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。 与公共健康相关：本申请中提出的工作将创造不产生生长激素但将产生生长激素的主要靶标之一的新小鼠品系，被称为胰岛素样生长因子1。这些小鼠将被用来评估这些激素对晚年生活变化和寿命的相对贡献。这些研究将为这些激素在老年人中的潜在治疗用途提供洞察力。

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. PUBLIC HEALTH RELEVANCE: The work proposed in this application will create new mouse line that do not produce growth hormone but will produce one of the primary targets of growth hormone, known as the Insulin-like growth factor type 1. These mice will be used to evaluate the relative contribution of these hormones to late life changes and lifespan. The studies will provide insight into potential therapeutic uses for these hormones in the elderly.