Intestinal fork head regulates nutrient absorption and promotes longevity

Reduced activity of nutrient-sensing signalingnetworks can extend organismal lifespan, yet the un-derlying biology remains unclear. We show that theanti-aging effects of rapamycin and reduced intesti-nal insulin/insulin growth factor (IGF) signaling (IIS)require the Drosophila FoxA transcrip tion factorhomolog Fork Head (FKH). Intestinal FKH inductionextends lifespan, highlighting a role for the gut.FKH binds to and is phosphorylated by AKT andTarget of Rapamycin. Gut-specific FKH upregulationimproves gut barrier function in aged flies. Addition-ally, it increases the expression of nutrient trans-porters, as does lowered IIS. Evolutionary conserva-tion of this effect of lowered IIS is suggested by theupregulation of related nutrient transporters in insulinreceptor substrate 1 knockout mouse intestine. Ourstudy highlights a critical role played by FKH in thegut in mediating anti-aging effects of reduced IIS.Malnutrition caused by poor intestinal abso rption isa major problem in the elderly, and a better under-standing of the mechanisms involved will haveimportant therapeutic implications for human aging.