedes the anti-aging effect of AMPK.This mutual inhibitory relationship between miR-146a and AMPK enriches our understanding of the molecular connections between AMPK and SIRT and provides new insight into miRNA-mediated NAD^(+)/SIRT regulation and an intervention point for the prevention of aging and age-related diseases.