Molecular Mechanisms of Longevity in Long-Lived Mice

描述（由申请人提供）：小鼠中少量天然存在的和工程改造的突变导致寿命延长。功能性生长激素（GH）缺乏与至少四种小鼠的寿命增加有关，其中两种，艾姆斯（Prop 1df/df）和小（Ghrhrlit/lit）小鼠，我们已经深入研究。GH缺乏，长寿小鼠，以及热量限制（因此长寿）小鼠的肝脏的全球基因表达分析显示，寿命增加和属于异生素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脱乙酰化是肝脏的主要功能。该途径由转运蛋白、细胞色素、转移酶和输出蛋白组成，在通过几种内源性化合物（包括胆汁酸、类固醇、维生素和脂质）激活核激素受体（NHR）后，这些转运蛋白、细胞色素、转移酶和输出蛋白被转录调节。C.线虫表现出类似的NHR，细胞色素和转移酶的升高（23，24）在这一提议中，我们将测试的假设，如在GH缺乏，长寿小鼠中看到的异生物质代谢的慢性激活，是有益于长寿。Specific Aim 1将使用突变小鼠系（细胞色素7 b1敲除），模拟长寿小鼠中发现的解毒途径的变化。该敲除小鼠模型具有与GH缺陷小鼠相似的异生物质代谢基因升高的模式。将检查Cyp 7 b1敲除小鼠的寿命延长。具体目标2旨在阐明控制解毒反应基因激活的分子机制，通过检查双重和三重KO小鼠对NHR的需求，并通过敲低肝脏中的特定NHR和候选转录因子。最后，将通过基因表达阵列评估肝脏中Stat Sab信号传导减少的后果，以确定肝脏中Stat Sab的减少是否是GH缺陷型艾姆斯和Little小鼠中观察到的大部分基因表达变化的原因，并鉴定潜在的共调节因子。这些目标将直接测试外源性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。

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.