Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity.
Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity.
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DOI：
10.1016/j.celrep.2017.09.042
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发表时间：
2017-10-17
期刊：
影响因子：
8.8
通讯作者：
Partridge L
中科院分区：
文献类型：
--
作者：
Bolukbasi E;Khericha M;Regan JC;Ivanov DK;Adcott J;Dyson MC;Nespital T;Thornton JM;Alic N;Partridge L
降低营养感应信号网络的活性可以延长生物体的寿命，但其背后的生物学机制仍不清楚。我们发现，雷帕霉素的抗衰老作用和减少肠道胰岛素/胰岛素生长因子（IGF）信号（IIS）需要果蝇FoxA转录因子同源物叉头（FKH）。肠道FKH诱导延长寿命，突出了肠道的作用。FKH与AKT和雷帕霉素的靶标结合并被其磷酸化。肠道特异性FKH上调可改善老年果蝇的肠道屏障功能此外，它增加了营养转运蛋白的表达，降低了IIS。胰岛素受体底物1基因敲除小鼠肠道中相关营养转运蛋白的上调提示了这种降低IIS的作用的进化保守性。我们的研究强调了FKH在肠道中介导IIS减少的抗衰老作用中发挥的关键作用。由肠道吸收不良引起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具有重要的治疗意义。果蝇FKH与AKT和TOR的生物化学相互作用IIS和雷帕霉素诱导的长寿需要FKH肠道组织，特别是分化的细胞，介导FKH的促长寿效应FKH在肠道中的活性上调肠道营养转运蛋白Bolukbasi et al.确定转录因子FKH作为果蝇中营养感应途径信号传导的介导者，并且他们表征了FKH通过该网络在延长寿命中的重要参与。他们指出了FKH对肠道的促长寿作用，并显示FKH活性增加了营养转运蛋白的表达和屏障功能的改善。
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. 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.
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