Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; and Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas 77555
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ABSTRACT |
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Compared with young
adults, fat oxidation is lower in elderly persons during endurance
exercise performed at either the same absolute or relative intensity.
We evaluated the effect of 16 wk of endurance training on fat and
glucose metabolism during 60 min of moderate intensity exercise
[50% of pretraining peak oxygen consumption
(O2 peak)] in
six elderly men and women (74 ± 2 yr). Training caused a 21%
increase in mean
O2 peak. The average
rate of fat oxidation during exercise was greater after (221 ± 28 µmol/min) than before (166 ± 17 µmol/min) training
(P = 0.002), and the average rate of
carbohydrate oxidation during exercise was lower after (3,180 ± 461 µmol/min) than before (3,937 ± 483 µmol/min) training
(P = 0.003). Training did not cause a significant change in glycerol rate of appearance
(Ra), free fatty acid (FFA)
Ra, and FFA rate of disappearance
during exercise. However, glucose
Ra during exercise was lower after
(1,027 ± 95 µmol/min) than before (1,157 ± 69 µmol/min)
training (P = 0.01). These results
demonstrate that a 16-wk period of endurance training increases fat
oxidation without a significant change in lipolysis (glycerol
Ra) or FFA availability (FFA
Ra) during exercise in elderly
subjects. Therefore, the training-induced increase in fat oxidation
during exercise is likely related to alterations in skeletal muscle
fatty acid metabolism.
aging; free fatty acids; glycerol; glucose; stable isotopes
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INTRODUCTION |
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ENDOGENOUS FAT is an important fuel for working muscles during endurance exercise. We have recently found that fat oxidation is lower in elderly (66-79 yr old) compared with young adult (20-30 yr old) persons during endurance exercise performed at either the same absolute or relative intensity (34). This phenomenon is presumably related to changes in skeletal muscle itself, because whole body lipolysis and plasma free fatty acid (FFA) availability were not rate limiting. In fact, during exercise performed at the same absolute intensity, fatty acid uptake from plasma was higher but fat oxidation was lower in the elderly compared with the young adults. Impairment of fat oxidation during physical activity could have important clinical implications by decreasing exercise capacity and making it more difficult to decrease body fat mass. Exercise training could have beneficial metabolic effects during exercise in elderly persons. Endurance training has been shown to increase fat oxidation during exercise in young adults (23, 30) and increase resting rates of fat oxidation in elderly persons (31). However, the effect of training on lipid metabolism during exercise has not been studied in elderly persons.
The present study was undertaken to evaluate the effect of endurance training on fat and carbohydrate metabolism during moderate intensity exercise in elderly subjects. We hypothesized that a program of physical training would normalize substrate oxidation by either correcting or compensating for the alterations in skeletal muscle metabolism. Stable isotope tracers and indirect calorimetry were used to assess substrate metabolism at rest and during 60 min of cycle ergometer exercise in elderly subjects before and after 16 wk of cycle ergometer exercise training.
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METHODS |
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Subjects. Six elderly subjects (74 ± 2 yr, 3 men and 3 women; Table 1) participated in this study, which was approved by the Institutional Review Board and the General Clinical Research Center (GCRC) Scientific Advisory Board of The University of Texas Medical Branch. All subjects performed normal daily activities, such as shopping, driving, and walking short distances, but none participated in regular aerobic exercise, such as walking, jogging, or cycling. All subjects were within 10% of ideal body weight according to the 1983 Metropolitan height-weight tables and were considered to be in good health after a comprehensive medical evaluation including history, physical examination, routine screening blood tests, and an oral glucose tolerance test. Subjects with a history of cigarette smoking, cardiovascular disease, diabetes, hypertension, or hyperlipidemia or those taking any medications were excluded. Subjects also completed an exercise stress test, and those with evidence of cardiovascular disease were excluded.
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Outpatient studies.
