Role of IGF-1 in Modulation of Longevity

描述(由申请人提供)：我们的中心假设是，IGF-1降低的动物表现出更长的寿命，至少部分原因是由于增强的应激抗性和代谢变化导致葡萄糖利用增加。我们已经确定了一种转基因模型，该模型具有IGF-1的特异性降低和与长寿、生长激素缺乏的侏儒小鼠相似的矮小表型。我们将利用这些动物来研究1GF-I对长寿的影响，并开始剖析IGF-1依赖的表型与长寿的关系。将对这些小鼠进行生命末期病理检查，以确定死亡原因，并评估与年龄相关的组织学变化的发生和严重程度。对这些动物的生存和病理进行详细的评估，对于与已经建立的寿命延长的小鼠模型进行比较至关重要，这些模型中的大多数也显示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。将Igf1亚型的不同表型与Snell、Ames和LIT/LIT小鼠模型进行比较和对比的能力将使我们能够重要地洞察那些对长寿很重要的表型方面。初步数据表明，IGF-1信号调节逆境抗性的一个主要介体HspVO。IGF-1和抗逆性之间的这种潜在的重要联系，这两个重要的长寿调节器，将被详细研究。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，特别是对葡萄糖代谢的影响。

DESCRIPTION (provided by applicant): 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 phenotype that 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.