Heart and Metabolism

Impact of aging on myocardial oxidative metabolism

Robert J. Gropler
Associate Professor of Radiology, Medicine and Biomedical Engineering,
Washington University School of Medicine, St Louis, MO, USA
Correspondence: Professor Robert J. Gropler, Cardiovascular Imaging Laboratory,
Mallinckrodt Institute of Radiology , Washington University School of Medicine, St Louis, MO, USA.
Tel: +1 3147473878, fax:+1 3147473882, e-mail:groplerr@mir.wustl.edu

Introduction
There is an age-related decline in cardiac function and an increase in both the frequency and manifestation in older individuals of various cardiovascular disorders such as coronary artery disease, hypertension-induced left ventricular dysfunction, and dilated cardiomyopathy. The primary cardiac manifestation of the aging process is a decline in myocardial mechanical function during episodes of increased cardiac work.[1,2] The decline in mechanical function is characterized by impaired left ventricular systolic reserve capacity and diastolic filling.[3] Although likely multifactorial, the mechanisms responsible for the age-related decline in mechanical function are poorly understood. A decline in both b-adrenergic sensitivity and myocardial vasodilator function appears to be contributory.[3–9] Given the close coupling between myocardial oxidative metabolism and mechanical function, it would appear likely that aging may have important myocardial metabolic effects. Summarized below is what is known about the effects of aging on myocardial oxidative metabolism.

Effects of aging on mitochondrial function
The machinery for oxidative metabolism resides within the mitochondria. Consequently, this organelle is a likely target for the effects of aging. Indeed, deletions and mutations of mitochondrial DNA (mtDNA) have been associated with aging. These age-associated mtDNA mutations appear to reflect the combined effects of intense oxidative damage and low efficiency of mtDNA repair systems.[10–13] Moreover, these mtDNA mutations and deletions have been proposed as a possible cause of senescence because of their potential negative impact on mitochondrial gene expression and oxidative capacity.[10] However, the presence and severity of aging-related decrements in myocardial mitochondrial oxidative metabolism remains unclear. In mitochondria isolated from the hearts of aging animals, the results of some studies suggest that decreased oxidative function is present,[14,15] whereas the results of other studies suggest that oxidative capacity remains unchanged.[16–18] Furthermore, whether any of these observations is applicable to humans is unknown.

Myocardial oxygen consumption
One of the ways to assess the impact of aging on myocardial oxidative metabolism is to determine whether the amount of oxygen consumed by the myocardium (MVO2) is altered by the aging process. To date, results of studies have provided conflicting results. For example, based on studies in experimental animals, it appears that MVO2 declines with age, both under resting conditions and during episodes of increased stress.[19–21] However, many of these differences may be explained by the fact that hearts from senescent animals achieved lower levels of cardiac work because, when corrected for the level of cardiac work, the level of MVO2 was comparable between senescent and mature animals.[21] However, in some studies, the amount of oxygen consumed per level of cardiac work (an index of efficiency) was slightly higher in aged animals compared with younger animals, suggesting that myocardial energy transduction may decrease with age.[21]
Definitive information regarding this topic in humans is lacking. Results of preliminary studies suggest that the level of MVO2 (measured by PET with 11C-acetate), both at rest and during catecholamine-induced stress, is comparable between younger (average age 25 years) and older (average age 65 years) healthy subjects.[22] However, myocardial work (calculated as the product of myocardial wall stress and strain measured by MRI) differed between the younger and older subjects. At rest, myocardial work levels were comparable between the two groups, but during catecholamine stimulation, older subjects exhibited a blunted increase in myocardial work. The blunted increase in myocardial work appears to be due to a blunted increase in myocardial strain. This resulted in myocardial efficiency (myocardial work divided by MVO2) being lower during catecholamine stimulation in older subjects than in younger individuals. As a result, myocardial efficiency during inotropic stimulation appears to be lower in older subjects than in younger adults. Intriguingly, these data are consistent with results obtained in experimental animals described above.[21] Clearly, more studies are necessary to confirm these findings and determine their significance.
However, one could speculate that the reduced efficiency in response to stress may help explain the reduced exercise capacity that is associated with aging, as well as why the hearts of older individuals are more susceptible to the manifestations of myocardial infarction.

Myocardial substrate oxidation
Another way to evaluate the effects of aging on myocardial oxidative metabolism is to determine how aging may alter the oxidization of the various substrates used by the heart. The heart can use a variety of substrates, such as fatty acids, glucose, lactate, pyruvate, and amino acids, to support oxidative metabolism. In general, fatty acids and glucose are the most common substrates to be used by the heart, their proportional contribution to oxidative metabolism being dependent upon a variety of factors such as the plasma substrate environment, hormonal milieu, and level of cardiac work. However, age also appears to affect this relationship. In the fetal heart, glucose utilization (the total amount of glucose used by the heart) and oxidation (the amount of glucose oxidized) predominate, most likely secondary to the relative hypoxia of the fetal state. In the normoxic state of the mature heart, fatty acids become the preferred source for oxidative metabolism. In experimental models of aging, with senescence, fatty acid oxidation declines and the proportion of glucose oxidation to overall oxidative metabolism increases even though absolute levels in glucose oxidation may still be less than those observed in mature animals.[19–21,23]
These observations appear to hold both under resting conditions and during episodes of increased cardiac work.
Results of a recent preliminary study suggest that a similar metabolic shift may occur in humans as they age. In this study, measurements of MVO2, myocardial fatty acid utilization, and glucose utilization were made by PET using 1-11C-acetate, 1-11C-palmitate and 1-11C-glucose, respectively, in younger (average age 27 years) and older (average age 67 years) healthy adults under resting conditions.[24]
It was observed that myocardial fatty acid utilization and oxidation were significantly lower in the older subjects than in the younger individuals (Figure 1A and 1B). In contrast, myocardial glucose utilization was significantly higher in the older subjects than in the younger subjects.

