Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway
Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway
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DOI：
10.1016/j.cub.2004.03.059
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发表时间：
2004-05-25
期刊：
影响因子：
9.2
通讯作者：
Benzer, S
中科院分区：
文献类型：
--
作者：
Kapahi, P;Zid, BM;Benzer, S
在许多物种中，在不导致营养不良的情况下减少营养摄入可延长寿命[1 - 3]。与饮食限制（DR）一样，对胰岛素信号通路中基因的调节（已知其可改变营养感知）已被证明可在多种物种中延长寿命[1 - 4]。在果蝇中，雷帕霉素靶蛋白（TOR）和胰岛素通路已成为生长和体型的主要调节因子。因此，我们利用果蝇研究了TOR通路基因在调节寿命中的作用。我们表明，通过改变这种从酵母到人类都保守的营养感知通路中的基因表达来抑制TOR信号通路，能够以一种可能与饮食限制对长寿的已知影响重叠的方式延长寿命。在果蝇中，TSC1和TSC2（结节性硬化症复合物基因1和2）共同作用以抑制TOR（雷帕霉素靶蛋白），TOR介导一个将氨基酸可用性与S6激酶、翻译起始和生长相耦合的信号通路[5]。我们发现，dTsc1、dTsc2的过表达，或者dTOR或dS6K的显性负性形式都能导致寿命延长。在脂肪中调节表达足以产生寿命延长的效果。寿命的延长取决于营养条件，这表明TOR通路和饮食限制之间可能存在联系。
In many species, reducing nutrient intake without causing malnutrition extends lifespan [1-3]. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species [1-4]. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth [5]. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.