Mitochondrial Genetics of Aging in Drosophila

项目摘要 衰老的主要原因被认为是线粒体中产生的活性氧（ROS） 作为氧化磷酸化（OXPHOS）的副产物。操作要么增加ROS 清除或减少ROS的产生延长了某些系统的寿命，但不是所有系统。 热量或饮食限制（CR或DR）仍然是唯一最可重复的干预措施， 延长了迄今为止研究的所有生物体的寿命。最近的研究表明 在CR或DR之间，改变线粒体功能，延长寿命。在本提案中，我们 提出明确的证据表明，mtDNA单倍型1）可以延长或缩短寿命，2）修改 饮食限制的长寿效应，3）改变胰岛素的长寿效应 受体底物突变chico 1。这些发现提供了核线粒体DNA 上位性作图是揭示饮食长寿遗传机制的有效方法 限制.这些结果导致了一个假设，即mtDNA中编码的基因对人类的免疫功能至关重要。 营养素对寿命的影响。我们将利用这些线粒体DNA替代菌株 为了验证这一假设，使用Rpd 3-Sir 2和TOR通路的上位性实验， 重要作用的营养为基础的变化寿命。这些基因构建体也将被用于 为了验证mtDNA基因型通过改变线粒体基因组中的蛋白质来改变寿命的一般假设， 氧化损伤程度。有三个具体目标将检验这些假设： 1)mtDNA基因型改变Rpd 3依赖的寿命延长吗？我们将测试 假设线粒体基因改变了Rpd 3对寿命的影响， 2）mtDNA基因型是否改变了Sir 2依赖的饮食效应 限制？我们将检验线粒体DNA基因型改变Sir 2在 通过将mtDNA与过表达和组织特异性配对来调节对DR的反应， 表达构建体上的不同饮食。3)线粒体DNA基因型改变TOR通路吗 对营养感知和寿命延长的影响？我们将检验线粒体DNA 基因型改变了TOR和Tsc 2在延长寿命中的作用， 这些基因的亚型和组织特异性表达构建体。

Project Summary A primary cause of aging is thought to be reactive oxygen species (ROS) produced in mitochondria as byproducts of oxidative phosphorylation (OXPHOS). Manipulations that either increase ROS scavenging or decrease ROS production have extended longevity in some, but not all systems. Caloric or dietary restriction (CR or DR) remains the single most repeatable intervention that extends longevity in all organisms studied to date. Recent studies have identified a relationship between CR or DR, altered mitochondrial function, and extended longevity. In this proposal we present clear evidence that mtDNA haplotypes 1) can extend or shorten longevity, 2) modify the longevity-extending effects of diet restriction, 3) modify the longevity-extending effects of the insulin receptor substrate mutation chico1. These findings provide proof of principle that nuclear-mtDNA epistasis mapping is effective in uncovering genetic mechanisms of longevity extension by diet restriction. The results lead to the hypothesis that genes encoded in mtDNA are critical for the nutrient-dependent modification of longevity. We will exploit these mtDNA replacement strains to test this hypothesis using epistasis experiments with the Rpd3 - Sir2 and TOR pathways that play important roles in nutrient-based changes in longevity. These genetic constructs will also be used to test the general hypothesis that mtDNA genotype modifies longevity through changes in the level of oxidative damage. There are three specific aims that will test each of these hypotheses: 1) Does mtDNA genotype alter the Rpd3-dependent extension of longevity? We will test the hypothesis that mitochondrial genes modify the effect of Rpd3 on longevity, and Rpd3's independence from DR. 2) Does mtDNA genotype alter the Sir2-dependent effects of dietary restriction? We will test the hypothesis that mtDNA genotype modifies the role Sir2 plays in regulating the response to DR by pairing mtDNAs with over-expression and tissue specific expression constructs on different diets. 3) Does mtDNA genotype modify the TOR pathway effects on nutrient sensing and longevity extension? We will test the hypothesis that mtDNA genotype modifies the role that TOR and Tsc2 play in extending longevity by pairing mtDNAs with hypomorphic and tissue specific expression constructs of these genes.