Coenzyme Q and Aging in Caenorhabditis elegans

辅酶 Q 与秀丽隐杆线虫的衰老

• 批准号: 6479157
• 负责人: CATHERINE FREITAG CLARKE
• 金额: $ 32.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479157
• 关键词: Caenorhabditis elegans; aging; antioxidants; cell component structure /function; cellular respiration; developmental genetics; diet; enzyme activity; free radical oxygen; gene environment interaction; gene mutation; gene targeting; genetic models; genetically modified animals; genotype; high performance liquid chromatography; imaging /visualization /scanning; longevity; metabolism; mitochondria; molecular genetics; nutrition of aging; nutrition related tag; phenotype; respiratory enzyme; ubiquinone

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.

线虫秀丽隐杆线虫是衰老过程遗传研究的绝佳模型。 在具有脊椎动物中具有同源物的秀丽隐杆线虫中已经鉴定出了增加寿命的基因突变，并且似乎是通过高度保守的机制以及与人类中存在的途径相似的途径。 秀丽隐杆线虫CLK-1基因中的突变导致寿命延长，发展缓慢和行为缓慢。 CLK-1和COQ7的同源性表明，寿命长的秀丽隐杆线虫CLK-1突变体在泛氨基酮（辅酶Q或COQ）生物合成中有缺陷。 通常为线虫提供COQ-复发大肠杆菌的饮食。 在没有饮食coq的情况下，CLK -1突变体显示出其真实的表型 - 早期发育中的生长停滞和从Dauer阶段出现时的无菌性。这些结果表明，CLK-1对于辅酶Q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转运的氧化还原活性辅酶作为必需的脂质可溶性抗氧化剂的作用，并在热生成（解偶联）和凋亡中起作用。 我们最近的研究表明，喂养无Q的饮食的野生型线虫的平均寿命和最大寿命均延长了60％。 这种寿命延长非常健壮，并且在迄今为止的所有年龄突变体中都可以观察到成年人的无Q饮食。 这一生命扩展的一个引人注目的假设是，标准的大肠杆菌Q8重生饮食会影响存在的奎因酮的数量和类型，这反过来又通过调节线粒体中线粒体呼吸的状态来影响活性氧的产生。 我们建议通过使用生物化学和分子遗传学来评估Q代谢和衰老之间的关系。 此处提出的研究可能会定义饮食中的COQ引起的代谢改变，并有助于确定饮食/环境和基因型如何相互作用以改变寿命。 基于COQ功能的强烈保护，我们的发现将与其他生物体的衰老非常相关。