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

Li, Xin1,2,3; Wang, Jiaqiang1; Wang, LeYun1; Gao, Yuanxu4,5; Feng, Guihai1; Li, Gen6; Zou, Jun5; Yu, Meixin6; Li, Yu Fei1; Liu, Chao1; Yuan, Xue Wei1; Zhao, Ling7; Ouyang, Hong7; Zhu, Jian-Kang8,9; Li, Wei1; Zhou, Qi1; Zhang, Kang3

2022-05-25

10.1038/s41392-022-00964-6

Signal Transduction and Targeted Therapy   影响因子和分区

2095-9907

2059-3635

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.

SCI

英语

通讯

Strategic Priority Research Program of the Chinese Academy of Sciences[XDA16030400] ; National Natural Science Foundation of China[31621004,31471395,31701286] ; Key Research Projects of the Frontier Science of the Chinese Academy of Sciences[QYZDY-SSW-SMC002] ; Key deployment projects of the Chinese Academy of Sciences[ZDRW-ZS-2017-4] ; National Basic Research Program of China[2014cB964801] ; China Postdoctoral Science Foundation["2017M610990","2017T100107"] ; China National Postdoctoral Program for Innovative Talents[BX201700243] ; National Key Research and Development Program[2017YFA0103803]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000799821000001

SPRINGERNATURE

2-s2.0-85130759716

Web of Science

1.Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China
2.Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92037 USA
3.Macau Univ Sci & Technol, Fac Med, Tapai 999078, Macau, Peoples R China
4.Macau Univ Sci & Technol, State Key Lab Lunar & Planetary Sci, Tapai 999078, Macau, Peoples R China
5.Sichuan Univ, West China Hosp, Clin Translat Innovat Ctr, Chengdu 610041, Peoples R China
6.Guangzhou Med Univ, Guangzhou Women & Children Med Ctr, Guangzhou 510623, Peoples R China
7.Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Peoples R China
8.Southern Univ Sci & Technol, Inst Adv Biotechnol, Shenzhen 518055, Peoples R China
9.Southern Univ Sci & Technol, Sch Life Sci, Shenzhen 518055, Peoples R China

Li, Xin,Wang, Jiaqiang,Wang, LeYun,et al. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging[J]. Signal Transduction and Targeted Therapy,2022,7(1).

Li, Xin.,Wang, Jiaqiang.,Wang, LeYun.,Gao, Yuanxu.,Feng, Guihai.,...&Zhang, Kang.(2022).Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.Signal Transduction and Targeted Therapy,7(1).

Li, Xin,et al."Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging".Signal Transduction and Targeted Therapy 7.1(2022).