Peak oxygen consumption
(O2 peak) and body
composition were determined during two outpatient visits 3-5 days
before each isotope infusion protocol, which was performed before and
after 16 wk of training. Exercise testing was started with a
"warm-up" by having the subjects cycle on a cycle ergometer for
5-10 min. The workload during exercise after this warm-up was
increased by 10 W every 2 min in women and by 15 W every 2 min in men
until volitional exhaustion. Oxygen consumption
(
O2) and carbon dioxide production (
CO2) were
monitored continuously by open-circuit spirometry using a 2900 Metabolic Cart (Sensormedics, Yorba Linda, CA). At least two of the
following three criteria were met to establish that
O2 peak was attained:
1) respiratory exchange ratio (RER)
>1.15, 2) a leveling off of
O2 and heart rate
despite increases in the workload, and
3) attainment of age-predicted maximal heart rate. Fat mass and fat-free mass were determined by dual
energy X-ray absorptiometry using Enhanced Whole-Body Software Ver.
5.64 (Hologic QDR 1,000/W, Waltham, MA) .
Inpatient studies.
Subjects were admitted to the GCRC in the afternoon 1 day before the
isotope infusion study. A standard meal and a snack were consumed at
1800 and at 2100, respectively, on the day of admission containing a
total of ~1,000 kcal and 175 g of carbohydrate. After subjects fasted
overnight, intravenous catheters were inserted in an antecubital vein
for infusion of isotope tracers and in a distal forearm vein above the
wrist of the contralateral arm, which was heated to obtain arterialized
blood samples (25). A primed (19 µmol/kg), constant (0.22 µmol · kg1 · min
1)
infusion of
[6,6-2H]glucose
[99% atom percent enrichment (APE); Isotec, Miamisburg, OH] dissolved in normal saline was started at 0800 and continued for 120 min using a calibrated syringe pump (Harvard Apparatus, Natick,
MA). At 0945 a primed (1.2 µmol/kg), constant (0.08 µmol · kg
1 · min
1)
infusion of
[1,1,2,3,3-2H]glycerol
(99% APE, Isotec) dissolved in normal saline and a constant (0.035 µmol · kg
1 · min
1)
infusion of
[1-13C]palmitate (98%
APE, Isotec) bound to human albumin were initiated and continued for
135 min. The exact isotope infusion rate was determined for each study
by measuring glucose, palmitate, and glycerol concentrations in the
infusates. After 120 min of isotope infusion at rest (
120
to 0 min), the subjects exercised on a Monarch 829E cycle
ergometer at 50%
O2 peak for 60 min.
At the onset of exercise, the isotope infusion rates were increased by 60% to minimize changes in substrate isotopic enrichment. Blood samples were drawn before the start of the isotope infusion to determine background substrate enrichment at
20,
10, and
0 min to measure basal glucose and lipid kinetics and at 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, and 60 min of exercise to determine glucose
and lipid kinetics during exercise. Blood samples were drawn for
insulin and catecholamine concentrations at the end of the basal (0 min) and exercise (60 min) periods. Blood obtained for the analysis of
substrate concentrations and isotopic enrichments was collected
in chilled 10-ml glass tubes containing lithium heparin. Plasma was
immediately separated by centrifugation at 4°C and frozen at
20°C until further processing. Samples for insulin were
collected in tubes containing EDTA and aprotinin. Samples for plasma
catecholamine were collected in iced tubes containing reduced
glutathione and EGTA. These samples were centrifuged immediately at
4°C and stored at
70°C until analysis.
O2 and
CO2 were determined at the
end of basal period and every 10 min during exercise using the
metabolic cart.
Training.
All subjects trained by pedaling Monark 818E cycle ergometers during
supervised outpatient visits. Initial exercise training bouts were 30 min long and were performed 3 days/wk. The duration of exercise was
gradually increased so that after 4 wk of training, each session lasted
45 min. Training frequency was increased to 4 days/wk after 4 wk and
finally to 5 days/wk during the last 3 wk of training. Training
intensity was monitored with a Polar Unique heart rate watch (Port
Washington, NY). Heart rate during exercise was maintained between 70 and 85% of the peak heart rate determined during
O2 peak testing.
