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PMID:15175753

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Citation

Hwangbo, DS, Gershman, B, Gersham, B, Tu, MP, Palmer, M and Tatar, M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562-6

Abstract

In Drosophila 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 ablated. But we have yet to resolve when insulin affects ageing, or whether insulin signals regulate ageing directly or indirectly through secondary hormones. Caenorhabditis elegans lifespan is also extended when insulin signalling is inhibited in certain tissues, or when repressed in adult worms, and this requires the forkhead transcription factor (FOXO) encoded by daf-16 (ref. 6). The D. melanogaster insulin-like receptor mediates phosphorylation of dFOXO, the equivalent of nematode daf-16 and mammalian FOXO3a. We demonstrate here that dFOXO regulates D. melanogaster ageing when activated in the adult pericerebral fat body. We further show that this limited activation of dFOXO reduces expression of the Drosophila insulin-like peptide dilp-2 synthesized 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.

Links

PubMed Online version:10.1038/nature02549

Keywords

Aging/physiology; Animals; Brain/metabolism; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/physiology; Fat Body/metabolism; Forkhead Transcription Factors; Genes, Insect/genetics; Insect Hormones/genetics; Insect Hormones/metabolism; Insulin/metabolism; Longevity/physiology; Neurons/metabolism; Organ Specificity; PTEN Phosphohydrolase; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptor, Insulin/genetics; Receptor, Insulin/metabolism; Signal Transduction; Stress, Physiological/physiopathology; Survival Rate; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:FOXO

involved_in

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:FOXO

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:FOXO

involved_in

GO:0008286: insulin receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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