IGF-I Signaling and Aging

Holzenberger等（2003）最近报道，在所有组织中IGF-I受体基因杂合的小鼠 （IgFlr+小鼠）具有与对百草枯毒性的抗性相关的延长的寿命。这一发现将 是开创性的，因为它表明，增加寿命和抗氧化应激观察到， 具有降低的胰岛素/IGF-1信号传导的无脊椎动物模型扩展到哺乳动物。这一结果还提供了 优雅的支持假说，延长寿命的机制，热量限制（CR） 动物和生长激素缺乏的侏儒小鼠，至少部分，减少IGF-I的作用。然而，有一些主要的 Holzenberger等人报告的概念和技术问题。首先，文献提供了 大量的证据表明IGF-I信号可以保护机体免受氧化应激。第二，目前还没有证据 可用的是，氧化损伤在Igf 1 r +/-小鼠的寿命期间减少，也没有任何证据表明 减少与年龄相关的病理学和生物老化的其他标志物。第三，控制野生动物的寿命- Holzenberger等人的研究中， LGF 1 R +/~小鼠是由于其对特定居住环境的应激的抵抗力而不是降低 生物老化与总体存活率差的问题相关的是观察到雄性lgf 1 r +/~小鼠 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。在UTHSCSA的设施中，使用适当数量的小鼠， 具有统计学意义。鉴于Holzenberger等人报告中的这些缺陷， 利用UTHSCSA在IGF-I信号传导、氧化 压力和损伤，以及生物老化来检验Igflr^-小鼠在体内延长寿命的假设。 与减少的氧化损伤和减少的生物老化相关。以下具体目标将 通过在lgf 1 r +/~小鼠和野生型对照的寿命期间测定， 小鼠是否：1）IGF-I受体数量减少和IGF-I受体活化减少的lgf 1 r +/~表型， IGF-I信号通路得以维持，这些变化对GH/IGF-I轴和胰岛素的影响 和葡萄糖耐量; 2）lgf 1 r +/~小鼠对百草枯诱导的氧化应激更具抵抗力， 在寿命期内减少对大分子的氧化损伤并增加抗氧化酶;以及3） Igflr+小鼠表现出减少的年龄相关的病理学和生物老化的标志物，并且具有延长的寿命。 跨度。这项研究的结果将提供第一个明确的数据，无论是IGF-I受体的减少， 信号传导减少氧化应激和损伤，并导致生物老化的广泛减少， 延长了哺乳动物的寿命。

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.