Absenteeism was rare, and all subjects completed >95% of the
scheduled workouts.
Sample analyses. Plasma fatty acid concentrations were determined by gas chromatography (24). Plasma glucose and glycerol concentrations were determined enzymatically by glucose oxidase and glycerol kinase methods, respectively. Plasma insulin concentrations were measured by RIA (11) and plasma catecholamines by a radioenzymatic method (14).
Isotopic enrichment of plasma palmitate, glycerol, and glucose in plasma was determined by gas chromatography-mass spectrometry, using electron impact ionization and an MSD 5971 system (Hewlett-Packard, Palo Alto, CA) with capillary column, as described previously (19). FFAs were isolated from plasma and converted to their methyl esters. Ions at mass-to-charge ratios (m/z) of 270.2 and 271.2, representing the molecular ions of unlabeled and labeled methyl esters, respectively, were selectively monitored. Plasma samples were prepared for analysis of glucose and glycerol isotopic enrichment as described previously (19). Plasma proteins were precipitated with barium hydroxide and zinc sulfate. After centrifugation the supernatant was passed through a mixed cation and anion exchange column. One-half of the sample was used to form a trimethylsilyl derivative of glycerol, and the other one-half was used to form a penta-acetate derivative of glucose. Glycerol enrichment was determined by selectively monitoring ions at m/z values of 205.1 and 208.1. Glucose enrichment was determined by selectively monitoring ions at m/z values of 200.1 and 202.1.Calculations. Steele's equation for steady-state conditions (37) was used to calculate substrate (glycerol, palmitate, and glucose) rate of appearance (Ra) and disappearance (Rd) during the last 20 min of the resting (preexercise) period, whereas Steele's equation for non-steady-state conditions (37) was used to calculate Ra and Rd during exercise. Fatty acid Ra was calculated by dividing palmitate Ra by the percent contribution of palmitate to total FFA concentration. The effective volume of distribution was assumed to be 270 ml/kg for glycerol, 50 ml/kg for palmitate, and 100 ml/kg for glucose.
Triglyceride and carbohydrate oxidation rates were calculated from measurement ofStatistical analysis.
All data are expressed as means ± SE. Comparisons between
pretraining and posttraining data were analyzed for statistical significance by using two-way (trial × time) ANOVA for repeated measures, using SigmaStat 2.0 (Jandel Scientific, San Rafael, CA).
Where appropriate, significant differences identified by ANOVA were
isolated using Tukey's highly significant difference tests. An value of 0.05 was used for all significance
testing.
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RESULTS |
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Although six subjects participated in this study, plasma hormone concentrations and substrate kinetics are not available for one subject because of technical problems in handling the plasma samples. Therefore, the body composition and indirect calorimetry data represent values from six subjects, while plasma hormone and substrate kinetic data represent values from five subjects.
Body composition and
O2 peak.
Training did not cause a change in total body weight (Table 1).
However, there was a small increase in fat-free mass
(P < 0.05), and fat mass tended to
be lower (P = 0.07) in the trained state. Mean
O2 peak
increased by 21% as a result of training (P < 0.01; Table 1).
Indirect calorimetry.
Resting O2 was the same
before (0.214 ± 0.024 l/min) and after (0.198 ± 0.014 l/min)
training as was resting
CO2
(0.167 ± 0.019 and 0.167 ± 0.016 l/min, respectively). Resting
RER was numerically but not statistically significantly greater after (0.824 ± 0.033) than before (0.789 ± 0.011) training because
one subject had a high and possibly erroneous resting value after training. Resting energy expenditure was also the same before and after
training (84 ± 4 and 78 ± 4 kJ · min
1 · kg
1
fat-free mass, respectively).