Figure 1A.-PET derived myocardial 1-11C-palmitate images obtained from a young female (left) and and older female (right) studied at rest after an overnight fast. Images represent data acquired from 20 to 30 minutes after injection of tracer. Images are displayed in the short axis view, S:Septum, A: Anterior,L: Lateral and I: Inferior. White indicates highest counts and blue lowest counts.
Figure 1B.- PET derived myocardial 1-11C-palmitate time-activity curves corresponding to the images shown above. The slower myocardial rate of clearance (solid lines) observed in the older female is indicative of a lower rate of fatty acid oxidation.

This metabolic shift occurred despite similar levels in hemodynamics and plasma insulin and substrate levels between the two groups. Although, this study did not measure the oxidation of glucose, the similar shift in utilization of fatty acids and glucose seen in experimental models of aging suggests that senescence alters the oxidation of these substrates in a similar way. Currently, no data are available on the impact of aging on the oxidation of glucose and fatty acids in humans during stress.

Potential mechanisms for the age-related shift in substrate oxidation
Potential mechanisms for the shift in substrate utilization and oxidation include changes in mitochondrial lipid content, lipid composition, and protein interactions as well as oxygen free radical injury with subsequent lipid peroxidation of mitochondrial membranes leading to significant membrane dysfunction.[11,12,25–28] Furthermore, oxygen free radical injury to key enzyme systems for fatty acid oxidation may play a role. Another potential mechanism includes changes in nitric oxide levels with age. Recently it has become apparent that nitric oxide, produced from endothelial nitric oxide synthase, plays an important role in the regulation of myocardial substrate metabolism. In various experimental models designed to alter the activity of this enzyme system, it has been shown that cardiac nitric oxide production inhibits myocardial glucose utilization. As a consequence, myocardial fatty utilization is increased.[29,30] It is unknown whether nitric oxide levels alter the oxidation of these substrates or indeed whether these observations are applicable to aging in humans. However, given that nitric oxide production decreases with age, it is tempting to speculate that the cardiac metabolic alterations observed with aging are at least partially due to changes in nitric oxide production.
The peroxisome proliferator-activated receptor-a (PPARa) is another intriguing potential site for age-related changes in substrate oxidation. PPARa is a member of the nuclear receptor superfamily of transcription factors and is involved in the metabolic control of fatty acid oxidation enzyme gene expression.[31,32] In experimental animal models lacking PPARa, myocardial fatty acid oxidation is markedly reduced. Moreover, it appears that levels of PPARa (at least in splenic tissue) decrease with age.[33] Consequently, an age-related decline in PPARa levels in the myocardium would also provide a partial explanation for the decrease in fatty acid oxidation in senescence.

Clinical implications
The clinical consequences of age-related alterations in myocardial oxidative metabolism are manifold. With advancing age, there is an increased incidence of impaired glucose tolerance and diabetes mellitus.
Consequently, a potential detrimental effect associated with this age-related shift in myocardial substrate metabolism includes impaired mechanical function due to the inability to increase glucose metabolism in response to an increase in myocardial
work. Recent studies in experimental models of left ventricular hypertrophy and initial studies in humans with hypertension-induced left ventricular hypertrophy have shown that myocardial energy substrate utilization is altered in association with hypertrophy as fatty acid utilization and oxidation decrease while glycolysis increases.[34,35] This switch in substrate metabolism is consistent with observations of the re-expression of fetal isoforms of a variety of contractile and calcium regulatory proteins in hypertrophied myocardium, suggesting that the development of left ventricular hypertrophy recapitulates the fetal heart phenotype.[36] Of note, these metabolic alterations in pressure-overload-induced hypertrophied myocardium may become more pronounced when left ventricular systolic dysfunction occurs, suggesting that this metabolic shift in substrate use is partly responsible, or at least presages, the transition from hypertrophy alone to hypertrophy with left ventricular dysfunction.[37,38]
These metabolic alterations would be additive to those due to aging. Consequently, the age-related changes in myocardial oxidative metabolism would provide at least a partial explanation as to why the incidence and manifestations of left ventricular hypertrophy and dilated cardiomyopathy are more pronounced in older subjects.

Conclusion
There is an ever-growing body of evidence that aging alters myocardial oxidative metabolism, both with respect to MVO2 and to the oxidation of specific substrates. However, most of this information has been obtained in experimental models of aging. More studies are necessary to determine whether these observations are applicable to aging humans. Moreover, further studies are necessary to delineate the mechanisms responsible for these metabolic alterations as well as the physiologic and pathologic implications of these changes. Once gathered, such information may prove useful in guiding the development of novel therapies designed to treat various cardiac diseases as well as potentially ameliorate the effects of aging on the heart.

REFERENCES

1: Circ Res 1991 Jun;68(6):1560-8