TOR, Translation and Aging

TOR、翻译和时效

• 批准号: 8214175
• 负责人: BRIAN K KENNEDY
• 金额: $ 37.84万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8214175
• 关键词: Address; Affect; Age; Aging; Amino Acids; Animal Model; Biogenesis; Biological Assay; Caenorhabditis elegans; Cardiovascular Diseases; Cell division; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Delaware; Diet; Disease; Eukaryota; Event; Fatty acid glycerol esters; Gene Deletion; Genes; Genetic; Genetic Translation; Health; Homeostasis; Housing; Human; Intervention; Invertebrates; Knock-out; Lead; Life; Link; Longevity; Malignant Neoplasms; Mammals; Maps; Mediator of activation protein; Metabolic; Metabolic syndrome; Mitochondria; Modeling; Monitor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nutrient; Obesity; Open Reading Frames; Organism; Orthologous Gene; Output; Pathway interactions; Peptide Initiation Factors; Phenotype; Phosphotransferases; Play; Prokaryotic Initiation Factor-2; Property; Proteins; Publishing; Regulation; Research Personnel; Ribosomal Protein S6 Kinase; Ribosomal Proteins; Ribosomes; Role; Series; Signal Transduction; Sirolimus; Stress; System; Testing; Transcript; Translation Initiation; Translational Regulation; Translations; Yeasts; age related; aging gene; biological adaptation to stress; cell growth; cohort; dietary restriction; fly; genome wide association study; mouse model; overexpression; protein metabolism; research study; safran; transcription factor; yeast genetics

DESCRIPTION (provided by applicant): Studies in worms and yeast have linked lifespan extension by dietary restriction to altered translational regulation. Consistently, reduced TOR signaling or S6 kinase activity leads to increased lifespan in both invertebrates, and delays the onset of age-related diseases in mammals. In addition to Protein Kinase A (PKA), TOR and Sch9 make three nutrient-responsive kinases linked to yeast longevity modulation. In this proposal, we employ yeast as a model organism to address the mechanisms by reduced nutrient signaling, dietary restriction, or altered translational regulation that lead to extension of yeast replicative lifespan. As a result of a genome-wide screen for long-lived yeast gene deletion strains, we identified a number of ribosomal large subunit gene deletions that result in reduced 60S subunit biogenesis. One mechanism by which reduced 60S subunit biogenesis lead to lifespan extension is through enhanced translation of the GCN4 transcription factor. GCN4 translation is also induced by reduced TOR signaling and required for maximum lifespan extension in this setting, making this a common mechanism modulating yeast aging. Gcn4 targets include amino acid biosynthetic genes as well as stress responsive and mitochondrial factors. The regulatory system controlling Gcn4 translation is highly conserved in all eukaryotes including humans. In Aim 1 of this proposal, we perform a series of experiments to determine the mechanisms leading to GCN4 activation and the targets of GCN4 important for yeast aging. While enhanced GCN4 translation is one mechanism underlying lifespan extension by reduced 60S subunit biogenesis and nutrient signaling, our evidence indicates that others exist as well. Therefore, in Aim 2 we describe efforts to identify these GCN4- independent mechanisms using a series of approaches both unbiased and directed. Finally, in Aim 3 we address a second major question: does reduced ribosome biogenesis lead to lifespan extension in mammals. To test this, we will determine the longevity of mice lacking ribosomal large subunit genes chosen because of similar mutations extend lifespan in worms and yeast. We will also test a series of age-associated phenotypes, focusing on metabolic outputs. Together, these studies will better define the mechanisms linking reduced nutrient signaling and ribosome biogenesis to aging and test whether their effects extend to mammals. PUBLIC HEALTH RELEVANCE: It is increasingly becoming recognized that interventions to slow aging will provide broad spectrum benefits to age-related diseases including neurodegeneration, cancer and cardiovascular disease. In this proposal, we address at the mechanistic level the relationship between protein translation and aging. Through achieving a better understand of the modulatory role played by regulated protein translation in aging, we will be able to pinpoint key targets for pharmacological interventions.

描述（由申请人提供）：蠕虫和酵母的研究通过饮食限制与改变的翻译调节，其寿命延长相关。一致地，降低的TOR信号传导或S6激酶活性会导致两种无脊椎动物的寿命增加，并延迟了哺乳动物与年龄相关的疾病的发作。除了蛋白激酶A（PKA）外，Tor和Sch9还使三种营养响应激酶与酵母寿命调节相关。在此提案中，我们采用酵母作为模型生物体来解决营养信号传导，饮食限制或变化的转化调节，从而延长酵母复制寿命。由于长寿命酵母基因缺失菌株的全基因组筛选，我们确定了许多核糖体大亚基基因缺失，从而降低了60年代的亚基生物发生。减少60s亚基生物发生导致寿命扩展的一种机制是通过增强GCN4转录因子的翻译。在这种情况下，TOR信号传导降低也会引起GCN4翻译，并且最大寿命延长所需，这使得这是调节酵母老化的常见机制。 GCN4靶标包括氨基酸生物合成基因以及应力响应性和线粒体因子。控制GCN4翻译的调节系统在包括人类在内的所有真核生物中都高度保守。在本提案的目标1中，我们执行一系列实验，以确定导致GCN4激活的机制和GCN4对酵母老化很重要的靶标。虽然增强的GCN4翻译是减少60年代亚基生物发生和营养信号传导的寿命扩展的一种机制，但我们的证据表明其他人也存在。因此，在AIM 2中，我们描述了使用一系列无偏见和指示的方法来识别这些GCN4独立机制的努力。最后，在AIM 3中，我们解决了第二个主要问题：核糖体生物发生减少会导致哺乳动物的寿命延长。为了测试这一点，我们将确定缺乏核糖体大亚基基因的小鼠的寿命，因为相似的突变延伸了蠕虫和酵母中的寿命。我们还将测试一系列与年龄相关的表型，重点是代谢输出。总之，这些研究将更好地定义将减少的营养信号传导和核糖体生物发生与衰老联系起来的机制，并测试其作用是否扩展到哺乳动物。公共卫生相关性：越来越多地认识到，缓慢衰老的干预措施将为与年龄有关的疾病提供广泛的益处，包括神经退行性疾病，癌症和心血管疾病。在此提案中，我们在机械水平上解决蛋白质翻译与衰老之间的关系。通过更好地理解调节蛋白质翻译在衰老中所起的调节作用，我们将能够指出药理学干预措施的关键目标。