IGF-I Signaling and Aging

描述（由申请人提供）：Holzenberger等人（2003年）最近报告称，所有组织中IGF-I受体基因杂合的小鼠（Igflr+/-小鼠）的寿命延长，与百草枯毒性抗性有关。这一发现将是开创性的，因为它表明在具有降低的胰岛素/IGF-1信号传导的无脊椎动物模型中观察到的增加的寿命和对氧化应激的抗性延伸到哺乳动物。这一结果也为以下假设提供了有力的支持：热量限制（CR）动物和GH缺乏侏儒小鼠寿命延长的机制至少部分是IGF-I作用降低。然而，Holzenberger等人的报告存在主要的概念和技术问题。首先，文献提供了大量证据表明IGF-I信号传导可以防止氧化应激。其次，目前还没有证据表明氧化损伤在Igf 1 r +/-小鼠的生命周期内减少，也没有任何证据表明年龄相关的病理学和其他生物衰老标志物减少。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lgf 1 r +/-小鼠寿命延长的可能性是由于其对特定居住环境压力的抵抗力，而不是生物老化的减少.与总体存活率低的问题有关的是，观察到雄性lgf 1 r +/~小鼠的寿命延长了16%，但在统计学上并不显著，而且雄性小鼠对百草枯没有抗药性。在UTHSCSA的设施中，使用适当数量的小鼠将寿命延长16%具有统计学意义。鉴于Holzenberger等人的报告中的这些缺陷，必须使用UTHSCSA在IGF-I信号传导、氧化应激和损伤以及生物老化领域中可用的组合资源和专业知识来测试Igflr+/-小鼠具有与减少的氧化损伤和减少的生物老化相关的延长的寿命的假设。通过在lgf 1 r +/-小鼠和野生型对照小鼠的寿命期内确定以下特定目的来检验该假设：1）IGF-I受体数量减少和IGF-I信号传导途径活化减少的lgf 1 r +/-表型是否得以维持，以及这些变化对GH/IGF-I轴和胰岛素及葡萄糖耐受性的影响; 2）lgf 1 r +/-小鼠对百草枯诱导的氧化应激更具抵抗力，并且在整个寿命期间对大分子的氧化损伤减少，抗氧化酶增加;和3）Igflr+/-小鼠表现出与年龄相关的病理学和生物衰老标志物减少，寿命延长。这项研究的结果将提供第一个明确的数据，即IGF-I受体信号传导的减少是否会降低氧化应激和损伤，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.