IGF-I Signaling and Aging

Holzenberger等人(2003)最近报道，小鼠在所有组织中都存在IGF-I受体基因杂合子 (Igflr^的小鼠)延长了寿命，这与对百草枯毒性的抗性有关。这一发现将会 是开创性的，因为它表明延长的寿命和对氧化应激的抵抗力在 胰岛素/胰岛素样生长因子-L信号降低的无脊椎动物模型延伸到哺乳动物。这一结果还提供了 优雅地支持了卡路里限制(CR)延长寿命的机制的假设 动物和生长激素缺乏的侏儒鼠至少在一定程度上减少了IGF-I的作用。然而，有一些主要的 对Holzenberger等人报告的概念和技术关切。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 有证据表明，在Igf1r+/‘小鼠的整个寿命中，氧化损伤都会减少，也没有任何证据表明 减少与年龄相关的病理和其他生物老化的标志。第三，对照野生动物的寿命- 在Holzenberger等人的研究中，类型小鼠很短，这表明可能延长了 Lgf1r+/~小鼠是由于对其特定住房环境的压力的抵抗而不是减少。 生物老化。与总体存活率低的问题有关的是观察到雄性lgf1r+/~小鼠 寿命延长了16%，这在统计上没有显著意义，而且雄性小鼠对 百草枯。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等人的报告中的这些不足之处，必须 利用UTHSCSA在IGF-I信号、氧化领域可用的综合资源和专业知识 应激和损伤，以及生物老化，以检验Igflr^的小鼠在 减少氧化损伤，减少生物衰老。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检验这一假设 小鼠是否：1)IGF-I受体数量减少和活化减少的lgf1r+/~表型 胰岛素样生长因子-I信号通路的维持以及这些变化对生长激素/胰岛素样生长因子-I轴和胰岛素的影响 和葡萄糖耐量；2)lgf1r+/~小鼠对百草枯诱导的氧化应激更具抵抗力，并具有 减少对大分子的氧化损伤，增加抗氧化酶的使用寿命；以及3) 小鼠表现出与年龄相关的病理减少和生物老化的标志，并延长了寿命。 跨度。这项研究的结果将提供第一个明确的数据，即IGF-I受体的减少 信号转导减少氧化应激和损伤，并导致生物衰老的广泛减少 延长哺乳动物的寿命。

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 invertebrates 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 is 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.