Aging and Arterial Dysfunction with a Western Diet: Exercise and AMPK

西方饮食导致的衰老和动脉功能障碍：运动和 AMPK

基本信息

批准号：
8064144
负责人：
DOUGLAS R SEALS
金额：
$ 38万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064144
关键词：
3-nitrotyrosine Acute Adenosine Monophosphate Adverse effects Aerobic Exercise Age Aging Anti-Inflammatory Agents Arteries Behavior Biological Availability Blood Vessels Carotid Arteries Chronic Development Diet Disease Elderly Electron Spin Resonance Spectroscopy Endothelium Environmental Risk Factor Enzymes Exercise Exposure to Fatty acid glycerol esters Functional disorder Goals Human Impairment In Vitro Inflammation Inflammatory Ingestion Intervention Knowledge Life Style Link Measurement Measures Mediating Mus Nitric Oxide Oral Oxidative Stress Physical activity Physiologic pulse Physiological Production Protein Kinase Proteins Research Resistance Risk Running Signal Pathway Sodium Salicylate Spin Trapping Superoxides Testing Tissues Tumor Necrosis Factor-alpha Vascular Diseases Work age effect age group cardiovascular disorder risk clinically relevant diet and exercise disorder risk insight middle age mouse model novel prevent protective effect protein expression response treatment duration vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Advancing age is associated with the development of arterial dysfunction and disease. Two major contributors to arterial disease with aging are endothelial dysfunction and stiffening of the large elastic arteries. However, the mechanisms involved and the ability of lifestyle behaviors to prevent these changes are incompletely understood. One novel and largely unexplored hypothesis is that "physiological resistance" to the adverse effects of common environmental factors to which we are chronically exposed decreases with aging, thus exacerbating the resulting dysfunction and increased risk of disease. One such factor may be a "western", i.e., high-fat, diet (WD). WD generally is associated with development of vascular inflammation linked to oxidative stress, a reduction in nitric oxide (NO) bioavailability and an increased risk of vascular dysfunction/disease. In contrast to WD, habitual aerobic exercise is associated with enhanced arterial function and reduced risk of vascular diseases. It is unknown if the potentially adverse effects of short-term or lifelong exposure to WD become greater with aging, if these effects can be prevented by habitual aerobic exercise (or an agent with potential "exercise-like" vascular effects), and the mechanisms that may be involved. Initial critical proof of concept evidence can be obtained from a mouse model of age-associated arterial dysfunction. Working Hypotheses 1. Older age is associated with progressively greater reductions in vascular endothelial function and increases in large elastic artery stiffness in response to both short-term and lifelong ingestion of WD. 2. The greater impairments in endothelial function and large elastic artery stiffness in response to WD with increasing age will be mediated by vascular inflammation, which will, in turn, be associated with oxidative stress, increased superoxide and reduced NO production, and altered protein expression. 3. Habitual aerobic exercise will prevent the greater reductions in vascular endothelial function and increases in large elastic artery stiffness in response to short-term and lifelong WD with older age. 4. This protective effect of habitual aerobic exercise will be mediated by preventing the exacerbation of arterial inflammation (and its associated effects on oxidative stress and NO) in response to WD. 5. Increased arterial expression and/or activity of adenosine monophosphate activated protein kinase (AMPK) will contribute to these protective effects of exercise. Importantly, chronic pharmacological activation of AMPK will prevent the adverse effects of WD in the absence of physical activity. Impact. The results will provide novel insight into the mechanisms by which aging increases vulnerability to the development of arterial dysfunction and disease, and if this might be prevented by lifestyle or "lifestyle mimicking" pharmacological interventions. New, clinically relevant knowledge will be gained as to how both short-term and lifelong exposure to a high fat diet interacts with aging to produce arterial dysfunction. PUBLIC HEALTH RELEVANCE: The goal of this research is to determine if the dysfunction of arteries that occurs in response to both short- term and lifelong ingestion of a "western" (high-fat) diet worsens with aging. We also will determine if regular exercise and a pharmacological compound with presumed exercise-like effects "protect" arteries from both short-term and lifelong exposure to a western diet. Finally, we will gain insight into why aging has an adverse influence on arteries exposed to a western diet, and how exercise and the exercise-like agent prevent this effect. We will study mice as a first step in investigating these issues.

描述（由申请人提供）：增长年龄与动脉功能障碍和疾病的发展有关。衰老的动脉疾病的两个主要因素是内皮功能障碍和大型弹性动脉的僵硬。但是，涉及的机制和生活方式行为防止这些变化的能力尚不完全理解。一种新颖且在很大程度上没有探索的假设是，我们长期暴露的常见环境因素的不利影响随着衰老而降低，从而加剧了由此导致的功能障碍和疾病风险增加。这样的因素之一可能是“西方”，即高脂，饮食（WD）。 WD通常与与氧化应激有关的血管炎症的发展，一氧化氮（NO）生物利用度的减少以及血管功能障碍/疾病的风险增加有关。与WD相反，习惯性有氧运动与动脉功能增强和血管疾病风险降低有关。尚不清楚短期或终身暴露于WD的潜在不利影响会随着老化而变得更大，是否可以通过习惯性有氧运动来预防这些影响（或具有潜在的“运动样”血管效应的药物）以及机制这可能涉及。可以从与年龄相关的动脉功能障碍的小鼠模型获得概念证据的初始关键证据。工作假设1。老年与血管内皮功能的逐渐降低有关，并且响应于WD的短期和终身摄入，大型动脉刚度的增加。 2。随着年龄的增长，内皮功能和大型弹性动脉刚度的较大损害将由血管炎症介导，而血管炎症将与氧化应激相关，超级氧化物增加和NO产生，并改变了蛋白质的表达。。 3。习惯性有氧运动将防止血管内皮功能的更大降低，并响应于年龄较大的短期和终身WD而大型弹性动脉刚度的增加。 4。习惯性有氧运动的这种保护作用将通过防止动脉炎症加重（及其对WD的氧化应激和NO的相关作用）来介导。 5。腺苷单磷酸激活蛋白激酶（AMPK）的动脉表达和/或活性将有助于这些运动的这些保护作用。重要的是，AMPK的慢性药理激活将防止在没有身体活动的情况下WD的不良影响。影响。结果将提供对衰老增加对动脉功能障碍和疾病发展的机制的新见解，如果生活方式或“模仿”药理学干预措施可以预防这种动脉功能障碍和疾病。关于短期和终身暴露于高脂肪饮食如何与衰老相互作用以产生动脉功能障碍，将获得新的临床相关知识。公共卫生相关性：这项研究的目的是确定响应短期和终生摄入“西方”（高脂）饮食的动脉功能障碍是否随着衰老而恶化。我们还将确定定期运动和药理学化合物是否具有假定运动效果“保护”动脉，以免短期和终身暴露于西方饮食。最后，我们将深入了解为什么衰老会对暴露于西方饮食的动脉产生不利影响，以及运动和运动剂如何阻止这种作用。我们将研究小鼠作为研究这些问题的第一步。