Commentary Cellscience Reviews Vol 4 No 1 ISSN 1742-8130

OutFOXed: Two distinct FOX/Forkhead transcription factors mediate longevity
effects of dietary restriction and insulin-like signaling

The insulin-like signaling (ILS) pathway in C. elegans furnished the first instances of genetic mutations able to extend longevity of animals, and at present is the best studied such pathway. It leads from a membrane receptor-kinase, with insulin-like ligands, via a cascade of kinases to a FOXO/Forkhead transcription factor known in the worm as DAF-16, which then modulates expression of a host of target genes. Life extension by dietary restriction (DR) has been established for a much longer time, but has remained poorly understood at the genetic level. Several studies have shown that ILS mutation and DR effects are additive — suggesting that they operate by distinct mechanisms — and moreover that DR does not require DAF-16 to extend life. In a paper recently published in Nature (Panowski, Wolff, et al., 2007), Andrew Dillin’s group tested all 15 Forkhead-like genes defined by sequence similarity, to ask whether any of these (unlike daf-16) is essential for DR effects on life span. RNA interference (RNAi) for one of these genes, known as pha-4 or fkh-1 (orthologous to 3 human Foxa genes) was far more effective than any others in reducing the life span of eat-2 worms, which are long-lived due to genetically restricted food intake. Both loss-of-function mutations and RNAi for pha-4 effectively block any DR influence on lifespan, but do not block life extension arising from mutations in components of ILS or the mitochondrial electron-transport chain. PHA-4 thus appears to function rather specifically in mediating DR effects.

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