IGF-I Signaling and Aging

描述（由申请人提供）：Holzenberger等人（2003）最近报道，所有组织中IGF-I受体基因杂合的小鼠（Igflr+/-小鼠）寿命延长，这与对百草枯毒性的抗性有关。这一发现具有开创性意义，因为它表明，在胰岛素/ igf - 1信号减少的无脊椎动物模型中观察到的延长寿命和抗氧化应激的现象也适用于哺乳动物。这一结果也为以下假设提供了有力的支持：卡路里限制（CR）动物和ghh缺陷侏儒小鼠延长寿命的机制，至少在一定程度上是减少了igf - 1的作用。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 - 1信号可以防止氧化应激。其次，目前还没有证据表明氧化损伤在Igf1r+/-小鼠的一生中会减少，也没有任何证据表明与年龄相关的病理和其他生物衰老标志物会减少。第三，Holzenberger等研究中的对照野生型小鼠寿命较短，提示lgf1r+/-小鼠寿命的延长可能是由于其对特定居住环境压力的抵抗，而不是生物衰老的减少。与总生存率较差的问题相关的是，观察到雄性lgf1r+/~小鼠的寿命延长了16%，这在统计学上并不显著，而且雄性小鼠对百草枯没有抗性。在UTHSCSA的设施中，使用适当数量的小鼠，寿命增加16%将具有统计学意义。鉴于Holzenberger等人报告中的这些不足，有必要利用UTHSCSA在IGF-I信号、氧化应激和损伤以及生物衰老等领域的综合资源和专业知识来验证Igflr+/-小鼠延长寿命与减少氧化损伤和减少生物衰老相关的假设。以下具体目标将通过确定lgf1r+/-小鼠和野生型对照小鼠的寿命来验证这一假设：1)IGF-I受体数量减少和IGF-I信号通路激活减少的lgf1r+/-表型是否维持，以及这些变化对GH/IGF-I轴和胰岛素和葡萄糖耐量的影响；2) lgf1r+/-小鼠对百草枯诱导的氧化应激具有更强的抵抗能力，在一生中对大分子的氧化损伤减少，抗氧化酶增加；3) Igflr+/-小鼠表现出与年龄相关的病理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 - 1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.