Role of IGF-1 in Modulation of Longevity

IGF-1 在长寿调节中的作用

• 批准号: 7247142
• 负责人: CHRISTIAN SELL
• 金额: $ 33.26万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247142
• 关键词: Adipose tissue; Alleles; Animals; Biological Models; Body Composition; Body Temperature; Cause of Death; Cells; Corticosterone; Data; Evaluation; Exhibits; Fasting; Genes; Genetic Transcription; Glucose; Hormones; Insulin; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like-Growth Factor I Receptor; Leptin; Life; Link; Longevity; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mouse Cell Line; Mus; Muscle; Pathology; Pathway interactions; Phenotype; Physical activity; Proteins; Rate; Regulation; Relative (related person); Research Personnel; Resistance; Role; Serum; Severities; Signal Transduction; Somatotropin; Stress; Testing; Thyroid Hormones; Tissues; Transgenic Model; Translations; adiponectin; age related; end of life; ghrelin; glucose metabolism; glucose tolerance; insight; mRNA Stability; mouse model; sodium arsenite; somatotropin-binding protein

DESCRIPTION (provided by applicant): Our central hypothesis is that animals with reduced IGF-1 show an enhanced longevity due, at least in part, to enhanced stress resistance and a metabolic shift leading to enhanced glucose utilization. We have identified a transgenic model with a specific reduction in IGF-1 and a dwarf phenotype similar to that seen in long-lived, growth hormone deficient dwarf mice. We will use these animals to examine the influence of 1GF-I on longevity and to begin to dissect the IGF-1 dependent phenotype relative to longevity. End of life pathology will be performed on these mice to determine causes of death and to evaluate the occurrence and severity of age-related histological changes. A detailed evaluation of survival and pathology in these animals is critical for comparison to the already established mouse models with enhanced longevity, the majority of which also display reduced IGF-1 levels. Our preliminary results indicate that the IGF-1 deficient mice display an extended lifespan relative to controls. The ability to compare and contrast different aspects of the phenotype of the Igfl hypomorphs with the Snell, Ames and lit/lit mouse models will give important insight into those aspects of the phenotype that are important to longevity. Preliminary data indicates that IGF-1 signaling regulates a major mediator of stress resistance, HspVO. This potentially important link between IGF-1 and stress resistance, two important modulators of longevity, will be examined in detail. Additional data indicates that the Igfl hypomorphs have lower fasting levels of glucose. Thus, whole body metabolism will be examined in these animals to determine the effect of lower IGF-1 levels on metabolism in general, and glucose metabolism in particular.

描述（由申请人提供）：我们的中心假设是，IGF-1降低的动物显示出延长的寿命，至少部分是由于增强的应激抵抗力和导致葡萄糖利用增强的代谢转变。 我们已经确定了一种转基因模型，其IGF-1特异性降低，侏儒表型与长寿的生长激素缺乏侏儒小鼠相似。我们将使用这些动物来检查IGF-1对寿命的影响，并开始剖析IGF-1依赖性表型与寿命的关系。将对这些小鼠进行生命末期病理学检查，以确定死亡原因并评价年龄相关组织学变化的发生率和严重程度。对这些动物的存活率和病理学进行详细评估对于与已经建立的寿命延长的小鼠模型进行比较至关重要，其中大多数小鼠模型也显示IGF-1水平降低。 我们的初步结果表明，IGF-1缺陷小鼠显示出相对于对照延长的寿命。将Igf 1亚型的表型的不同方面与Snell、艾姆斯和lit/lit小鼠模型进行比较和对比的能力将给予对长寿重要的表型的那些方面的重要洞察。 初步数据表明，IGF-1信号调节应激抗性的主要介质，HspVO。IGF-1和抗应激性，两个重要的长寿调节剂之间的这种潜在的重要联系，将详细研究。另外的数据表明，Igfl亚型物具有较低的空腹葡萄糖水平。因此，将在这些动物中检查全身代谢，以确定较低IGF-1水平对一般代谢，特别是葡萄糖代谢的影响。