The importance of mTOR signaling in cardiac aging and lifespan in mammals

mTOR 信号传导在哺乳动物心脏衰老和寿命中的重要性

• 批准号: 8481494
• 负责人: PETER S RABINOVITCH
• 金额: $ 29.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481494
• 关键词: Accounting; Aging; Biogenesis; Cardiac; Data; Elderly; Functional disorder; Genetic; Health; Health Benefit; Heart; Human; Intervention; Knock-out; Knockout Mice; Knowledge; Lead; Link; Longevity; Mammals; Mediating; Metabolism; Mitochondria; Monitor; Mus; Nutrient; Pathway interactions; Physiological; Protein Biosynthesis; Proteins; Reactive Oxygen Species; Research; Research Personnel; Resistance; Signal Pathway; Signal Transduction; Transgenic Mice; Translational Regulation; Translations; Yeasts; arm; cell growth; design; dietary restriction; human morbidity; human mortality; insight; mTOR protein; mortality; novel therapeutic intervention; programs

DESCRIPTION (provided by applicant) Nutrient signaling is central and evolutionarily conserved in pathways that modulate aging and lifespan, as our Program Project investigators have demonstrated in preliminary studies of yeast and worms. The mTOR (mammalian target of rapamycin) signaling pathway monitors Intracellular amino add levels and regulates protein synthesis, cell growth, and ribosomal biogenesis. We hypothesize that reduced signaling through the mTOR pathway has positive effects on aging and lifespan, which are mediated by translational regulation. Furthermore, signaling through mTOR may be intimately linked to mitochondrial metabolism and reactive oxygen species (ROS), thus providing a mechanistic connection between the paradigms of ROS and dietary restriction in aging. Evidence, including our preliminary data, suggests that these effects may be particularly important in cardiac aging, an important cause of human morbidity and mortality. The focus of the research in Project 2 derives from these key findings. We will use knockout, conditional knockout and transgenic mice to delineate the effects of reduced signaling through the TORCl arm of the mTOR pathway and the interactions of this signaling with dietary restriction and reactive oxygen species (ROS). Specific Aim 1 is to establish whether reduced TORCl signaling enhances cardiac resistance to aging. We will determine whether this mechanism can account for the cardiac benefits of dietary restriction, whether it is mediated by alterations in protein translation and whether reduced levels of ROS are a significant part of this mechanism. In Aim 2, we will extend these studies to effects on mouse lifespan to confirm that reduced TORCl signaling Increases mouse longevity. These genetic approaches will lead to fundamental insights into key regulators of longevity and determinants of health span, and that with this knowledge, pharmacologic interventions can be designed to confer similar health benefits to humans. Cardiac aging Is a significant cause of late-life mortality and diastolic dysfunction is a major contributor to the physiological declines in the aging heart. The proposed studies may reveal novel therapeutic interventions for diastolic dysfunction which currently are sorely lacking.

描述（由申请人提供）正如我们的项目研究人员在酵母和蠕虫的初步研究中所证明的那样，营养信号在调节衰老和寿命的途径中处于核心地位，并且在进化上是保守的。 mTOR（雷帕霉素哺乳动物靶标）信号通路监测细胞内氨基水平并调节蛋白质合成、细胞生长和核糖体生物合成。我们假设通过 mTOR 通路减少信号传导具有积极意义 对衰老和寿命的影响是由翻译调控介导的。此外，通过 mTOR 的信号传导可能与线粒体代谢和活性氧 (ROS) 密切相关，从而在 ROS 范式与衰老过程中的饮食限制之间提供了机制联系。包括我们的初步数据在内的证据表明，这些影响可能特别明显 对心脏衰老很重要，而心脏衰老是人类发病和死亡的重要原因。项目 2 的研究重点源自这些关键发现。我们将使用敲除小鼠、条件敲除小鼠和转基因小鼠来描绘通过mTOR途径的TORC1臂减少信号传导的影响以及该信号传导与饮食限制和活性氧(ROS)的相互作用。具体目标1是确定减少的TORC1信号传导是否增强心脏对 老化。我们将确定这种机制是否可以解释饮食限制对心脏的益处，它是否是通过蛋白质翻译的改变介导的，以及活性氧水平的降低是否是该机制的重要组成部分。在目标2中，我们将把这些研究扩展到对小鼠寿命的影响，以确认TORC1信号传导的减少会增加小鼠的寿命。 这些遗传学方法将带来对长寿关键调节因素和健康寿命决定因素的基本见解，并且利用这些知识，可以设计药物干预措施来为人类带来类似的健康益处。心脏衰老是晚年死亡的一个重要原因，而舒张功能障碍是导致衰老心脏生理衰退的主要原因。 拟议的研究可能会揭示目前非常缺乏的舒张功能障碍的新治疗干预措施。