Substrate oxidation. Fat oxidation increased from 79 ± 11 µmol/min at rest to an average of 166 ± 17 µmol/min during exercise before training (P < 0.001) and from 59 ± 12 µmol/min at rest to an average of 221 ± 28 µmol/min during exercise after training (P < 0.001); (P = 0.002 for values obtained during exercise before training compared with values after training; Fig. 1). Carbohydrate oxidation increased from 315 ± 81 µmol/min at rest to an average of 3,937 ± 483 µmol/min during exercise before training (P < 0.001) and from 587 ± 190 µmol/min at rest to an average of 3,180 ± 461 µmol/min during exercise after training (P < 0.001); (P = 0.003 for values obtained during exercise before training compared with values after training; Fig. 1).
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Plasma hormone concentrations. Before training, plasma epinephrine and norepinephrine concentrations increased two- to threefold during exercise (from 0.30 ± 0.06 and 1.45 ± 0.16 nmol/l, respectively, at rest to 0.94 ± 0.018 and 4.44 ± 0.51 nmol/l, respectively, during exercise; P < 0.001). After training, basal plasma epinephrine and norepinephrine concentrations (0.25 ± 0.04 and 1.75 ± 0.38 nmol/l, respectively) were similar to values obtained before training. Plasma epinephrine and norepinephrine concentrations also increased two- to threefold during exercise (P < 0.001) after training to values (0.56 ± 0.11 and 6.07 ± 1.81 nmol/l, respectively) that were not significantly different from those observed before training. Mean basal plasma insulin concentrations were the same before (57.4 ± 7.2 pmol/l) and after (57.4 ± 21.5 pmol/l) training. During exercise, plasma insulin concentrations did not change significantly from baseline values either before (43.1 ± 7.2 pmol/l) or after (57.4 ± 14.4 pmol/l) training.
Plasma substrate concentrations. No significant differences in plasma substrate concentrations were observed after training compared with values obtained before training. Plasma FFA concentrations decreased during early exercise but increased as exercise continued so that mean values at the end of the exercise bout were similar to the mean resting values both before training and after training (0.472 ± 0.050 and 0.463 ± 0.039 µmol/ml before and at the end of exercise, respectively, before training; 0.397 ± 0.026 and 0.364 ± 0.020 µmol/ml before and at the end of exercise, respectively, after training). Plasma glycerol concentration increased progressively during exercise, and values obtained at the end of exercise were greater (P < 0.001) than resting values both before and after training (0.076 ± 0.006 and 0.137 ± 0.010 µmol/ml before and at the end of exercise before training; 0.054 ± 0.011 and 0.116 ± 0.019 µmol/ml before and at the end of exercise after training). Plasma glucose concentrations did not change during exercise performed either before or after training (5.56 ± 0.25 and 5.54 ± 0.23 µmol/ml before and at the end of exercise before training; 5.45 ± 0.20 and 5.50 ± 0.17 µmol/ml before and at the end of exercise after training).
Substrate kinetics. Fatty acid Ra increased from 379 ± 21 µmol/min at rest to an average of 497 ± 49 µmol/min during exercise before training (P < 0.01) and from 406 ± 42 µmol/min at rest to an average of 559 ± 79 µmol/min during exercise after training (P < 0.01) (Fig. 2). Fatty acid Rd increased from 379 ± 21 µmol/min at rest to an average of 491 ± 47 µmol/min during exercise before training (P < 0.001) and from 406 ± 42 µmol/min at rest to an average of 554 ± 78 µmol/min during exercise after training (P < 0.001). Neither fatty acid Ra nor Rd during exercise was significantly different after training compared with values obtained before training.
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DISCUSSION |
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Endogenous fat stores provide an important source of fuel for endurance exercise. We have recently found that elderly persons oxidize less fat than young adults during endurance exercise performed at either the same absolute or relative intensity (34). The decrease in fat oxidation was presumably related to alterations in skeletal muscle metabolism because FFA release from adipose tissue was higher in elderly than young adults during exercise performed at the same absolute intensity. The results of the present study demonstrate that endurance training can correct, or compensate for, the reduced rate of fat oxidation during exercise in elderly persons. Sixteen weeks of supervised exercise training increased the rate of fat oxidation during exercise to values previously observed in young adults exercising at the same absolute intensity (34).
