The precursor of PI(3,4,5)P3 alleviates aging by activating daf-18(Pten) and independent of daf-16

Dawei Shi, Xian Xia, Aoyuan Cui, Zhongxiang Xiong, Yizhen Yan, Jing Luo, Guoyu Chen, Yingying Zeng, Donghong Cai, Lei Hou, Joseph McDermott, Yu Li, Hong Zhang and Jing-Dong J. Han ()
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Dawei Shi: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Xian Xia: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Aoyuan Cui: University of Chinese Academy of Sciences
Zhongxiang Xiong: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Yizhen Yan: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Jing Luo: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Guoyu Chen: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Yingying Zeng: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Donghong Cai: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Lei Hou: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Joseph McDermott: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)
Yu Li: CAS Key Laboratory of Nutrition, Metabolism and Food Safety, SINH, SIBS, CAS
Hong Zhang: University of Chinese Academy of Sciences
Jing-Dong J. Han: Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS)

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates—metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI’s anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.

Date: 2020
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DOI: 10.1038/s41467-020-18280-4

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