Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body

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Abstract

InDrosophila melanogaster,ageing is slowed when insulin-like signalling is reduced: life expectancy is extended by more than 50% when the insulin-like receptor (InR) or its receptor substrate (chico) are mutated, or when insulin-producing cells are ablated1-3. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones.Caenorhabditis eleganslifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms4,5, and this requires the forkhead transcription factor (FOXO) encoded bydaf-16(ref.6). TheD. melanogasterinsulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a7,8. We demonstrate here that dFOXO regulatesD. melanogasterageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of theDrosophilainsulin-like peptidedilp-2synthesized in neurons, and represses endogenous insulin-dependent signalling in peripheral fat body. These findings suggest that autonomous and non-autonomous roles of insulin signalling combine to control ageing.

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