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

基本信息

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
项目类别：
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

项目摘要

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）：饮食氨基酸的平衡发生了变化，已证明在几种模型系统中调节寿命。但是，这些效果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蠕虫中氨基酸分解与寿命延长之间的关系。我们假设通过增加琥珀酰辅酶A和乙酰辅酶A的水平以及乙酰基-COA水平的增加，包括苏氨酸，异亮氨酸和丝线在秀丽隐杆线虫中增加寿命的几种氨基酸将通过CREB结合蛋白-1（CBP-1）组蛋白乙酰基转移酶增加组蛋白乙酰化。该研究的具体目的是首先确定蠕虫的寿命单独给药，该葡萄酒单独给药，并确定激活以延长寿命的信号传导途径。随后将确定负责寿命扩展的氨基酸分解产品。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-COA激活是否参与了此过程。最后，在添加了几种氨基酸并敲低乙酰辅酶A产生酶以确定乙酰基-COA或琥珀酰-COA水平是否与寿命正相关，将测量乙酰辅酶A和琥珀酰-COA水平。该研究计划是新颖的，因为它结合了生化代谢和遗传分析来研究衰老。线粒体生物能学在确定衰老率和相关疾病的发作方面起着非常重要的作用。我们的研究实验室着重于秀丽隐杆线虫衰老的线粒体分析。组成项目团队为期两年调查的研究人员由PI组成，第二年博士学位。学生和一家第四年博士学生。该项目将提供博士学位的重要组成部分。两位研究生的培训计划。提出的工作具有创新性，因为它有可能引起我们对氨基酸代谢如何与寿命有关的分子机制的理解的范式转移。我们的结果将在代谢和衰老领域的交集中回答三个非常重要的问题。首先，将建立导致氨基酸诱导寿命延伸的分子途径。其次，将确定是否在TCA循环代谢物乙酰-COA和琥珀酰-COA中起作用在代谢物诱导的寿命延长中起作用。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与衰老相关疾病的疗法奠定基础。