Dietary Prevention of Cardiac Mitochondrial Aging

心脏线粒体老化的饮食预防

• 批准号: 7479114
• 负责人: TORY M HAGEN
• 金额: $ 29.51万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479114
• 关键词: Accounting; Affect; Age; Aging; Antioxidants; Apoptosis; Apoptotic; Atrophic; Attenuated; Bioenergetics; Cardiac; Cardiac Death; Cardiolipins; Cardiotoxicity; Carnitine O-Palmitoyltransferase; Cell Death; Ceramidase; Ceramides; Cessation of life; Chronic; Condition; Congestive Heart Failure; Data; Dietary Supplementation; Dyslipidemias; Elderly; Electron Transport; Energy Metabolism; Exhibits; Fatty Acids; Functional disorder; Goals; Health Care Costs; Heart; Heart Diseases; Heart Mitochondria; Heel; Heterogeneity; Homeostasis; Hospitalization; Hospitals; Human Resources; Ions; Lesion; Levocarnitine Acetyl; Lipids; Localized; Micronutrients; Mitochondria; Molecular; Molecular Target; Muscle Cells; Myocardial; Myofibrils; Nature; Nonesterified Fatty Acids; Oxidative Stress; Pathology, Other; Plant Roots; Play; Prevention; Publishing; Pump; Rate; Rattus; Reactive Oxygen Species; Relaxation; Research; Research Personnel; Risk; Role; Sarcolemma; Site; Sphingomyelinase; Sphingomyelins; Stimulus; Supplementation; Therapeutic Intervention; Thioctic Acid; Time; Toxic effect; age related; aged; base; experience; feeding; heart function; hemodynamics; improved; mitochondrial dysfunction; oxidation; prevent; programs; research study

DESCRIPTION (provided by applicant): Mitochondrial decay may contribute significantly to the age-related decline in cardiac function. However, the precise role of mitochondria is confounded by their heterogeneity: two mitochondrial subpopulations in the heart, interfibrillary (IFM) and subsarcolemmal (SSM), may asymmetrically decay with age. IFM, but not SSM, from aging rat hearts show heightened levels of oxidative stress, lower rates of ?3-oxidation, and have elevated levels of free fatty acids (FFA) and ceramides. The consequences of this IFM dyslipidemia are unknown but likely dire for the heart; other conditions exhibiting increased FFA/ceramides result in chronic oxidative stress and apoptosis with decline in cardiac contractility. IFM dyslipidemia would also be expected to affect mitochondrial contractility and contribute to cardiac stiffness. It is tantalizing to suggest that IFM dyslipidemia may be a major factor contributing to myocyte loss and congestive heart failure - hallmarks of the aging heart. Feeding old rats acetyl-L-carnitine (ALCAR) reverses IFM dyslipidemia, while (R)-a-lipoic acid (LA) lowers oxidative stress in IFM and the aging heart. Thus, the hypothesis, that IFM but not SSM decays with age resulting in a localized dyslipidemia but ALCAR and/or LA supplementation lower(s) FFA/ceramide accumulation and attendant oxidative insult, will be explored in the following aims: .1). Determine the mechanism(s) causing IFM dyslipidemia in the aging rat heart. The hypothesis is that IFM dyslipidemia is due to the decline in fatty acid ?3-oxidation and accumulation of non-oxidizable FFAs and that ceramides accumulate as a result of both elevated synthesis and sphingomyelin breakdown locally in IFM. The goal is to quantify the precise mechanism(s) leading to FFA/ceramide accumulation. 2). Identify the consequences of IFM dyslipidemia in terms of oxidative stress, increased risk for myocyte death and cardiac function. The hypothesis is that elevated FFA/ceramides induce an oxidative stress in IFM and lower the threshold to induce apoptosis and that IFM dyslipidemia contributes to cardiac stiffness. 3). Determine the mechanism(s) how ALCAR and/or LA protect(s) IFM from dyslipidemia, lower(s) oxidative stress, prevent(s) cell death, and restore(s) cardiac function. The hypothesis is that ALCAR and/or LA lower(s) the age-related IFM dyslipidemia (Aim 1) and/or ameliorate(s) oxidative stress, lipotoxicity, and improve(s) cardiac function (Aim 2). The interfibrillary mitochondria of the heart are affected by aging and can contribute to the decline in heart function, the leading cause of hospitalization and death in the elderly. The long-term objectives of this research are to examine the causes and consequences of mitochondrial decay and how the micronutrients acetyl-L-carnitine and/or (R)-a-lipoic acid may maintain mitochondrial function during aging.

描述（由申请人提供）：线粒体衰变可能对年龄相关的心脏功能下降有显着影响。然而，线粒体的确切作用因其异质性而被混淆：心脏中的两个线粒体亚群，即纤维间（IFM）和肌膜下（SSM），可能会随着年龄的增长而不对称地衰减。来自衰老大鼠心脏的 IFM（而非 SSM）显示氧化应激水平升高、β3-氧化率降低，并且游离脂肪酸 (FFA) 和神经酰胺水平升高。这种 IFM 血脂异常的后果尚不清楚，但可能对心脏造成可怕的后果。其他表现出 FFA/神经酰胺增加的病症会导致慢性氧化应激和细胞凋亡，并导致心肌收缩力下降。 IFM 血脂异常预计还会影响线粒体收缩力并导致心脏僵硬。令人着迷的是，IFM 血脂异常可能是导致心肌细胞丢失和充血性心力衰竭（心脏老化的标志）的一个主要因素。喂养老年大鼠乙酰左旋肉碱 (ALCAR) 可逆转 IFM 血脂异常，而 (R)-α-硫辛酸 (LA) 可降低 IFM 和衰老心脏的氧化应激。因此，IFM 而不是 SSM 会随着年龄的增长而衰退，导致局部血脂异常，但补充 ALCAR 和/或 LA 会降低 FFA/神经酰胺积累和随之而来的氧化损伤，这一假设将在以下目标中进行探讨： .1)。确定导致衰老大鼠心脏 IFM 血脂异常的机制。该假设认为，IFM 血脂异常是由于脂肪酸 β3-氧化的下降和不可氧化的 FFA 的积累而引起的，而神经酰胺的积累是由于 IFM 中局部合成增加和鞘磷脂分解所致。目标是量化导致 FFA/神经酰胺积累的精确机制。 2）。确定 IFM 血脂异常在氧化应激、心肌细胞死亡风险增加和心脏功能方面的后果。假设是，FFA/神经酰胺升高会诱导 IFM 中的氧化应激，并降低诱导细胞凋亡的阈值，并且 IFM 血脂异常会导致心脏僵硬。 3）。确定 ALCAR 和/或 LA 如何保护 IFM 免受血脂异常、降低氧化应激、预防细胞死亡和恢复心脏功能的机制。假设 ALCAR 和/或 LA 可降低与年龄相关的 IFM 血脂异常（目标 1）和/或改善氧化应激、脂毒性并改善心脏功能（目标 2）。心脏的纤维间线粒体受到衰老的影响，会导致心脏功能下降，这是老年人住院和死亡的主要原因。这项研究的长期目标是研究线粒体衰变的原因和后果，以及微量营养素乙酰基-L-肉碱和/或(R)-α-硫辛酸如何在衰老过程中维持线粒体功能。