Fasting (intermittent, IF, or alternate day, ADF) may be the newest diet craze rivaling calorie restriction (CR) to increase longevity and improve health. Recent reports have shown that fasting diets can confer health benefits similar to (or even greater than) those of chronic calorie restriction (CR), without reducing the number of calories consumed relative to an ad libitum diet. The molecular mechanisms underlying the IF diet induced longevity are not well understood.

Honjoh et. al. established a fasting diet regimen in C. elegans to study molecular pathways involved in fasting induced longevity. They found that alternate day fasting (ADF) had a 40.4% increase in lifespan, and intermittent fasting (IF: every two days) had a 56.6% increase in lifespan over ad libitum fed worms. In contrast, chronic CR only increased lifespan by an average of 13.2%.

CR and IF may have similar effects on lifespan, but results reported in this paper indicate that signals in each of these processes are distinct. skn-1 and pha-4 have been shown to be essential genes in the CR longevity phenotype, but are dispensable in IF longevity.

Two proteins that were found to be important in this model of IF induced longevity are RHEB-1 (Ras homologue enriched in brain) and it’s downstream target, TOR (target of rapamycin). Inactivating either of these genes suppressed the longevity of worms on the IF diet, adding support to the role RHEB and TOR proteins play in influencing lifespan. Interestingly, inactivation of RHEB-1 did not mimic IF longevity, instead it recapitulated CR in lifespan increase and target gene activation. Thus, the authors conclude that RHEB-1 has a dual role in lifespan regulation.

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

RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signaling 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 signaling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signaling 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 signaling pathway.

The authors performed a microarray on fasted worms with or without RHEB-1 or TOR RNAi to identify gene expression changes. They found that the majority of genes that were upregulated as a result of fasting were dependent on RHEB-1 and TOR (100 out of 112 genes and 94 out of 112, respectively). RNAi of either RHEB-1 or TOR suppressed the induction of these genes in fasting. Through further analyses, hsp-12.6 (the C. elegans orthologue of αB-crytallin) and ins-7 (insulin-like peptide 7) were identified as downstream targets of RHEB-1 and TOR and are critical for mediating the IF-induced longevity phenotype.

It will be important to follow up on these findings, which elucidate the molecular pathways behind longevity diets, to determine how different diets overlap (or are distinguished) at the molecular level – especially considering that it seems improbable that people will willingly embrace a lifelong restricted diet to improve their health and lifespan. Understanding these pathways and factors involved will hopefully advance our ability to develop pharmaceuticals to mimic the benefits observed in these longevity diets.