It is well known that endurance training increases fat oxidation during exercise at a given absolute exercise intensity in sedentary young adults. The present study demonstrates that a training-induced shift in substrate oxidation also occurs in elderly subjects. Because endurance training did not cause a significant increase in lipolytic rate (glycerol Ra) or FFA availability (FFA Ra), the increase in fat oxidation was presumably caused by adaptive changes within skeletal muscle itself, most likely related to the training-induced increase in skeletal muscle mitochondrial content. Although muscle mitochondrial respiratory enzyme activities are 25-40% lower in sedentary elderly persons than in sedentary young adults (26, 32), endurance exercise training can increase muscle respiratory capacity in both elderly and young subjects (4, 5, 32). The increase in mitochondrial mass favors the oxidation of fat over carbohydrate (6, 12, 26, 27). Increased muscle respiratory capacity decreases skeletal muscle glycolytic flux (12), which in turn facilitates the oxidation of fatty acids. Although the cellular mechanism(s) responsible for this relationship is not known, it is clear that alterations in skeletal muscle carbohydrate metabolism affect the oxidation of fat. It has recently been shown that decreasing glycolytic flux during exercise by manipulating exercise intensity (35) or dietary intake (7) increases plasma long-chain, but not medium-chain, fatty acid oxidation. These findings suggest that decreased glycolytic flux may enhance long-chain fatty acid transport into skeletal muscle mitochondria. Alternatively, a decrease in glycolytic flux and acetyl-CoA production from pyruvate may simply allow more fatty acid-derived acetyl-CoA to enter the tricarboxylic acid cycle. In either case, it is likely that a training-induced increase in muscle respiratory capacity in our subjects contributed to the observed increase in fat oxidation.
The source of the additional fatty acids oxidized during exercise after training cannot be directly determined from our study. It is unlikely that plasma triglycerides contributed to the increase in fat oxidation because plasma triglycerides are not normally an important fuel during exercise (28), and training does not increase triglyceride uptake during exercise (17). Although training did not have a significant effect on FFA Rd, it is possible that a greater percentage of FFAs taken up from plasma were oxidized by muscle. Several factors may enhance the use of plasma FFAs by skeletal muscle in the trained state. Endurance training increases skeletal muscle capillarization (1), fatty acid binding protein content (16), and carnitine palmitoyltransferase activity (27), which together provide a favorable fatty acid concentration gradient from plasma to cytosol to mitochondria for oxidation. It is likely that increased use of nonadipose tissue triglyceride, presumably intramuscular triglyceride, was responsible for a large portion of the increase in fat oxidation. In sedentary subjects, whole body skeletal muscle contains ~300 mmol of triglyceride (13), which has the potential to provide >2,000 kcal of energy during exercise. Therefore, a small increase in the percentage of intramuscular triglycerides oxidized can make a considerable contribution to whole body fat oxidation. Training may increase the amount of intramuscular triglycerides used during exercise (13, 23, 30). Previous studies using isotope tracer methodology have indirectly shown that training increases intramuscular fat oxidation during exercise because oxidation of adipose tissue-derived fatty acids could not explain the increased use of fat in trained subjects (15, 23, 30). Moreover, endurance exercise training causes greater depletion of intramuscular triglyceride during moderate intensity exercise performed at the same absolute workload after than before training (13, 29).
To our knowledge, the effect of endurance training on lipid kinetics
during exercise in elderly subjects has not been previously evaluated.
