S6 Kinase, Aging and Age-related Disease

S6 激酶、衰老和年龄相关疾病

• 批准号: 8147770
• 负责人: BRIAN K KENNEDY
• 金额: $ 38.69万
• 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: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147770
• 关键词: Address; Age; Aging; Aging-Related Process; Albumins; Animal Model; Biology of Aging; Brain; Candidate Disease Gene; Cardiovascular system; Cell Line; Cells; Control Animal; Coupled; Data; Diet; Disease; Disease model; Embryo; Event; Fatty acid glycerol esters; Feedback; Fibroblasts; Funding Agency; Generations; Genes; Individual; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Invertebrates; Joints; Knock-out; Knockout Mice; Life; Link; Liver; Longevity; Malignant Neoplasms; Mammals; Measures; Mediating; Metabolic; Metabolic syndrome; Modeling; Monitor; Mus; Muscle; Myoblasts; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organism; Orthologous Gene; Output; Pathology; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Polyribosomes; Protein Analysis; Proteins; Regulation; Reporting; Research; Resistance; Ribosomal Protein S6 Kinase; Ribosomal Proteins; Signal Transduction; Source; Testing; Tissues; Transcript; Translations; Whole Blood; Work; Yeasts; adiponectin; age related; base; cohort; driving force; improved; in vivo; insight; insulin receptor substrate 1 protein; insulin signaling; mouse model; mutant; nestin protein; prevent; protective effect; public health relevance; response; uptake

DESCRIPTION (provided by applicant): Recent evidence has implicated the TOR pathway as a key modulator of invertebrate aging. Consistently, reduced TOR signaling has been shown to be protective for a variety of age-related disease models, including cardiovascular, neurodegenerative and metabolic syndromes, as well as cancer. The mechanisms by which TOR activity accelerates aging or age-related disease remain to be determined. Preliminary data presented in this proposal, namely the enhanced longevity of mice lacking S6K1, delimits potential mechanisms. In this proposal, we will define the tissue in which loss of S6K1 is beneficial for these phenotypes and test potential functions of S6 kinase that may be linked to aging and age-related disease. Specifically, in Aim 1 (with work to be performed in both the Kennedy and Withers lab), we will generate and characterize four tissue-specific S6K1-/- knockout lines lacking S6K1 in liver, fat, muscle or brain to determine in which tissues loss of S6K1 leads to protection from diet-induced obesity. Studies in Aim 2 (performed in the Withers lab with translation studies performed in the Kennedy lab) we will examine links between S6K1 function and insulin/IGF-1 signaling. That S6K1-/- and Irs1-/- mice are both long-lived is paradoxical since S6K1 exerts feedback inhibition on insulin/IGF-1 signaling through phosphorylation of IRS1. Thus, one long-lived mouse has reduced insulin/IGF-1 signaling and the other has enhanced signaling. We will compare and contrast these two mouse models, examining metabolic parameters as well as markers of insulin/IGF-1 and TORC1 signaling together with analysis of protein translation, to better understand the crosstalk between these two pathways and its potential relevance to aging and age-related disease. Finally, in Aim 3 (performed in the Kennedy lab) we will examine general levels of translation in S6K1-/- tissues and cells in cultures, and monitor translation of specific messages linked to S6K1 regulation. Unlike invertebrate models in which loss of S6K1 leads to reduced translation levels, the data in S6K1-/- mice is limited and equivocal. Studies in Aim 3 will resolve this important question. We will generate cells lines lacking both S6K1 and IRS1 to address genetically the interactions between these pathways. Collectively, these studies will provide insight (1) into the activities of S6K1 linked to aging and age-related disease and (2) preliminary data to dictate longevity studies in S6K1 conditional knockout mice. PUBLIC HEALTH RELEVANCE: Identifying the genes that influence mammalian aging is critical to understanding the biology of aging and to developing interventions which improve healthspan, the age to which an individual remains healthy and productive. We have determined that reduced S6 kinase function leads to lifespan extension in organisms ranging from yeast to mice. In this proposal, we will dissect the mechanisms by which S6 kinase activity accelerates the aging process.

描述（由申请人提供）：最近的证据已将TOR途径视为无脊椎动物衰老的关键调节剂。一致地，降低的TOR信号传导已被证明对各种与年龄相关的疾病模型具有保护性，包括心血管，神经退行性和代谢综合症以及癌症。 TOR活性加速衰老或与年龄相关的疾病的机制仍有待确定。该提案中介绍的初步数据，即缺乏S6K1的小鼠的寿命增强，划分了潜在的机制。在此提案中，我们将定义S6K1损失对这些表型有益的组织，并测试可能与衰老和与年龄相关的疾病有关的S6激酶的潜在功能。具体而言，在AIM 1中（在肯尼迪和Withers Lab中都进行工作），我们将生成和表征四个组织特异性的S6K1 - / - 敲除线，缺少S6K1的S6K1在肝，脂肪，肌肉或脑中，以确定S6K1的组织损失在哪些组织中损失饮食诱导的肥胖症。在AIM 2中的研究（在Withers Lab中进行了在肯尼迪实验室进行的翻译研究），我们将检查S6K1功能与胰岛素/IGF-1信号传导之间的联系。 S6K1 - / - 和IRS1 - / - 小鼠都是长寿命的，因为S6K1通过IRS1的磷酸化对胰岛素/IGF-1信号的反馈抑制。因此，一只长寿命的小鼠减少了胰岛素/IGF-1信号传导，另一种是增强的信号传导。我们将比较和对比这两种小鼠模型，研究代谢参数以及胰岛素/IGF-1和TORC1信号的标记以及蛋白质翻译的分析，以更好地了解这两种途径之间的串扰及其与衰老和年龄相关疾病的潜在相关性。最后，在AIM 3（在肯尼迪实验室进行）中，我们将检查培养物中S6K1 - / - 组织和细胞中的一般翻译水平，并监视与S6K1调节相关的特定消息的翻译。与无脊椎动物模型不同，S6K1的损失导致翻译水平降低，S6K1 - / - 小鼠中的数据受到限制和模棱两可。 AIM 3中的研究将解决这个重要问题。我们将生成缺乏S6K1和IRS1的细胞线，以解决这些途径之间的相互作用。总的来说，这些研究将为与衰老和与年龄有关的疾病相关的S6K1的活性提供洞察力（1），以及（2）初步数据，以决定S6K1条件敲除小鼠的寿命研究。 公共卫生相关性：确定影响哺乳动物衰老的基因对于理解衰老的生物学和开发改善健康范围的干预措施，即个人保持健康和生产力的年龄至关重要。我们已经确定降低的S6激酶功能会导致从酵母到小鼠的生物的寿命延长。在此提案中，我们将剖析S6激酶活性加速衰老过程的机制。