Institute 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.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Cell Rep. 2017 Oct 17;21(3):641-653. 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.
营养感应信号网络活性降低可以延长生物体的寿命，但潜在的生物学机制仍不清楚。我们发现雷帕霉素和降低肠道胰岛素/胰岛素生长因子（IGF）信号（IIS）的抗衰老作用需要果蝇 FoxA 转录因子同源物 Fork Head（FKH）。肠道 FKH 的诱导可以延长寿命，这突出了肠道的作用。FKH 与 AKT 和雷帕霉素靶蛋白结合并被其磷酸化。肠道特异性 FKH 的上调可改善老年果蝇的肠道屏障功能。此外，它还像降低 IIS 一样增加营养转运蛋白的表达。降低 IIS 的这种作用的进化保守性可以从胰岛素受体底物 1 敲除小鼠肠道中相关营养转运蛋白的上调得到证明。我们的研究强调了 FKH 在肠道中在介导降低 IIS 的抗衰老作用方面的关键作用。由于肠道吸收不良导致的营养不良是老年人的一个主要问题，更好地了解所涉及的机制将对人类衰老的治疗具有重要意义。
