Role of IGF-1 in Modulation of Longevity

我们的中心假设是，IGF-1降低的动物表现出更长的寿命，至少部分原因是 增强的抗逆性和新陈代谢的转变导致葡萄糖利用率的提高。 我们已经确定了一种转基因模型，该模型具有IGF-1的特异性降低和类似于 长寿生长激素缺乏的侏儒小鼠。我们将使用这些动物来检测1GF-I对 并开始剖析IGF-1依赖的表型与长寿的关系。临终病理将是 在这些小鼠身上进行检查，以确定死亡原因，并评估与年龄相关的 组织学改变。对这些动物的生存和病理进行详细的评估对于与 已经建立了寿命更长的小鼠模型，其中大多数也表现出IGF-1水平降低。 我们的初步结果表明，与对照组相比，IGF-1缺陷小鼠的寿命更长。这个 能够比较和对比不同方面的免疫球蛋白F1亚型与Snell，Ames和 轻/轻鼠标模型将提供对长寿重要的表型的那些方面的重要洞察。 初步数据表明，IGF-1信号调节逆境抗性的一个主要介体HspVO。这 IGF-1和抗逆性之间潜在的重要联系，这两个重要的长寿调节器将是 仔细检查了一下。其他数据表明，Igf1亚型的空腹血糖水平较低。因此， 将对这些动物的全身代谢进行检查，以确定较低的IGF-1水平对代谢的影响 总体而言，尤其是葡萄糖代谢。

Our central hypothesis is that animals with reduced IGF-1 show an enhanced longevity due, at least in part, to enhanced stress resistance and a metabolic shift leading to enhanced glucose utilization. We have identified a transgenic model with a specific reduction in IGF-1 and a dwarf phenotype similar to that seen in long-lived growth hormone deficient dwarf mice. We will use these animals to examine the influence of 1GF-I on longevity and to begin to dissect the IGF-1 dependent phenotype relative to longevity. End of life pathology will be performed on these mice to determine causes of death and to evaluate the occurrence and severity of age-related histological changes. A detailed evaluation of survival and pathology in these animals is critical for comparison to the already established mouse models with enhanced longevity, the majority of which also display reduced IGF-1 levels. Our preliminary results indicate that the IGF-1 deficient mice display an extended lifespan relative to controls. The ability to compare and contrast different aspects of the phenotype of the Igfl hypomorphs with the Snell, Ames and lit/lit mouse models will give important insight into those aspects of the phenotypethat are important to longevity. Preliminary data indicates that IGF-1 signaling regulates a major mediator of stress resistance, HspVO. This potentially important link between IGF-1 and stress resistance, two important modulators of longevity, will be examined in detail. Additional data indicates that the Igfl hypomorphs have lower fasting levels of glucose. Thus, whole body metabolism will be examined in these animals to determine the effect of lower IGF-1 levels on metabolism in general and glucose metabolism in particular.