Coenzyme Q and Aging in Caenorhabditis elegans

秀丽隐杆线虫是衰老过程遗传研究的极好模型。已经在秀丽隐杆线虫中发现了延长寿命的基因突变，这些突变在脊椎动物中有同源物，并且似乎通过高度保守的机制起作用，其途径与人类相似。秀丽隐杆线虫的clk-1基因突变导致寿命延长、发育减慢和行为迟缓。clk-1和COQ7的同源性表明，长寿的秀丽隐杆线虫clk-1突变体在泛醌（辅酶Q或CoQ）的生物合成中存在缺陷。通常给线虫提供富含辅酶q的大肠杆菌的食物。在缺乏膳食CoQ的情况下，clk-1突变体显示出其真正的表型-在早期发育时生长停滞，在从生育期出现时不育。这些结果表明，clk-1对辅酶Q的生物合成至关重要，并且先前描述的衰老和发育表型可能归因于CoQ水平。CoQ在细胞中作为线粒体和质膜电子传递的氧化还原活性辅酶，是一种必需的脂溶性抗氧化剂，在产热（解偶联）和细胞凋亡中起作用。我们最近的研究表明，喂食低q食物的野生型线虫的平均寿命和最长寿命都延长了60%。这种寿命延长是相当稳健的，并且在迄今为止测试的所有年龄突变体中都观察到，当成年后转移到低q饮食时。关于这种延长寿命的一个令人信服的假设是，标准的富含q8的大肠杆菌饮食会影响存在的醌的数量和类型，而醌又通过调节线虫线粒体呼吸状态来影响活性氧的产生。我们建议采用生物化学和分子遗传学的方法来评价Q代谢与衰老的关系。这里提出的研究很可能将定义由膳食CoQ引起的代谢改变，并将有助于确定饮食/环境和基因型如何相互作用以改变寿命。基于CoQ功能的强保守性，我们的发现将与其他生物体的衰老非常相关。

The nematode Caenorhabditis elegans is an excellent model for genetic studies of the aging process. Gene mutations that increase life span have been identified in C. elegans that have homologs in vertebrates and appear to act by highly conserved mechanisms, and in pathways that parallel those present in humans. Mutations in the C. elegans clk-1 gene result in an extended life span, slowed development and sluggish behavior. Homology of clk-1 and COQ7 suggested that the long-lived C. elegans clk-1 mutants are defective in ubiquinone (coenzyme Q or CoQ) biosynthesis. Normally nematodes are provided a diet of CoQ-replete E. coli. In the absence of dietary CoQ, the clk-1 mutants display their true phenotype - growth arrest in early development and sterility when emerging from the dauer stage. These results suggest that clk-1 is essential for coenzyme Q biosynthesis, and that the aging and developmental phenotypes previously described may be attributed to CoQ levels. CoQ functions in cells as a redox-active coenzyme of both mitochondria and plasma membrane electron transport, as an essential lipid soluble antioxidant, and plays a role in thermogenesis (uncoupling) and apoptosis. Our recent studies indicate that both mean and maximum life span of wild-type nematodes fed Q-less diets is extended 60 percent. This life span extension is quite robust and is observed in all Age mutants tested so far, when transferred to the Q-less diet as adults. A compelling hypothesis for this life extension is that the standard E. coli Q8-replete diet affects the amount and type of quinones present, which in turn affects reactive oxygen species production by modulating the state of mitochondrial respiration in the nematode. We propose to evaluate the relationship between Q metabolism and aging by employing biochemistry and molecular genetics. It is likely that the studies proposed here will define the metabolic alterations resulting from dietary CoQ, and will help determine how diet/environment and genotype interact to change longevity. Based on the strong conservation of CoQ function, our findings will be very relevant to aging in other organisms.