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: 8284369
• 负责人: PETER S RABINOVITCH
• 金额: $ 30.74万
• 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/8284369
• 关键词: Accounting; Aging; Biogenesis; Cardiac; Data; Diet; 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, condltional 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 restricfion 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）营养信号是调节衰老和寿命的途径中的核心和进化保守，正如我们的计划项目研究人员在酵母和蠕虫的初步研究中所证明的那样。mTOR（雷帕霉素的哺乳动物靶标）信号传导途径监测细胞内氨基酸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通路的信号减少对细胞凋亡有积极的影响。 对衰老和寿命的影响，这是由翻译调节介导的。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，从而提供了ROS和衰老中饮食限制的范例之间的机制联系。包括我们的初步数据在内的证据表明，这些影响可能特别 心脏老化是人类发病率和死亡率的重要原因。项目2的研究重点来自这些关键发现。我们将使用基因敲除、条件性基因敲除和转基因小鼠来描绘通过mTOR途径的TORCl臂的信号传导减少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TORCl信号传导是否增强心脏对心肌细胞的抵抗力。 衰老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，它是否是由蛋白质翻译的改变介导的，以及ROS水平的降低是否是这种机制的重要组成部分。在目标2中，我们将这些研究扩展到对小鼠寿命的影响，以确认减少的TORCl信号传导增加小鼠寿命。 这些遗传学方法将导致对长寿的关键调节因子和健康寿命的决定因素的基本见解，并且有了这些知识，可以设计药理学干预措施来为人类提供类似的健康益处。心脏衰老是晚年死亡率的重要原因，而舒张功能障碍是衰老心脏生理衰退的主要原因。 拟议的研究可能揭示舒张功能障碍的新的治疗干预措施，目前严重缺乏。