Molecular Mechanisms of Longevity in Long-Lived Mice

长寿小鼠长寿的分子机制

• 批准号: 8113256
• 负责人: Gretchen J. Darlington
• 金额: $ 29.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113256
• 关键词: Accounting; Age; Aging-Related Process; Amino Acids; Animals; Autopsy; Bile Acid Biosynthesis Pathway; Bile Acids; Caenorhabditis elegans; Cataract; Categories; Cause of Death; Chronic; Cross-Sectional Studies; Cytochromes; Data; Drug Metabolic Detoxication; Engineering; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Goals; Histopathology; Intervention; Knock-out; Knockout Mice; Life; Lipids; Liver; Longevity; Measurable; Measures; Mediating; Metabolic; Metabolism; Modeling; Molecular; Molecular Target; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Nuclear Hormone Receptors; Organism; Oxidative Phosphorylation; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Play; Proteins; Regulation; Repression; Research Personnel; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Somatotropin; Steroids; Testing; Toxin; Transferase; Tumor Burden; Vitamins; Weight; Xenobiotic Metabolism; Xenobiotics; constitutive androstane receptor; design; genetic analysis; growth hormone deficiency; liver function; mouse model; muscle strength; mutant; pregnane X receptor; programs; receptor; receptor function; response; stressor; trait; transcription factor

DESCRIPTION (provided by applicant): A small number of naturally occurring and engineered mutations in mice result in extension of lifespan. Functional growth hormone (GH) deficiency has been associated with increased longevity in at least four strains of mice, two of which, the Ames (Prop1df/df) and Little (Ghrhrlit/lit) mice, we have studied intensively. Global gene expression analysis of the liver in GH deficient, long-lived mice, as well as calorically restricted (and thus long-lived) mice, shows a correlation between increased lifespan and elevation of genes which belong to the category of xenobiotic or detoxification metabolism. Detoxification of endogenous metabolic intermediates is a major function of the liver. This pathway is comprised of transporters, cytochromes, transferases, and exporters which become transcriptionally regulated by nuclear hormone receptors (NHRs) upon activation of the NHRs by several endogenous compounds including bile acids, steroids, vitamins, and lipids. Long-lived mutants of C. elegans show similar elevations of NHRs, cytochromes, and transferases (23, 24) In this proposal, we will test the hypothesis that chronic activation of xenobiotic metabolism as seen in the GH deficient, long-lived mice, is beneficial to longevity. Specific Aim 1 will use a mutant mouse line (a knockout of cytochrome 7b1) that mimics the changes in detoxification pathways that are found in the long-lived mice. This knockout mouse model has patterns of elevation of xenobiotic metabolism genes similar to the GH deficient mice. The Cyp 7b1 null mice will be examined for longevity extension. Specific Aim 2 is designed to elucidate the molecular mechanisms that control the activation of the detoxification response genes by examining the requirement for NHRs in double and triple KO mice and by knockdown of specific NHRs and candidate transcription factors in the liver. Finally, the consequences of reduction of Stat Sab signaling in the liver will be assessed by gene expression arrays to determine whether or not a reduction in Stat Sab in the liver accounts for the majority of gene expression changes seen in the GH deficient Ames and Little mice, and to identify potential co-regulators. These aims will directly test whether or not chronic activation of xenobiotic metabolism impacts lifespan and will elucidate molecular targets that may be useful points of intervention in the aging process.

描述(由申请人提供)：少量自然发生的和转基因的小鼠突变导致寿命延长。在至少四个品系的小鼠中，功能性生长激素(GH)缺乏与寿命延长有关，其中两个品系，Ames(Prop1df/df)和Little(Ghrhrlight/Lit)小鼠，我们进行了深入的研究。对GH缺乏、长寿小鼠以及热量受限(从而长寿)小鼠肝脏的全局基因表达分析表明，长寿小鼠的寿命延长与属于异物或解毒代谢类别的基因升高之间存在相关性。内源性代谢中间产物的解毒是肝脏的主要功能。该途径由转运体、细胞色素、转移酶和出口体组成，当核激素受体(NHR)被胆汁酸、类固醇、维生素和脂类等内源性化合物激活时，NHR在转录上受到NHR的调控。线虫的长寿突变株表现出类似的NHR、细胞色素和转移酶(23，24)的升高。在这项提议中，我们将检验如下假设，即在生长激素缺乏的长寿小鼠中看到的异物代谢的慢性激活有利于长寿。特殊目的1将使用一种突变的小鼠品系(细胞色素7B1的敲除)，模拟在长寿小鼠中发现的解毒途径的变化。这种基因敲除的小鼠模型具有与生长激素缺陷小鼠相似的异物代谢基因升高的模式。将对Cyp 7B1基因缺失的小鼠进行延长寿命的检查。特异性目标2旨在通过检测双重和三重KO小鼠对NHR的需求以及通过敲除肝脏中特定的NHR和候选转录因子来阐明控制解毒反应基因激活的分子机制。最后，肝脏中Stat Sab信号减少的后果将通过基因表达阵列进行评估，以确定肝脏中Stat Sab的减少是否可以解释生长激素缺陷Ames和小鼠中出现的大部分基因表达变化，并确定潜在的共同调节因素。这些目标将直接测试异种代谢的慢性激活是否会影响寿命，并将阐明可能是衰老过程中有用的干预点的分子靶点。

项目成果

Direct activation of forkhead box O3 by tumor suppressors p53 and p73 is disrupted during liver regeneration in mice.

• DOI: 10.1002/hep.23746
• 发表时间: 2010-09
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Kurinna, Svitlana;Stratton, Sabrina A.;Tsai, Wen-Wei;Akdemir, Kadir C.;Gu, Weisong;Singh, Pallavi;Goode, Triona;Darlington, Gretchen J.;Barton, Michelle Craig
• 通讯作者: Barton, Michelle Craig