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减少的动物表现出更长的寿命，至少部分是由于增强的应激抵抗和导致葡萄糖利用增强的代谢转变。我们已经确定了一个转基因模型，具有特异性的IGF-1减少和矮化表型，类似于长寿的生长激素缺乏矮化小鼠。我们将使用这些动物来检验1gf -1对寿命的影响，并开始剖析与寿命相关的IGF-1依赖表型。将对这些小鼠进行临终病理学检查，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。这些动物的生存和病理的详细评估对于与已经建立的延长寿命的小鼠模型进行比较至关重要，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，与对照组相比，IGF-1缺陷小鼠的寿命更长。将Igfl亚型表型的不同方面与Snell、Ames和lit/lit小鼠模型进行比较和对比的能力，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信号调节应激抵抗的主要媒介HspVO。IGF-1和抗逆性（两种重要的寿命调节因子）之间的潜在重要联系将被详细研究。另外的数据表明，Igfl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水平对一般代谢，特别是葡萄糖代谢的影响。

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.