Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response.

Dietary restriction (DR) increases lifespan in diverse organisms. However, the mechanisms by which DR increases survival are unclear. The insulin/IGF-like signaling (IIS) pathway has been implicated in the response to DR in some studies, while in others it has appeared to play little or no role. We used the fruitfly Drosophila melanogaster to investigate the responses to DR of flies mutant for the transcription factor dFOXO, the main transcription factor target of IIS. We found that lifespan extension by DR does not require dFOXO. However, flies with dFOXO overexpressed in the adult fat body showed an altered response to DR and behaved as though partially dietarily restricted. These results suggest that, although DR extends lifespan of flies in the absence of dFOXO, the presence of active dFOXO modulates the response to DR, possibly by modifying expression of its target genes, and may therefore mediate the normal response to DR.