Abstract

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.

Details

Title
Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging
Author
Li, Xin 1 ; Wang, Jiaqiang 2 ; Wang LeYun 2 ; Gao Yuanxu 3 ; Feng Guihai 2 ; Li, Gen 4 ; Zou, Jun 5 ; Yu Meixin 4 ; Li, Yu Fei 2 ; Liu, Chao 2 ; Yuan Xue Wei 2 ; Zhao, Ling 6 ; Ouyang, Hong 6   VIAFID ORCID Logo  ; Jian-Kang, Zhu 7 ; Li, Wei 2   VIAFID ORCID Logo  ; Zhou, Qi 2 ; Zhang, Kang 8 

1  State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (GRID:grid.458458.0) (ISNI:0000 0004 1792 6416); University of California San Diego, Institute for Genomic Medicine, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Faculty of Medicine, Macau University of Science and Technology, Tapai, Macau, China (GRID:grid.259384.1) (ISNI:0000 0000 8945 4455) 
2  State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (GRID:grid.458458.0) (ISNI:0000 0004 1792 6416) 
3  Macau University of Science and Technology, Tapai, State Key Laboratory of Lunar and Planetary Sciences, Macau, China (GRID:grid.259384.1) (ISNI:0000 0000 8945 4455); Sichuan University, Clinical Translational Innovation Center, West China Hospital, Chengdu, China (GRID:grid.13291.38) (ISNI:0000 0001 0807 1581) 
4  Guangzhou Medical University, Guangzhou Women and Children Medical Center, Guangzhou, China (GRID:grid.410737.6) (ISNI:0000 0000 8653 1072) 
5  Sichuan University, Clinical Translational Innovation Center, West China Hospital, Chengdu, China (GRID:grid.13291.38) (ISNI:0000 0001 0807 1581) 
6  Sun Yat-sen University, Zhongshan Ophthalmic Center, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
7  Southern University of Science and Technology, Institute of Advanced Biotechnology and School of Life Sciences, Shenzhen, China (GRID:grid.263817.9) (ISNI:0000 0004 1773 1790) 
8  Faculty of Medicine, Macau University of Science and Technology, Tapai, Macau, China (GRID:grid.259384.1) (ISNI:0000 0000 8945 4455) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
ISSN
20959907
e-ISSN
20593635
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41392-022-00964-6
ProQuest document ID
2668568592
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.