Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity

• Published in: Cell reports (Cambridge) 2017-10, Vol.21 (3), p.641-653
• Main Authors: Bolukbasi, Ekin, Khericha, Mobina, Regan, Jennifer C., Ivanov, Dobril K., Adcott, Jennifer, Dyson, Miranda C., Nespital, Tobias, Thornton, Janet M., Alic, Nazif, Partridge, Linda
• Format: Article
• Language: English
• Subjects: absorption; Animals; Caloric Restriction; Cell Differentiation - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Drosophila; Drosophila melanogaster - metabolism; Drosophila melanogaster - physiology; Drosophila Proteins - metabolism; enterocytes; Enterocytes - drug effects; Enterocytes - metabolism; Female; Food; Forkhead Transcription Factors - metabolism; FOXA; insulin; Insulin - metabolism; Insulin Receptor Substrate Proteins - metabolism; Intestinal Absorption - drug effects; Intestinal Mucosa - metabolism; Intestines - cytology; lifespan; longevity; Longevity - drug effects; Membrane Transport Proteins - metabolism; midgut; Nuclear Proteins - metabolism; Oxidative Stress - drug effects; Phosphorylation - drug effects; Protein Binding - drug effects; Protein Transport - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Sirolimus - pharmacology; Somatomedins - metabolism; Transcription, Genetic - drug effects; Up-Regulation - drug effects
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.09.042

Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. Our study highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging. [Display omitted] •Drosophila FKH biochemically interacts with AKT and TOR•IIS- and rapamycin-induced longevity requires FKH•Gut tissue, specifically differentiated cells, mediates FKH’s pro-longevity effects•FKH activity in the gut upregulates intestinal nutrient transporters Bolukbasi et al. identify the transcription factor FKH as a mediator of nutrient-sensing pathway signaling in Drosophila, and they characterize FKH’s essential involvement in increased longevity via this network. They pinpoint FKH’s pro-longevity effect to the gut, and they show increased expression of nutrient transporters and improvement of barrier function by FKH activity.