DIETARY PREVENTION OF CARDIAC MITOCHONDRIAL AGING

心脏线粒体老化的饮食预防

• 批准号: 6734653
• 负责人: TORY M HAGEN
• 金额: $ 24.65万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6734653
• 关键词: aging; antioxidants; bioenergetics; carbonyl compound; cardiac myocytes; cardiolipins; cardiovascular disorder prevention; carnitine; dietary supplements; fluorescence spectrometry; heart function; laboratory rat; mitochondria; nutrition related tag; oxidative stress; oxidizing agents; oxygen consumption; short chain fatty acid

Her heart undergoes several adverse age-related changes that lead to loss of performance and ultimately to heart failure, the major cause of death for people over the age of 65 in the U.S. Oxidative damage, loss of energy supply, and tissue atrophy are thought to be underlying factors causing cardiac dysfunction with age, which in turn are likely caused by mitochondrial decay. However, little is known about the extent or nature of mitochondrial decay in the aging heart and whether dietary supplements that ameliorate mitochondrial decline improves cardiac function. Some studies on mitochondrial decay have been performed using isolated mitochondria, but results are conflicting and difficult to interpret. This is primarily due to a technical problem: extensive mitochondrial lysis and damage during isolation from aged tissue. We proposed to characterize and compare mitochondrial function in intact freshly isolated cardiac myocytes from old and young rats. Advances in methodology now make analysis of mitochondrial function within intact cells feasible, and we now have preliminary evidence that mitochondrial decay occurs in isolated cardiac myocytes from old rats. Advances in methodology now make analysis of mitochondrial functions within intact cells feasible, and we now have preliminary evidence that mitochondrial decay occurs is isolated cardiac myocytes from old rats. Thus, the questions to be addressed in this proposal are A) what is the nature and extent of mitochondrial decay in cardiac myocytes with age? B) does mitochondrial decay affect cardiac function? C) does feeding old rats acetyl-L-carnitine (ALCAR) and (R)-lipoic acid (LA), compounds that we showed to enhance mitochondrial function and quench mitochondrial oxidants in isolated hepatocytes, also improve mitochondrial function in cardiac myocytes? We propose to investigate these questions in 3 specific aims: 1) Characterize and compare mitochondrial functions in isolated cardiac myocytes form young, adult, mature and old rats. Characterization will include oxygen consumption characteristics, bioenergics, and cardiolipin content in quiescent cells and in myocytes stimulated to contract. Other studies using isolated cardiac myocytes or isolated perfused hearts will determine the consequences of mitochondrial decay to cardiac performance. 2) Examine age-related changes in mitochondrial antioxidants, oxidant production, and myocardial oxidative damage. These studies will be instrumental in determining not only the impact of mitochondrial decay on oxidant production, but also the effect of mitochondrial production on the cell as a whole. 3) Assess whether feeding rats ALCAR and/or LA improves mitochondrial function, lowers oxidative stress in cardiac myocytes and improves cardiac performance. These experiments will measure the same experimental end-points as in specific aims 1 and 2. This project will thus be the first step in our long term goals of determining the importance of mitochondrial decay in pathologies of the aging human heart and whether dietary regimens that improve mitochondrial performance can be inexpensive yet effective therapies for cardiac dysfunction in aging.

她的心脏发生了几种与年龄相关的不利变化，导致表现丧失并最终导致心力衰竭，这是美国65岁以上的人的主要死亡原因，在美国氧化损害，能源供应丧失和组织萎缩是潜在的因素，导致心脏功能障碍导致年龄，这反过来可能是由线粒体造成的。 然而，关于线粒体衰变在衰老心脏的程度或性质以及减轻线粒体下降的饮食补充剂是否可以改善心脏功能的程度或性质。一些有关线粒体衰减的研究是使用孤立的线粒体进行的，但结果矛盾且难以解释。这主要归因于技术问题：从老化组织分离过程中的广泛线粒体裂解和损害。我们提议表征和比较来自老鼠和年轻大鼠完整新鲜分离的心肌细胞中的线粒体功能。方法论的进展现在使得完整细胞内的线粒体功能可行，我们现在有初步的证据表明，线粒体衰减发生在旧大鼠的孤立心肌细胞中。方法论的进步现在使得完整细胞内的线粒体功能可行，我们现在有初步证据表明，线粒体衰减发生的是来自旧大鼠的心肌细胞。因此，该提案中要解决的问题是a）随着年龄的增长，心肌细胞中线粒体衰减的性质和程度是什么？ b）线粒体衰减会影响心脏功能吗？ c）喂养旧大鼠乙酰基-L-肉碱（AlcAR）和（R） - 脂肪酸（LA），我们所显示的化合物是为了增强线粒体功能和淬灭线粒体氧化剂而在分离的肝脏肝细胞中的淬灭，也可以改善心脏肌细胞中的线粒体功能？我们建议在3个特定目的中研究这些问题：1）表征和比较孤立的心肌细胞中的线粒体功能，形成了年轻，成人，成熟和老鼠。表征将包括静态细胞中的氧气消耗特性，生物甲基能和心磷脂含量以及刺激收缩的心肌细胞。使用孤立的心肌细胞或孤立的灌注心脏的其他研究将决定线粒体衰变对心脏性能的后果。 2）检查与年龄相关的线粒体抗氧化剂，氧化剂产生和心肌氧化损伤的变化。这些研究将不仅有助于确定线粒体衰变对氧化剂产生的影响，还可以确定线粒体产生对整个细胞的影响。 3）评估喂养大鼠Alcar和/或LA是否可以改善线粒体功能，降低心肌细胞的氧化应激并改善心脏性能。这些实验将测量与特定目标1和2中相同的实验终点。因此，该项目将是我们长期目标的第一步，即确定线粒体衰变在衰老人类心脏的病理学中的重要性，以及改善线粒体表现的饮食方案是否可以是便宜而有效的心脏型心动治疗方法，以实现心动良好的治疗方法。