IGF-I Signaling and Aging

IGF-I 信号传导与衰老

• 批准号: 7795983
• 负责人: MARTIN L ADAMO
• 金额: $ 25.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795983
• 关键词: 129/Sv Mouse; Age; Aging; Aging-Related Process; Animals; Antioxidants; Appearance; Area; Attenuated; Biological Aging; Biological Markers; Caloric Restriction; Cause of Death; Data; Data Reporting; Development; Drosophila genus; Endocrine; Environment; Enzymes; Exhibits; Female; Future; Gender; Genetic; Genetic Models; Glucose; Glucose Intolerance; Hepatic; Housing; Injection of therapeutic agent; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Invertebrates; Investigation; Lead; Life; Lipid Peroxidation; Literature; Longevity; Mammals; Measures; Modeling; Mus; Mutant Strains Mice; Nematoda; Outcome; Outcomes Research; Oxidative Stress; Paraquat; Pathology; Phenotype; Predisposition; Process; Proteins; Receptor Gene; Receptor Signaling; Reporting; Research; Resistance; Resources; Seminal; Serum; Sex Characteristics; Signal Pathway; Signal Transduction; Stress; Technology; Testing; Tissues; Toxic effect; Wild Type Mouse; age effect; age related; anti aging; glucose metabolism; glucose tolerance; growth hormone deficiency; in vivo; insulin tolerance; macromolecule; male; mutant; oxidation; oxidative damage; stressor; study characteristics; theories; trait

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.

Holzenberger等（2003）最近报道了所有组织中IGF-I受体基因的杂合小鼠 （Igflr^'小鼠）具有延长的寿命，与对帕拉quat毒性的抗性相关。这个发现将是 要开创性，因为它表明寿命跨度增加和对氧化应激的抵抗力 胰岛素/IGF-L信号降低的无脊椎动物模型扩展到哺乳动物。这个结果也提供了 优雅的支持，即延长卡路里限制寿命的机制（CR） 动物和缺乏GH的矮小小鼠至少部分降低了IGF-I作用。但是，有专业 Holzenberger等人的报告的概念和技术问题。首先，文献提供 大量证据表明IGF-I信号传导可预防氧化应激。其次，还没有证据 在IGF1R+/'小鼠的寿命中可降低氧化损伤，也没有任何证据表明 与年龄相关的病理学和生物衰老的其他标志物减少。第三，控制野生的寿命 - 在Holzenberger等人的研究中，小鼠很短，这表明可能增强的寿命 LGF1R+/〜小鼠是由于抵抗其特定外壳环境的压力而不是减少 生物衰老。与总体生存不良的问题有关的是雄性LGF1R+/〜小鼠的观察 寿命的延长16％在统计学上没有显着意义，雄性小鼠对 Paraquat。在UTHSCSA的设施中，使用适当数量的小鼠增加了16％的寿命 具有统计学意义。鉴于Holzenberger等人的报告中的这些缺陷，必须 在IGF-I信号传导领域，使用UTHSCSA上可用的合并资源和专业知识，氧化 压力和损害以及生物衰老，以检验Igflr^'小鼠已经延长寿命的假设 与氧化损伤减少和生物学衰老降低相关。以下具体目标将 通过确定LGF1R+/〜小鼠的寿命和野生型控制的寿命来检验该假设 小鼠是否：1）减少IGF-I受体数量减少的LGF1R+/〜表型 维持IGF-I信号通路，这些变化对GH/IGF-I轴和胰岛素的影响 和葡萄糖耐受性； 2）lgf1r+/〜小鼠对帕拉奎特诱导的氧化应激具有更抗性，并且具有 在整个生命周期内，对大分子的氧化损伤减少了抗氧化酶； 3） Igflr^'小鼠表现出降低的与年龄相关的病理学和生物衰老的标志物，并具有延长寿命 跨度。这项研究的结果将提供第一个确定的数据，即IGF-I受体是否减少 信号传导减轻氧化应激和损伤，并导致生物衰老的广泛减少 哺乳动物的寿命延长。