Novel models for longevity research

描述(由申请人提供)：当今生物老年学中最重要的问题之一是理解与胰岛素/IGF-I信号通路活性降低相关的寿命延长的机制。虽然IGF-I受体和信号通路的单一突变可以延长秀丽线虫和黑腹果蝇的寿命，但哺乳动物寿命延长的最有力例子与IGF-I和生长激素的减少有关。表现出垂体发育或生长激素产生和/或信号缺陷的小鼠模型显示IGF-I水平降低，寿命显著延长。然而，在生长激素缺乏的背景下，不可能将这些动物的寿命影响完全归因于IGF-I的减少，排除了生长激素在哺乳动物寿命调节中的潜在独特作用。表现出IGF-I信号减少的小鼠的寿命延长幅度要小得多，这表明仅抑制IGF-I可能不足以产生在缺乏生长激素和IGF-I的动物中所看到的强劲的寿命延长。然而，目前的模型没有提供必要的工具来定义IGF-I和生长激素在调节哺乳动物寿命方面所扮演的角色。我们建议创造新的小鼠模型，展示生长激素非依赖地产生IGF-I。我们将从IGF-I的产生、发育、新陈代谢、骨骼生长和寿命方面对这些小鼠进行表征。如果我们发现生长激素对长寿的主要影响独立于IGF-I，这些研究的结果将为我们对IGF-I和长寿的影响的思维范式的转变铺平道路。

DESCRIPTION (provided by applicant): Among the most important issues in biogerontology today is an understanding of the mechanisms that underlie lifespan extension associated with reduced activity in the insulin/IGF-I signaling pathway. Whereas single mutations in the IGF-I receptor and signaling pathways impart lifespan extension in Caenorhabditis elegans and Drosophila melanogaster, the most robust examples of lifespan extension in mammals are associated with reductions in both IGF-I and growth hormone. Mouse models exhibiting deficiency in pituitary development or growth hormone production and/or signaling show decreased IGF-I levels and a dramatic increase in lifespan. Against a backdrop of growth hormone deficiency, however, it is impossible to attribute the effect on lifespan in these animals solely to reductions in IGF-I, excluding a potentially distinct role for growth hormone in mammalian lifespan modulation. Mouse lines which exhibit reduced IGF-I signaling show much smaller increases in lifespan suggesting that IGF-I suppression alone may not be sufficient to produce the robust lifespan extension seen in animals which lack both growth hormone and IGF-I. However, current models do not provide the tools necessary to define the roles that IGF-I and growth hormone play in modulating longevity in mammals. We propose to create novel mouse models, exhibiting growth hormone independent production of IGF-I. We will perform a characterization of these mice in terms of IGF-I production, development, metabolism, bone growth and lifespan. If we find a major influence of GH on longevity independent of IGF-I, the results of these studies would pave the way for a paradigm shift in our thinking regarding the influence of IGF-I and longevity.