Number 52, 2011
Equality of care for the elderly

Energy metabolism in the aging heart

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Jason R.B. Dyck, Miranda M.Y. Sung
Cardiovascular Research Centre, Mazankowski Alberta Heart Institute,
Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
Correspondence: Jason R.B. Dyck, 458 Heritage Medical Research Centre, University of Alberta,
Edmonton, Alberta, T6G 2S2 Canada.
Tel: +1 780 492 0314; fax: +1 780 492 9753; e-mail: jason.dyck@ualberta.ca

Introduction
Age is a significant risk factor for the development of a number of cardiovascular diseases (CVDs), such as ischemic heart disease and heart failure [1,2]. The prevalence of CVD increases dramatically with advanced age [3], and given the rapidly growing size of the aging population, this will undoubtedly increase the burden of age-related diseases on the healthcare system. Progressive alterations in cardiovascular structure and deterioration of cardiac function may be intrinsically associated with the normal process of aging even in the absence of atherosclerosis and hypertension [2,4], which are major contributing factors to aging-related cardiac dysfunction [5,6]. As such, these specific age-related changes in the heart may then predispose the elderly to developing age-mediated cardiomyopathy or negatively impact cardiac disease outcomes. Indeed, advanced age is associated with several cardiovascular abnormalities, including endothelial dysfunction, arterial stiffening, cardiac interstitial fibrosis, blunted β-adrenergic response and cardiomyocyte apoptosis [1,7,8]. These cardiac changes are considered part of the normal aging process that is then influenced by environmental factors such as diet and physical activity. Although the mechanisms responsible for age-related cardiac dysfunction are likely multifactorial, derangements in the pattern of myocardial energy metabolism is thought to play an important role in the progressive decline of cardiac function with age [9–11].

Cardiac energy substrate metabolism
The heart possesses a high energy demand and must produce considerable amounts of adenosine5’-triphosphate (ATP) in order to support proper contractile function and ionic homeostasis [12]. Normally, the heart displays a high degree of metabolic flexibility and can utilize multiple substrates to generate ATP including fatty acids, glucose, lactate, and ketone bodies [11,13]. Under normal physiological conditions, >>95 % of total ATP is derived from mitochondrial oxidative phosphorylation, with the remainder coming from glycolysis [12]. The healthy adult heart has a preference for fatty acids as a fuel substrate and obtains 50–70% of its ATP from the oxidation of fatty acids, with the remainder largely accounted for by carbohydrate (glucose and lactate) oxidation [14,15].

Glucose utilization
Glucose is taken up from the circulation by facilitative glucose transporters and can be stored in the form of glycogen or undergo glycolysis [15,16]. Under aerobic conditions, the process of glycolysis converts glucose into pyruvate where the majority of pyruvate enters the mitochondria, is converted to acetyl coenzyme A (CoA) by pyruvate dehydrogenase (PDH) and then enters the tricarboxylic acid (TCA) cycle to eventually produce significant amounts of ATP [15]. During anaerobic conditions, mitochondrial oxidative metabolism is inhibited, and glycolysis becomes the major source of ATP [12]. How glucose utilization is altered in the aged heart and the relation that this has to age-mediated cardiac dysfunction has yet to be fully explained.

Fatty acid utilization
Long-chain fatty acids can enter the cardiac myocyte either by passive diffusion via a flip-flop mechanism of fatty acids across the lipid bilayer or by protein facilitated transport [17]. The three major fatty acid transport proteins identified to date, include fatty acid trans-locase (FAT)/cluster of differentiation 36 (CD36), the plasma membrane isoform of fatty acid binding protein (FABPpm), and fatty acid transport protein (FATP) 1–6 [17]. Of these, CD36 has been shown to mediate >>50% of myocardial fatty acid uptake [18] and significantly impacts subsequent fatty acid oxidation in the mitochondria [19]. Another major site of regulation of fatty acid oxidation is the import of the intracellular fatty acids into the mitochondria [14]. The rate-limiting enzyme involved in this process is carnitine palmitoyl transferase (CPT)-1, and alterations in the activity of this enzyme indirectly governs mitochondrial β-oxidation and subsequent ATP production [12]. Importantly, many of these pathways involved in regulating myocardial fatty acid utilization have been shown to be altered in the aged heart and have been suggested to contribute to cardiac dysfunction in the elderly [20,21].

Energy metabolism in the aging heart
Alterations in cardiac energy substrate metabolism occur in several cardiac pathologies, such as myocar-dial ischemia, ventricular hypertrophy, and heart failure [12]. Interestingly, only a few studies have investigated the effect of advanced age on myocardial energy metabolism. Although earlier studies have reported that fatty acid oxidation is reduced in hearts from both aged rodents [22] and humans [20], detailed examination of these studies reveal that overall oxidative metabolism may be depressed as opposed to just fatty acid oxidation. Given the close relationship between metabolism and cardiac contractile function, impaired oxidative metabolism may contribute to the age-related decline in mechanical function and increases in CVD commonly observed in older patients [8,23]. Consistent with this, we have shown using the ex vivo isolated working mouse heart model that both glucose and fatty acid oxidation are reduced by 2.5-and 4-fold, respectively, in hearts from aged mice as compared to young mice under both normal and high workloads [21]. This reduction in glucose and fatty acid oxidation rates translated into a 60% decrease in total acetyl CoA-derived ATP production in the aged heart [21] (Fig. 1f). However, whether this is due to a specific decrease in fatty acid oxidation or to an overall reduction in oxidative metabolism has not been fully explored. Consistent with the latter concept, Hyyti et al. [24] have recently shown that fatty acid and ketone oxidation is impaired in the aged murine heart, supporting that overall oxidative metabolism may be reduced.

Conclusion
A growing body of evidence suggests that alterations in myocardial energy substrate metabolism occur with advancing age. A decline in overall mitochondrial oxidation may potentially contribute to impaired cardiac mechanical function, as well as predispose the aged heart to the development of cardiac dysfunction and susceptibility to ischemic injury. Indeed, it is clear that further studies are necessary to delineate the precise metabolic changes that occur and molecular mechanisms responsible for and, more importantly, the clinical implications of these changes. Together, this may lead to more targeted metabolic therapies for the treatment and/or prevention of the progressive decline in cardiac function that can occur with age.

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