IGF-I Signaling and Aging

IGF-I 信号传导与衰老

• 批准号: 7033369
• 负责人: MARTIN L ADAMO
• 金额: $ 26.94万
• 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 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033369
• 关键词: aging; genetically modified animals; glucose tolerance; growth factor receptors; insulinlike growth factor; laboratory mouse; longevity; oxidative stress; paraquat; pesticide biological effect; somatotropin

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.

描述（由申请人提供）：Holzenberger等人（2003年）最近报道说，所有组织中IGF-I受体基因的杂合子（IGFLR +/-小鼠）的杂合子具有延长的寿命，并且对paraquat毒性的耐药性。这一发现将是开创性的，因为它表明在胰岛素/IGF-L信号降低的无脊椎动物模型中观察到的寿命和对氧化应激的耐药性延伸至哺乳动物。该结果还为假设的假设提供了优雅的支持，即延长卡路里限制性（CR）动物和缺乏GH缺乏的矮人小鼠的寿命机制至少部分降低了IGF-I作用。但是，关于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信号传导可防止氧化应激。其次，尚无证据表明在IGF1R +/-小鼠的寿命中减少氧化损伤，也没有任何证据表明与年龄相关的病理学和其他生物衰老的标志物减少。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LGF1R +/-小鼠的寿命增强的可能性是由于抵抗了其特定住房环境的压力而不是减少生物学老化的可能性。与总体生存不良的问题有关的问题是，雄性LGF1R+/〜小鼠的寿命延长16％，这在统计学上没有显着意义，并且雄性小鼠对paraquat没有抗性。在UTHSCSA的设施中，使用适当数量的小鼠的寿命增加了16％，这在统计上很重要。鉴于Holzenberger等人的报告中的这些缺陷，必须在IGF-I信号传导，氧化压力和损伤的领域使用UTHSCSA可用的组合资源和专业知识，并测试IGFLR +/-鼠标的假设，即IGFLR +/-鼠标具有延长的氧化损伤和减少的氧化损害，并减少了衰老。通过确定LGF1R +/-小鼠的寿命和Wild-Type对照小鼠的寿命，将追求以下具体目标来检验该假设 宽容; 2）LGF1R +/-小鼠对帕拉quat诱导的氧化应激具有更大的抵抗力，并减少了对大分子对大分子的氧化损伤，并且在整个生命周期内增加了抗氧化酶； 3）IGFLR +/-小鼠表现出降低与年龄相关的病理学和生物衰老的标志物，并具有延长的寿命。这项研究的结果将提供第一个确定的数据，即IGF-I受体信号传导的降低是否会减少氧化应激和损伤，并导致哺乳动物延长寿命的生物衰老的广泛降低。