IGF-1 and Longevity in Mammals

生物老年学的一个中心问题是调节物种的机制的性质 寿命。对线虫和黑腹果蝇的遗传学研究发现， 调节长寿的细胞途径。降低IGF-I/胰岛素受体同系物功能的突变延长了线虫和果蝇的寿命。同样，对啮齿动物的研究表明，生长激素/IGF-I轴的减少会导致寿命的延长。这些研究表明，IGF-I的减少可能会延长哺乳动物的寿命，但没有直接证据支持这一假设。我们建议使用转基因小鼠模型直接测试降低IGF-I水平可以延长寿命的可能性。 我们已经获得了一个独特的转基因小鼠系，它含有IGF-1基因的插入，导致IGF-I的特异性减少和矮小表型(IGF-Im/m小鼠)。特定目标1将在本研究过程中检查IGF-I小鼠相对于对照组的存活率，特定目标2将检查IGF-I m/m小鼠的年龄相关变化，如免疫衰老、胶原蛋白交联和激素变化，以确定与对照组相比是否有任何变化。我们的长期目标是利用IGF-Im/m小鼠和携带其他已知可延长寿命的突变的小鼠进行互补分析。这样，我们就可以确定这些突变是通过单独的机制还是通过共同的机制来调节寿命。在小鼠研究的同时，我们计划确定对IGF-I的依赖 使用从这些小鼠衍生的细胞培养模型研究与长寿相关的途径。

A central issue in biogerontology is the nature of the mechanisms that modulate species lifespan. Genetic studies in Caenohabditis elegans and Drosophila melanogaster have identified a cellular pathway that modulates longevity. Mutations that reduce the function of the homolog of the IGF-I/insulin receptors extends lifespan in both nematodes and flies. Similarly, studies in rodents indicate that a reduction in the growth hormone/IGF-I axis leads to an extension in lifespan. These studies suggest that a reduction in IGF-I may extend lifespan in mammals but no direct evidence for this hypothesis exists. We propose to test directly the possibility that a reduction in IGF-I levels can increase lifespan using a transgenic mouse model. We have obtained a unique transgenic mouse line that contains an insertion in the igf-1 gene leading to a specific reduction in IGF-I and a dwarf phenotype (IGF-I m/m mice). Specific aim 1 will examine survival of the IGF-I mice relative to controls over the course of this study and Specific aim 2 will examine age related changes in the IGF-I m/m mice such as immune senescence, collagen crosslinking and hormonal changes to determine whether there is any change relative to controls. Our long-term goals are to perform complementation analysis using the IGF-I m/m mice and mice that harbor other mutations that are known to extend lifespan. In this way, we can determine whether these mutations act through separate or common mechanisms to regulate longevity. In parallel to the mouse studies we plan to identify the IGF-I dependent pathways relevant to longevity using cell culture models derived from these mice.