Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), 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 a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb 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.
Illumina HiSeq 2000 paired end sequencing; Illumina sequencing of C. elegans dauer entry daf-2(el370) sample 1-1 DauerEntryDAF2-1-1 polyA+ 100bp PE RNAseq random fragment library RW0001
Illumina HiSeq 2000 paired end sequencing; Illumina sequencing of C. elegans dauer entry daf-2(el370) sample 1-1 DauerEntryDAF2-1-1 polyA+ 101bp PE RNAseq random fragment library RW0001
Illumina HiSeq 2000 paired end sequencing; Illumina sequencing of C. elegans dauer entry daf-2(el370) sample 1-1 DauerEntryDAF2-1-1 polyA+ 100bp SE RNAseq random fragment library RW0001
Illumina HiSeq 2000 paired end sequencing; Illumina sequencing of C. elegans dauer entry daf-2(el370) sample 1-1 DauerEntryDAF2-1-1 polyA+ 101bp SE RNAseq random fragment library RW0001
We showed that KLF-1 is needed for longevity of isp-1(qm150);ctb-1(qm189) mutant specifically in adulthood. We aimed to determine the expression changes that occur specifically upon adulthood klf-1 RNAi compared to developmental RNAi that did not affect the lifespan of isp-1(qm150);ctb-1(qm189) mutant.