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Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans

Abstract

Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of dietary restriction, intermittent fasting (IF) and chronic caloric restriction, have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that the low molecular weight GTPase RHEB-1 has a dual role in lifespan regulation; RHEB-1 is required for the IF-induced longevity, whereas inhibition of RHEB-1 mimics the caloric-restriction effects. RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signalling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signalling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.

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Figure 1: IF extends C. elegans lifespan.
Figure 2: RHEB-1 has a dual role in dietary restriction.
Figure 3: DAF-16 partially mediates IF-induced longevity.
Figure 4: Microarray analyses identify fasting-regulated genes involved in IF-induced longevity.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited with Gene Expression Omnibus at NCBI under the accession number GSE9682.

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Acknowledgements

We thank members of our laboratory for technical comments and helpful discussion. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to E.N.). Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR).

Author Contributions S.H. conceived the study, designed and performed the experiments, and wrote the manuscript with the help of E.N.; S.H. and T.Y. analysed the microarray data; M.U. conducted DAF-16::GFP localization experiments; E.N. supervised the project. All authors discussed the results and commented on the manuscript.

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Correspondence to Eisuke Nishida.

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Honjoh, S., Yamamoto, T., Uno, M. et al. Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans. Nature 457, 726–730 (2009). https://doi.org/10.1038/nature07583

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