However, several cross-sectional and longitudinal training studies
evaluated the effect of training on glycerol and FFA kinetics during
exercise in young adults. Glycerol
Ra during exercise performed at
the same absolute intensity is similar in trained and untrained subjects (18, 30) but higher in trained than in untrained subjects
during exercise performed at the same relative intensity (20). Two
longitudinal training studies found that FFA
Ra during cycle ergometer exercise
performed at ~60% of the pretraining O2 peak was lower after
than before training (23, 30). However, the effect of training on FFA
kinetics during exercise may only become apparent during more prolonged
bouts of exercise than that performed in the present study. During the
first 60 min of cycling, the time period evaluated in the present
study, FFA Ra was similar before
and after training in one study (30) and was not measured in the other
study (23). Therefore, data from the present study are consistent with
the observations made in young adults and suggest that a 16-wk period
of rigorous cycle ergometer exercise training in elderly subjects does
not cause a significant change in either glycerol or FFA
Ra during the first 60 min of
exercise performed at the same absolute intensity. Although we observed a trend toward increased glycerol and FFA
Ra during exercise after training,
it is unlikely that a true difference was missed because of a type II
statistical error. On the basis of the data from the present study, 38 subjects would be needed to demonstrate a significant effect of
training on FFA Ra with a
value of 0.9 and an
value of 0.05; 19 subjects would be needed to
demonstrate a difference in glycerol
Ra.
The adaptive changes in carbohydrate metabolism in our subjects were similar to those reported in younger persons. Glucose Ra and glucose oxidation during 60 min of cycle ergometer exercise decreased significantly after training. Coggan et. al. (3) and Phillips et. al. (30) found similar changes in young adults after 84 and 31 days of endurance training, respectively.
Our posttraining studies were performed 72 h after the last bout of exercise to eliminate the influence of acute exercise. It is possible that fat oxidation rates at rest and during exercise might have been different had we studied our subjects closer to the last exercise session, particularly if glycogen stores were not fully repleted. For example, although we did not observe a training effect on the rate of fat oxidation during resting conditions, Poehlman et al. (31) found that fat oxidation at rest was greater after than before training when elderly subjects were studied ~36 h after exercise.
The results from our study demonstrate that endurance training
can improve aerobic fitness and cause moderate alterations in body
composition in elderly persons. Sixteen weeks of cycle ergometer
exercise training increased
O2 peak by
21%, which is similar to the relative effect of training reported in
younger subjects (5, 21, 23, 36). In addition, we found that total body
fat mass tended (P = 0.07) to be lower
and fat-free mass was higher after training compared with values
obtained before training. Other longitudinal training studies have
reported either no change in body composition after 12 wk of endurance
training (26) or a small increase in fat-free mass and a decrease in body fat mass after as much as 12 mo of endurance training in elderly
persons (10, 22, 33). The small decrease in body fat mass may seem
surprising in view of the rigorous training program completed by our
subjects. However, alterations in body fat mass reflect alterations in
total energy balance. Cycling exercise was performed for only 45 min
3-5 days per week, so most of the day was spent in nonexercise
activities. Furthermore, Goran and Poehlman (9) found that endurance
training in elderly subjects did not increase total daily energy
expenditure, presumably because of a compensatory decrease in physical
activity the rest of the day.
In summary, a 16-wk period of endurance training increases fat oxidation and decreases carbohydrate oxidation during exercise in elderly subjects to values similar to those observed in untrained young adults. Training did not cause a significant change in lipolysis (glycerol Ra) or FFA availability (FFA Ra) during exercise. Therefore, the training-induced increase in fat oxidation during exercise is likely related to changes within skeletal muscle, possibly an increase in the fractional oxidation of plasma fatty acids taken up by muscle and/or an increase in the use of nonadipose tissue, presumably intramuscular, triglycerides.
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ACKNOWLEDGEMENTS |
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The authors thank the nursing staff of the GCRC for help in performing the experimental protocols and Lisa Mendenhall for technical assistance.
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FOOTNOTES |
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This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-49989, the National Institute on Aging Institutional National Research Service Award AG-00078, and GCRC Grant RR-00036.
Address for reprint requests: S. Klein, Washington Univ. School of Medicine, 660 S. Euclid Ave., Box 8127, St. Louis, MO 63110-1093.
Received 25 September 1997; accepted in final form 27 January 1998.
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