Coenzyme Q and Aging in Caenorhabditis elegans

线虫秀丽线虫是研究衰老过程的一个很好的模型。在线虫中已经发现了延长寿命的基因突变，这种线虫在脊椎动物中有同源基因，似乎通过高度保守的机制发挥作用，而且其作用途径与人类相似。线虫CLK-1基因的突变会导致寿命延长、发育缓慢和行为迟缓。CLK-1和COQ7的同源性表明，长寿线虫CLK-1突变体在辅酶Q或辅酶Q的生物合成方面存在缺陷。正常情况下，线虫得到的食物是充满辅酶Q的大肠杆菌。在没有辅酶Q的情况下，CLK-1突变体在早期发育和从Dauer阶段出来时表现出真正的表型-生长停滞和不育。这些结果表明，CLK-1对辅酶Q的生物合成是必不可少的，前面描述的衰老和发育表型可能与辅酶Q水平有关。辅酶Q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，作为必需的脂溶性抗氧化剂，在产热(解偶联)和细胞凋亡中发挥作用。我们最近的研究表明，喂食无Q饲料的野生型线虫的平均和最长寿命都延长了60%。这种寿命延长是相当强劲的，在所有到目前为止测试过的年龄突变中，当成年后转移到无Q饮食时，都观察到了这种延长寿命。关于这种寿命延长的一个令人信服的假说是，标准的大肠杆菌Q8-完全饮食影响存在的苯醌的数量和类型，这反过来又通过调节线虫线粒体呼吸的状态来影响活性氧的产生。我们建议用生物化学和分子遗传学的方法来评估Q代谢与衰老的关系。很可能这里提出的研究将定义饮食辅酶Q引起的代谢变化，并将有助于确定饮食/环境和基因如何相互作用来改变寿命。基于辅酶Q功能的强大保守性，我们的发现将非常适用于其他生物的衰老。

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.