Novel models for longevity research

长寿研究的新模型

• 批准号: 8331435
• 负责人: CHRISTIAN SELL
• 金额: $ 23.18万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331435
• 关键词: Address; Aging; Animal Model; Animals; Biochemical; Biological Models; Bone Growth; Brain; Caenorhabditis elegans; Cardiac Myosins; Cause of Death; Climacteric; Development; Drosophila melanogaster; Elderly; Exhibits; Genetic; Gerontology; Growth; Growth Hormone Receptor; Hormones; Human; Insulin; Insulin-Like Growth Factor I; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolism; Modeling; Mus; Muscle; Mutation; Organ; Pathology; Play; Prealbumin; Production; Receptor Signaling; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Somatomedins; Somatotropin; Therapeutic; Therapeutic Uses; Thinking; Tissues; Work; attenuation; base; bone; cost; end of life; field study; glucose metabolism; growth hormone deficiency; improved; insight; mouse model; novel; pituitary gland development; promoter; tool

DESCRIPTION (provided by applicant): Among the most important issues in biogerontology today is an understanding of the mechanisms that underlie lifespan extension associated with reduced activity in the insulin/IGF-I signaling pathway. Whereas single mutations in the IGF-I receptor and signaling pathways impart lifespan extension in Caenorhabditis elegans and Drosophila melanogaster, the most robust examples of lifespan extension in mammals are associated with reductions in both IGF-I and growth hormone. Mouse models exhibiting deficiency in pituitary development or growth hormone production and/or signaling show decreased IGF-I levels and a dramatic increase in lifespan. Against a backdrop of growth hormone deficiency, however, it is impossible to attribute the effect on lifespan in these animals solely to reductions in IGF-I, excluding a potentially distinct role for growth hormone in mammalian lifespan modulation. Mouse lines which exhibit reduced IGF-I signaling show much smaller increases in lifespan suggesting that IGF-I suppression alone may not be sufficient to produce the robust lifespan extension seen in animals which lack both growth hormone and IGF-I. However, current models do not provide the tools necessary to define the roles that IGF-I and growth hormone play in modulating longevity in mammals. We propose to create novel mouse models, exhibiting growth hormone independent production of IGF-I. We will perform a characterization of these mice in terms of IGF-I production, development, metabolism, bone growth and lifespan. If we find a major influence of GH on longevity independent of IGF-I, the results of these studies would pave the way for a paradigm shift in our thinking regarding the influence of IGF-I and longevity.

描述（由申请人提供）：当今生物老年学中最重要的问题之一是理解与胰岛素/IGF-I信号通路活性降低相关的寿命延长机制。尽管igf - 1受体和信号通路的单一突变使秀丽隐杆线虫和黑胆果蝇的寿命延长，但哺乳动物寿命延长的最有力的例子是与igf - 1和生长激素的减少有关。显示垂体发育或生长激素产生和/或信号缺乏的小鼠模型显示IGF-I水平下降，寿命急剧增加。然而，在生长激素缺乏的背景下，不可能将这些动物的寿命影响仅仅归因于igf - 1的减少，排除了生长激素在哺乳动物寿命调节中的潜在独特作用。表现出igf - 1信号减少的小鼠品系的寿命增长要小得多，这表明仅抑制igf - 1可能不足以产生在缺乏生长激素和igf - 1的动物中所见的强劲寿命延长。然而，目前的模型并没有提供必要的工具来定义igf - 1和生长激素在调节哺乳动物寿命中所起的作用。我们建议创建新的小鼠模型，显示生长激素独立生产igf - 1。我们将从igf - 1的产生、发育、代谢、骨骼生长和寿命等方面对这些小鼠进行表征。如果我们发现生长激素对寿命的主要影响独立于igf - 1，这些研究的结果将为我们关于igf - 1和寿命影响的思维模式转变铺平道路。

项目成果

Comment on: C57BL/6 neuromuscular healthspan scoring system.

评论：C57BL/6 神经肌肉健康寿命评分系统。

• DOI: 10.1093/gerona/glt113
• 发表时间: 2013
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Sell,Christian

Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion.

• DOI: 10.3389/fendo.2014.00122
• 发表时间: 2014
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Nacarelli T;Azar A;Sell C
• 通讯作者: Sell C