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。 增加寿命的基因突变已经在C.在脊椎动物中有同源物的线虫，似乎通过高度保守的机制起作用，并且在与人类中存在的途径平行的途径中起作用。 C. elegans基因导致寿命延长，发育迟缓和行为迟缓。与COQ 7的同源性表明，长寿的C.秀丽线虫β-1突变体在泛醌（辅酶Q或CoQ）生物合成中有缺陷。 通常线虫的食物中含有辅酶Q。杆菌 在缺乏膳食辅酶Q的情况下，突变体在早期发育中表现出真正的表型-生长停滞，并且在从dauer阶段出现时表现出不育。这些结果表明，辅酶Q的生物合成，以及上述衰老和发育表型可能归因于辅酶Q水平的β-1是必不可少的。 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，作为一种必需的脂溶性抗氧化剂，并在产热（解偶联）和细胞凋亡中发挥作用。 我们最近的研究表明，野生型线虫的平均寿命和最大寿命都延长了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观察到，当转移到成年人的低Q饮食时。 一个令人信服的假设，这种寿命延长是标准的E。大肠杆菌Q8-充满饮食影响醌类的数量和类型，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价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导致的代谢改变，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。 基于辅酶Q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.