Role of IGF-1 in Modulation of Longevity

我们的中心假设是，IGF-1减少的动物显示出更长的寿命，至少部分原因是， 增强的抗应激性和导致葡萄糖利用增强的代谢转变。 我们已经鉴定了一种转基因模型，其IGF-1特异性降低，并且具有与在 长寿命的生长激素缺乏侏儒小鼠。我们将使用这些动物来检查1GF-I对 长寿，并开始剖析与长寿相关的IGF-1依赖性表型。生命末期病理学将是 在这些小鼠上进行，以确定死亡原因并评估年龄相关的死亡的发生和严重程度。 组织学变化对这些动物的存活率和病理学的详细评价对于与对照组进行比较至关重要。 已经建立的小鼠模型具有增强的寿命，其中大多数也显示出降低的IGF-1水平。 我们的初步结果表明，IGF-1缺陷小鼠显示出相对于对照延长的寿命。的 能够将Igfl亚型的表型的不同方面与Snell、艾姆斯和 lit/lit小鼠模型将对那些对长寿很重要的表型方面提供重要的见解。 初步数据表明，IGF-1信号调节应激抗性的主要介质，HspVO。这 IGF-1和抗应激性之间潜在的重要联系，这两个重要的长寿调节剂，将是 详细检查。另外的数据表明，Igfl亚型物具有较低的空腹葡萄糖水平。因此，在本发明中， 将检查这些动物的全身代谢，以确定较低的IGF-1水平对代谢的影响 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.