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

• 批准号: 8206866
• 负责人: DOUGLAS R SEALS
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 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/8206866
• 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

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.

增长年龄与动脉功能障碍和疾病的发展有关。两个主要贡献者 衰老的动脉疾病是内皮功能障碍和大动脉僵硬的。然而， 所涉及的机制和生活方式行为防止这些变化的能力是不完全的 理解。一种新颖且在很大程度上没有探索的假设是对不利的“生理抗药性” 我们长期暴露的常见环境因素随着衰老而降低的影响，因此 加剧由此产生的功能障碍和疾病风险增加。这样一个因素可能是“西方”，即 高脂，饮食（WD）。 WD通常与与氧化有关的血管炎症的发展有关 压力，一氧化氮（NO）生物利用度的降低以及血管功能障碍/疾病的风险增加。在 与WD形成鲜明对比的是，习惯性有氧运动与动脉功能增强和降低的风险有关 血管疾病。尚不清楚短期或终身暴露于WD的潜在不利影响 随着衰老而变得更大，如果可以通过习惯性有氧运动来预防这些影响（或 潜在的“运动状”血管效应）以及可能涉及的机制。最初的关键证据 概念证据可以从与年龄相关的动脉功能障碍的小鼠模型中获得。 工作假设 1。老年与血管内皮功能的逐渐减少有关 响应于WD的短期和终身摄入，大型弹性动脉刚度的增加。 2。响应于WD的内皮功能和大型弹性动脉刚度的较大损害 增长年龄将由血管炎症介导，而血管炎症将与氧化有关 应力，超氧化物增加并降低没有产生以及蛋白质表达改变。 3。习惯性有氧运动将防止更大的血管内皮功能减少并增加 在大的弹性动脉刚度中，响应于年龄较大的短期和终身WD。 4。习惯性有氧运动的这种保护作用将通过防止加重的 动脉炎症（及其对WD的氧化应激的相关影响）。 5。腺苷单磷酸激活蛋白激酶（AMPK）的动脉表达和/或活性增加 将有助于这些锻炼的保护作用。重要的是，慢性药理激活 在没有体育锻炼的情况下，AMPK将防止WD的不利影响。 影响。结果将为衰老增加脆弱性的机制提供新的见解 动脉功能障碍和疾病的发展，如果生活方式或生活方式可以阻止这种情况 模仿“药理学干预措施。将获得新的，临床上相关的知识 短期和终身暴露于高脂肪饮食与衰老相互作用，以产生动脉功能障碍。