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Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity.

Ekin Bolukbasi1, Mobina Khericha1, Jennifer C Regan1

  • 1Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Gower St, London WC1E 6BT, UK; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.

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|October 19, 2017
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Summary
This summary is machine-generated.

The gut transcription factor Fork Head (FKH) is crucial for extending lifespan through reduced nutrient sensing. Upregulating FKH in the intestine improves gut function and nutrient absorption, offering therapeutic potential for aging.

Keywords:
DrosophilaFOXAabsorptionenterocytesinsulinlifespanlongevitymidgut

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Area of Science:

  • Aging Biology
  • Molecular Genetics
  • Gastroenterology

Background:

  • Reduced activity in nutrient-sensing pathways, like insulin/IGF signaling (IIS), is linked to extended lifespan.
  • The precise molecular mechanisms underlying these anti-aging effects are not fully understood.
  • The gut's role in aging and nutrient absorption is a significant area of research.

Purpose of the Study:

  • To investigate the role of the Drosophila FoxA homolog, Fork Head (FKH), in mediating the anti-aging effects of reduced nutrient-sensing signaling.
  • To determine if intestinal FKH induction can extend lifespan and improve gut function.
  • To explore the molecular interactions of FKH with key aging pathways like AKT and Target of Rapamycin (TOR).

Main Methods:

  • Utilized Drosophila melanogaster as a model organism.
  • Investigated the requirement of FKH for the lifespan-extending effects of rapamycin and reduced IIS.
  • Examined the impact of intestinal FKH induction on lifespan, gut barrier function, and nutrient transporter expression.
  • Analyzed FKH binding and phosphorylation by AKT and TOR.
  • Assessed nutrient transporter expression in insulin receptor substrate 1 knockout mice.

Main Results:

  • The anti-aging effects of rapamycin and reduced IIS in Drosophila depend on the transcription factor FKH.
  • Induction of FKH specifically in the intestine extends fly lifespan.
  • Upregulation of FKH in the gut improves barrier function in aged flies and increases nutrient transporter expression.
  • FKH interacts with and is phosphorylated by AKT and TOR.
  • Lowered IIS also increases nutrient transporter expression, an effect conserved in mouse models.

Conclusions:

  • FKH in the gut is a critical mediator of anti-aging effects associated with reduced IIS.
  • Targeting FKH in the intestine may offer therapeutic strategies for age-related decline in nutrient absorption and overall health.
  • This research highlights the gut as a key organ in aging processes and nutrient sensing.