Two conserved epigenetic regulators prevent healthy ageing

Jie Yuan, Si-Yuan Chang, Shi-Gang Yin, Zhi-Yang Liu, Xiu Cheng, Xi-Juan Liu, Qiang Jiang, Ge Gao, Lin De-Ying, Xin-Lei Kang, Shi-Wei Ye, Zheng Chen, Jiang-An Yin, Pei Hao, Lubin Jiang () and Shi-Qing Cai ()
Additional contact information
Jie Yuan: Chinese Academy of Sciences
Si-Yuan Chang: Chinese Academy of Sciences
Shi-Gang Yin: Chinese Academy of Sciences
Zhi-Yang Liu: Chinese Academy of Sciences
Xiu Cheng: Chinese Academy of Sciences
Xi-Juan Liu: Chinese Academy of Sciences
Qiang Jiang: Chinese Academy of Sciences
Ge Gao: Chinese Academy of Sciences
Lin De-Ying: Chinese Academy of Sciences
Xin-Lei Kang: Chinese Academy of Sciences
Shi-Wei Ye: Chinese Academy of Sciences
Zheng Chen: Zhejiang Wanli University
Jiang-An Yin: Chinese Academy of Sciences
Pei Hao: Chinese Academy of Sciences
Lubin Jiang: Chinese Academy of Sciences
Shi-Qing Cai: Chinese Academy of Sciences

Nature, 2020, vol. 579, issue 7797, 118-122

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41586-020-2037-y

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