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首页> 外文期刊>Aging cell. >Reduced insulin/IGF-1 signalling and human longevity.
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Reduced insulin/IGF-1 signalling and human longevity.

机译：降低胰岛素/ IGF-1信号传导和人类寿命。

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Summary Evidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the long-lived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components (GHRHR, GH1, IGF1, INS, IRS1), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower (P = 0.007) and mortality 0.80-fold reduced (P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.
机译：总结越来越多的证据表明，衰老是由进化上保守的胰岛素/ IGF-1信号传导（IIS）途径调节的。 IIS组件中的突变会影响秀丽隐杆线虫，果蝇和小鼠的寿命。大多数寿命较长的IIS突变体还显示出对氧化应激的增强抵抗力。在D. melanogaster和小鼠中，几种IIS突变体的长寿表型仅限于雌性。在这里，我们在一项前瞻性随访研究中分析了IIS信号，人体身高和寿命之间的关系。基于IIS途径组件（GHRHR，GH1，IGF1，INS，IRS1）中选定变体的预期效果（增加或减少的信号传导），我们计算了综合IIS评分以估算IIS途径的活动。此外，我们分析了多变量模型中各个变量对寿命和体型的相对影响。在女性中，较低的IIS分数与较低的身高和改善的老年生存率显着相关。多变量分析表明，对于GH1 SNP，IGF1 CA重复序列和IRS1 SNP，这些结果最为明显。在女性中，与野生型等位基因携带者相比，GH1 SNP的变异等位基因携带者的身高低了2 cm（P = 0.007），死亡率降低了0.80倍（P = 0.019）。因此，在女性中，导致IIS激活降低的遗传变异对老年生存是有益的。对于GH1 SNP而言，此效应要强于保守的IIS基因的变异，后者被发现会影响模型生物的寿命。

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