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

Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species(1). 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 disorders(2). An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake(2). 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.