Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging  

作　　者：Xin Li Jiaqiang Wang LeYun Wang Yuanxu Gao Guihai Feng Gen Li Jun Zou Meixin Yu Yu Fei Li Chao Liu Xue Wei Yuan Ling Zhao Hong Ouyang Jian-Kang Zhu Wei Li Qi Zhou Kang Zhang 

机构地区：[1]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,100101 Beijing,China [2]Institute for Genomic Medicine,University of California San Diego,La Jolla,CA 92037,USA [3]Faculty of Medicine,Macao University of Science and Technology,Tapai,Macao 999078,China [4]State Key Laboratory of Lunar and Planetary Sciences,Macao University of Science and Technology,Tapai,Macao 999078,China [5]Clinical Translational Innovation Center,West China Hospital,Sichuan University,Chengdu 610041,China [6]Guangzhou Women and Children Medical Center,Guangzhou Medical University,Guangzhou 510623,China [7]Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou 510060,China [8]Institute of Advanced Biotechnology and School of Life Sciences,Southern University of Science and Technology,Shenzhen 518055,China

出　　处：《Signal Transduction and Targeted Therapy》2022年第6期2105-2116,共12页信号转导与靶向治疗（英文）

基　　金：supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030400 to Q.Z.and W.L.);National Natural Science Foundation of China(31621004 to Q.Z.and W.L.,31471395 to Q.Z.,and 31701286 to G.F.);Guangzhou Laboratory(to K.Z.),the Key Research Projects of the Frontier Science of the Chinese Academy of Sciences(QYZDY-SSW-SMC002 to Q.Z.);the Key deployment projects of the Chinese Academy of Sciences(ZDRW-ZS-2017-4 to W.L.);the National Basic Research Program of China(2014cB964801 to W.L.);the China Postdoctoral Science Foundation(2017M610990 and 2017T100107 to J.W.);the China National Postdoctoral Program for Innovative Talents(BX201700243 to L.W.);the National Key Research and Development Program(2017YFA0103803 to Q.Z.).

摘　　要：Epigenetic alterations and metabolic dysfunction are two hallmarks of aging.However,the mechanism of how their interaction regulates aging,particularly in mammals,remains largely unknown.Here we show ELOVL fatty acid elongase 2(Elovl2),a gene whose epigenetic alterations are most highly correlated with age prediction,contributes to aging by regulating lipid metabolism.We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate.Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction,leading to key aging phenotypes at both cellular and physiological level.Furthermore,restoration of mitochondrial activity can rescue age-related macular degeneration(AMD)phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial(RPE)cells;this indicates a conservative mechanism in both human and mouse.Taken together,we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies.

关 键 词：METABOLISM alterations DYSFUNCTION 

分 类 号：R589[医药卫生—内分泌]