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Nature. 2020 Mar;579(7797):118-122. doi: 10.1038/s41586-020-2037-y. Epub 2020 Feb 26.

Two conserved epigenetic regulators prevent healthy ageing.

Yuan J1,2, Chang SY1,2, Yin SG3,2,4, Liu ZY1,2, Cheng X3,2, Liu XJ1, Jiang Q1, Gao G1,2, Lin DY1,2, Kang XL1, Ye SW1, Chen Z5, Yin JA1, Hao P3, Jiang L6,7, Cai SQ8,9.

Author information

1
Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
2
University of Chinese Academy of Sciences, Beijing, China.
3
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
4
Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
5
College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo, China.
6
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China. lbjiang@ips.ac.cn.
7
School of Life Science and Technology, ShanghaiTech University, Shanghai, China. lbjiang@ips.ac.cn.
8
Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. sqcai@ion.ac.cn.
9
Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China. sqcai@ion.ac.cn.

Abstract

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated1-6. Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan4,7. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases8,9 shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.

PMID:
32103178
DOI:
10.1038/s41586-020-2037-y

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