S6 Kinase, Aging and Age-related Disease

描述（由申请人提供）：最近的证据表明TOR通路是无脊椎动物衰老的关键调节剂。一致地，减少的TOR信号传导已被证明对各种年龄相关的疾病模型具有保护作用，包括心血管、神经退行性和代谢综合征以及癌症。TOR活性加速衰老或年龄相关疾病的机制仍有待确定。本提案中提供的初步数据，即缺乏S6 K1的小鼠寿命延长，界定了潜在的机制。在这项提案中，我们将定义S6 K1缺失对这些表型有益的组织，并测试可能与衰老和年龄相关疾病有关的S6激酶的潜在功能。具体来说，在目标1中（肯尼迪和威瑟斯实验室都将进行工作），我们将产生并表征肝脏、脂肪、肌肉或大脑中缺乏S6 K1的四种组织特异性S6 K1-/-敲除细胞系，以确定哪些组织中S6 K1的缺失导致保护免受饮食诱导的肥胖。目标2中的研究（在威瑟斯实验室进行，在肯尼迪实验室进行翻译研究）我们将研究S6 K1功能和胰岛素/IGF-1信号之间的联系。S6 K1-/-和Irs 1-/-小鼠都是长寿的是矛盾的，因为S6 K1通过IRS 1的磷酸化对胰岛素/IGF-1信号传导施加反馈抑制。因此，一个长寿的小鼠具有减少的胰岛素/IGF-1信号传导，而另一个具有增强的信号传导。我们将比较和对比这两种小鼠模型，检查代谢参数以及胰岛素/IGF-1和TORC 1信号传导的标志物，并分析蛋白质翻译，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，在目标3（在肯尼迪实验室进行）中，我们将检查培养物中S6 K1-/-组织和细胞的一般翻译水平，并监测与S6 K1调控相关的特定信息的翻译。与S6 K1缺失导致翻译水平降低的无脊椎动物模型不同，S6 K1-/-小鼠中的数据有限且不明确。目标3中的研究将解决这一重要问题。我们将产生缺乏S6 K1和IRS 1的细胞系，以从遗传学上解决这些途径之间的相互作用。总的来说，这些研究将提供（1）与衰老和年龄相关疾病相关的S6 K1活性的见解，以及（2）指导S6 K1条件性敲除小鼠长寿研究的初步数据。 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寿命的干预措施至关重要，健康寿命是个体保持健康和生产力的年龄。我们已经确定，降低S6激酶功能导致从酵母到小鼠的生物体寿命延长。在这个提议中，我们将剖析S6激酶活性加速衰老过程的机制。

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.