Nature 457, 726-730 (5 February 2009) | doi:10.1038/nature07583; Received 31 July 2008; Accepted 23 October 2008; Published online 14 December 2008

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

Sakiko Honjoh1, Takuya Yamamoto1, Masaharu Uno1 & Eisuke Nishida1

  1. Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto, 606-8502, Japan

Correspondence to: Eisuke Nishida1 Correspondence and requests for materials should be addressed to E.N. (Email: L50174@sakura.kudpc.kyoto-u.ac.jp).

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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