IGF-I Signaling and Aging

描述(由申请人提供)：Holzenberger等人(2003)最近报道，在所有组织中IGF-I受体基因杂合子的小鼠(Igflr+/-小鼠)可以延长寿命，这与抵抗百草枯毒性有关。这一发现将是开创性的，因为它表明在胰岛素/胰岛素样生长因子-L信号减弱的无脊椎动物模型中观察到的寿命延长和对氧化应激的抵抗力延伸到哺乳动物。这一结果也为卡路里限制(CR)动物和生长激素缺乏的侏儒小鼠延长寿命的机制至少部分地减少了IGF-I的作用这一假说提供了优雅的支持。然而，Holzenberger等人的报告存在重大的概念和技术问题。首先，文献提供了大量证据表明IGF-I信号可以保护机体免受氧化应激。其次，目前还没有证据表明氧化损伤在Igf1r+/-小鼠的寿命中有所减少，也没有任何证据表明与年龄相关的病理和其他生物衰老的标志减少了。第三，在Holzenberger等人的研究中，对照野生型小鼠的寿命很短，这表明lgf1r+/-小鼠寿命的提高可能是由于对其特定住房环境的压力的抵抗，而不是减少生物衰老。与总体存活率低的问题相关的是观察到雄性lgf1r+/~小鼠的寿命延长了16%，但没有统计学意义，而且雄性小鼠对百草枯没有抵抗力。在UTHSCSA的设施中，使用适当数量的小鼠，寿命增加16%将在统计上具有显著意义。鉴于Holzenberger等人的报告中的这些不足之处，有必要利用UTHSCSA在IGF-I信号、氧化应激和损伤以及生物衰老领域可用的综合资源和专业知识来验证这样的假设，即Igflr+/-小鼠的寿命与减少氧化损伤和减少生物衰老有关。为了验证这一假说，将通过确定lgf1r+/-小鼠和野生型对照小鼠的寿命是否：1)IGF-I受体数量减少、IGF-I信号通路激活减少的表型得以维持以及这些变化对GH/IGF-I轴、胰岛素和糖耐量的影响；2)lgf1r+/-小鼠对百草枯诱导的氧化应激更具抵抗力，减少对大分子的氧化损伤，增加抗氧化酶的寿命；3)Igflr+/-小鼠表现出与年龄相关的病理以及生物衰老的标志，延长了寿命。这项研究的结果将提供第一个明确的数据，即IGF-I受体信号的减少是否会减少氧化应激和损伤，并导致哺乳动物生物衰老的广泛减少和寿命的延长。

DESCRIPTION (provided by applicant): Holzenberger et al (2003) recently reported that mice heterozygous for the IGF-I receptor gene in all tissues (Igflr+/- mice) have extended life span in association with resistance to paraquat toxicity. This finding would be seminal since it shows that the increased life span and resistance to oxidative stress observed in invertebrate models with reduced insulin/IGF-l signaling extends to mammals. This result also provides elegant support for the hypothesis that the mechanism of extended life span of calorie-restricted (CR) animals and GH-deficient dwarf mice is, at least in part, reduced IGF-I action. However, there are major conceptual and technical concerns about the report of Holzenberger et al. First, the literature provides abundant evidence that IGF-I signaling protects against oxidative stress. Secondly, there is no evidence yet available that oxidative damage is reduced over the life span of Igf1r+/- mice, nor are there any evidence of reduced age-related pathology and other markers of biological aging. Third, the life span of the control wild- type mice in the study of Holzenberger et al was short, suggesting the possibility that enhanced life span of the lgf1r+/- mice was due to resistance to a stress of their particular housing environment rather than reduced biological aging. Related to the problem of poor overall survival was the observation that male lgf1r+/~ mice had a 16% extension of life span that was not statistically significant and that male mice were not resistant to paraquat. In the facilities at UTHSCSA, a 16% increase in life span using the proper number of mice would be statistically significant. In view of these deficiencies in the report of Holzenberger et al, it is essential to use the combined resources and expertise available at UTHSCSA in the areas of IGF-I signaling, oxidative stress and damage, and biological aging to test the hypothesis that Igflr+/- mice have extended life span in association with reduced oxidative damage and reduced biological, aging. The following Specific Aims will be pursued to test this hypothesis by determining over the lifespan of the lgf1r+/- mice and wild-type control mice whether: 1) the lgf1r+/- phenotypes of reduced numbers of IGF-I receptors and reduced activation of IGF-I signaling pathways are maintained and the effects of these changes on the GH/IGF-I axis and insulin and glucose tolerance; 2) lgf1r+/- mice are more resistant to paraquat-induced oxidative stress and have reduced oxidative damage to macromolecules and increased anti-oxidant enzymes over the lifespan; and 3) Igflr+/- mice exhibit reduced age-related pathology and markers of biological aging and have extended life span. Outcomes of this research will provide the first definitive data whether a reduction in IGF-I receptor signaling decreases oxidative stress and damage and leads to a broad reduction in biological aging with extended life span in mammals.