Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.

中文翻译：

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胰岛素信号的蛋白质组图谱揭示了长寿保证的组织特异性机制。


降低胰岛素/IGF 信号 (IIS) 网络的活性可以改善实验动物（可能还有人类）的衰老影响。尽管长寿命 IIS 突变体的转录组重塑已被广泛记录，但有助于延长寿命的因果机制，特别是在特定组织中，仍不清楚。我们对长寿果蝇 IIS 突变体和对照中四个关键胰岛素敏感组织的蛋白质组进行了表征，并检测到了 44% 的预测蛋白质组（6,085 个蛋白质）。在突变体中，脂肪体中核糖体相关蛋白的表达减少，相应的组织特异性翻译减少。脂肪体中线粒体电子传递链蛋白的表达增加，导致呼吸增加，这是 IIS 介导的寿命延长所必需的，并且单独足以介导它。蛋白酶体亚基在 IIS 突变肠道中表现出表达改变，并且 RPN6 蛋白酶体亚基的肠道特异性过度表达足以增加蛋白酶体活性并延长寿命，而抑制蛋白酶体活性则消除了 IIS 介导的寿命。因此，我们的研究揭示了细胞过程对降低 IIS 的显着组织特异性反应，从而共同改善衰老。