Metabolic mechanisms of amino acid-mediated lifespan extension in C. elegans

氨基酸介导的线虫寿命延长的代谢机制

• 批准号: 8699468
• 负责人: Patrick Christopher Bradshaw
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8699468
• 关键词: Acetates; Acetoacetates; Acetyl Coenzyme A; Age; Age of Onset; Aging; Amino Acids; Aspartate; Biochemical; Bioenergetics; Biological Models; Branched-Chain Amino Acids; CREB-binding protein; Caenorhabditis elegans; Catabolism; Citrates; Citric Acid Cycle; Coenzyme A; Consumption; Dependence; Diet; Disease; Doctor of Philosophy; Dose; EP300 gene; Eating; Enzymes; Equilibrium; Essential Amino Acids; Eukaryota; Fumarates; Future; Genes; Genetic; Glutamates; Glutamine; Glycine Hydroxymethyltransferase; Goals; Histone Acetylation; Histone H4; Homocysteine; Homocystine; Human; Individual; Investigation; Isoleucine; Ketone Bodies; Laboratory Research; Leucine; Life; Link; Longevity; Longevity Pathway; Lysine; Malates; Measures; Mediating; Metabolic; Metabolism; Methionine; Mitochondria; Molecular; Nematoda; Oxaloacetates; Oxidoreductase; Pathway interactions; Phosphotransferases; Play; Process; Proline; Pyruvate; RNA Interference; Reliance; Research; Research Personnel; Rodent; Role; Signal Pathway; Students; Succinates; System; Testing; Threonine; Threonine Dehydratase; Training Programs; Tryptophan; Valine; Work; age related; base; dietary restriction; fatty acid oxidation; genetic analysis; glucose metabolism; graduate student; histone acetyltransferase; human CREBBP protein; human HAT1 protein; innovation; knock-down; mutant; novel; programs; protein intake; public health relevance; research study; response; succinyl-coenzyme A

DESCRIPTION (provided by applicant): An altered balance of dietary amino acids has been shown to modulate lifespan in several model systems. But the mechanisms through which these effects occur are still relatively unknown. The goal of this proposal is to explore the relationshi between amino acid breakdown and lifespan extension in C. elegans worms. We hypothesize that several amino acids including threonine, isoleucine, and valine increase lifespan in C. elegans by increasing succinyl-CoA and acetyl-CoA levels and the increased acetyl-CoA levels will increase histone acetylation by CREB-binding protein-1 (CBP-1) histone acetyltransferase. The specific aims for this investigation are to first determine the lifespan of worms individually administered each of the 20 amino acids and to determine the signaling pathways that are activated to extend lifespan. The amino acid breakdown products responsible for lifespan extension will subsequently be identified. Next, it will be determined if acetyl-CoA activation of the histone acetyltransferase CREB binding protein-1 (CBP-1) is involved in this process. Lastly, acetyl-CoA and succinyl-CoA levels will be measured following addition of several amino acids and knockdown of acetyl-CoA generating enzymes to determine if acetyl-CoA or succinyl- CoA levels positively correlate with lifespan. This research program is novel because it combines biochemical metabolism and genetic analysis to study aging. Mitochondrial bioenergetics plays a very important role in determining the rate of aging and the onset of aging related diseases. Our research laboratory focuses on mitochondrial analysis of C. elegans aging. The researchers who make up the project team for this two year investigation consist of the PI, one second year Ph.D. student and one fourth year Ph.D. student. The project will provide an important component of the Ph.D. training program for the two graduate students. The proposed work is innovative because it has the possibility to induce a paradigm shift in our understanding of the molecular mechanisms of how metabolism of amino acids is linked to longevity. Our results will answer three very important questions at the intersections of the fields of metabolism and aging. First, the molecular pathways leading to amino acid-induced lifespan extension will be established. Second, it will be determined if the TCA cycle metabolites acetyl-CoA and succinyl-CoA play a role in metabolite-induced lifespan extension. And third, a role for CBP-1 in amino acid induced lifespan extension will be tested. These experiments will lay the groundwork for metabolite-based therapies for human aging-related disorders.

描述（由申请人提供）：在几个模型系统中，膳食氨基酸的平衡改变已被证明可以调节寿命。但这些影响发生的机制仍然相对未知。该提案的目的是探索秀丽隐杆线虫氨基酸分解与寿命延长之间的关系。我们假设包括苏氨酸、异亮氨酸和缬氨酸在内的几种氨基酸通过增加琥珀酰辅酶 A 和乙酰辅酶 A 水平来延长线虫的寿命，并且增加的乙酰辅酶 A 水平将增加 CREB ​​结合蛋白-1 (CBP- 1）组蛋白乙酰转移酶。这项研究的具体目的是首先确定单独施用 20 种氨基酸的线虫的寿命，并确定被激活以延长寿命的信号通路。随后将鉴定负责延长寿命的氨基酸分解产物。接下来，将确定组蛋白乙酰转移酶 CREB ​​结合蛋白 1 (CBP-1) 的乙酰辅酶 A 激活是否参与该过程。最后，在添加几种氨基酸并敲低乙酰辅酶A生成酶后测量乙酰辅酶A和琥珀酰辅酶A水平，以确定乙酰辅酶A或琥珀酰辅酶A水平是否与寿命正相关。该研究项目很新颖，因为它结合了生化代谢和遗传分析来研究衰老。线粒体生物能量学在确定衰老速度和衰老相关疾病的发生方面起着非常重要的作用。我们的研究实验室专注于线虫衰老的线粒体分析。组成这项为期两年的调查的项目团队的研究人员包括 PI、一名二年级博士。学生和一名四年级博士生。学生。该项目将提供博士学位的重要组成部分。两名研究生的培训计划。这项工作具有创新性，因为它有可能引发我们对氨基酸代谢与长寿之间分子机制的理解发生范式转变。我们的研究结果将回答新陈代谢和衰老领域交叉领域的三个非常重要的问题。首先，将建立导致氨基酸诱导寿命延长的分子途径。其次，将确定 TCA 循环代谢物乙酰辅酶 A 和琥珀酰辅酶 A 是否在代谢物诱导的寿命延长中发挥作用。第三，将测试 CBP-1 在氨基酸诱导的寿命延长中的作用。这些实验将为基于代谢物的人类衰老相关疾病的治疗奠定基础。