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.

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National Institute on Aging (NIA)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Finkelstein, David B
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Oregon State University
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