Dietary Prevention of Cardiac Mitochondrial Aging

描述（由申请人提供）：线粒体衰退可能对与年龄相关的心功能下降有重要影响。然而，线粒体的确切作用被它们的异质性所混淆：心脏中的两个线粒体亚群，纤维间（IFM）和肌层下（SSM），可能随着年龄的增长而不对称地衰退。衰老大鼠心脏中的IFM，而不是SSM，显示出更高的氧化应激水平，更低的？3-氧化，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，但对心脏可能是可怕的；其他表现出FFA/神经酰胺增加的情况会导致慢性氧化应激和细胞凋亡，同时心脏收缩力下降。IFM血脂异常也可能影响线粒体收缩力并导致心脏僵硬。IFM血脂异常可能是导致心肌细胞丧失和充血性心力衰竭的主要因素，这是心脏老化的标志。给老年大鼠喂食乙酰左旋肉碱（ALCAR）可逆转IFM血脂异常，而(R)-a-硫辛酸（LA）可降低IFM中的氧化应激和老化的心脏。因此，IFM而非SSM会随着年龄的增长而衰退，导致局部血脂异常，而ALCAR和/或LA的补充会降低FFA/神经酰胺的积累和随之而来的氧化损伤，这一假设将在以下目的中进行探讨：1)。确定引起衰老大鼠心脏IFM血脂异常的机制。假设IFM血脂异常是由于脂肪酸的减少？3-氧化和非氧化性游离脂肪酸的积累，以及神经酰胺的积累是IFM中合成升高和鞘磷脂局部分解的结果。目的是量化导致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、心肌细胞死亡和心功能风险增加方面的后果。假设是，升高的FFA/神经酰胺在IFM中诱导氧化应激，降低诱导细胞凋亡的阈值，IFM血脂异常导致心脏僵硬。3）. 确定ALCAR和/或LA如何保护IFM免受血脂异常、降低氧化应激、防止细胞死亡和恢复心功能的机制。假设是ALCAR和/或LA降低了与年龄相关的IFM血脂异常（Aim 1）和/或改善了氧化应激、脂肪毒性，并改善了心功能（Aim 2）。心脏的纤维间线粒体受到衰老的影响，可导致心脏功能下降，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退的原因和后果，以及微量营养素乙酰左旋肉碱和/或(R) a-硫辛酸如何在衰老过程中维持线粒体功能。

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.