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Department of Integrative Physiology (C.B., D.S.D., P.P.J., D.D.C., D.S.P., D.R.S.), University of Colorado at Boulder, Boulder, Colorado 80309; Department of Food Science and Human Nutrition (K.O., C.L.M.), Colorado State University, Fort Collins, Colorado 80523; and Department of Medicine (Geriatric Medicine) (D.R.S.), University of Colorado Health Sciences Center, Denver, Colorado 80262
Address all correspondence and requests for reprints to: Christopher Bell, Ph.D., Department of Integrative Physiology, 354UCB, University of Colorado, Boulder, Colorado 80309-0354. E-mail: christopher.bell{at}colorado.edu.
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Abstract |
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Introduction |
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We (4, 6, 7) and others (5, 8) have demonstrated that RMR (corrected for fat-free mass) is greater in middle-aged and older adults who perform regular aerobic endurance exercise than in their sedentary peers. Recently, we established that these differences can be attributed in part to greater tonic sympathetic nervous system (SNS) ß-adrenergic receptor (ß-AR) stimulation of RMR in habitually exercising older adults (4, 7). However, the mechanism underlying the greater SNS ß-AR support of RMR in exercising older adults is unknown.
Energy flux refers to the absolute level of energy intake and expenditure under conditions of energy balance (9, 10, 11). In general, a habitually exercising adult is in a higher state of energy flux than a sedentary adult as a result of greater physical activity-related energy expenditure being matched by a correspondingly greater energy intake. In regularly exercising young adults, RMR is reduced during a short-term decrease in energy flux produced by proportional reductions in physical activity-related energy expenditure and caloric intake (9). Importantly, the reduction in RMR in response to the low energy flux state is positively related to the associated decrease in plasma norepinephrine concentration, suggesting reduced SNS activity as a possible mechanism (9).
In the present study, we tested the hypothesis that the greater RMR and SNS ß-AR support of RMR in habitually exercising older adults is mediated in part by their tonically elevated state of energy flux. To do so, we determined RMR and ß-AR support of RMR under both normal high (baseline) and experimentally reduced energy flux conditions in a group of older men and women who regularly performed vigorous aerobic endurance exercise. To control for a possible time effect, we also performed these measurements before and after a similar period of unchanged energy flux in a control group of older adults.
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Subjects and Methods |
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Twenty-two older adults (12 males and 10 females, aged 60–73 yr) were studied in the General Clinical Research Center at the University of Colorado-Boulder. All subjects were healthy as assessed by medical history, physical examination, and electrocardiography and blood pressure at rest and during incremental exercise to exhaustion. All subjects were nonsmokers and nonobese, reported being weight stable over the previous 12 months, and were not taking any medications known to affect metabolism or cardiovascular function. Fifteen subjects had consistently engaged in vigorous, competition-driven, endurance exercise (running, cycling, and/or swimming) for at least 40 min/d, 4 d/wk during the previous 2 yr and were assigned to an intervention group. The remaining seven subjects ranged in their levels of physical activity from sedentary to moderately active (noncompetitive moderate-intensity exercise up to 3 times per week) and were assigned to a time control condition. The nature, purpose, and risks of participation in the study were explained to each subject before written informed consent was obtained. The Human Research Committee at the University of Colorado-Boulder approved the experimental protocol.
Data from five of the original 15 habitually exercising subjects were excluded from final analyses for one of the following reasons: 1) appreciable change in body mass (>2 kg) during the intervention; 2) subjects identified as under- (<1.35) or overreporters (>2.4) of habitual diet based on their ratio of energy intake to RMR according to published guidelines (12), as described previously (13); or 3) aborted iv administration of a ß-AR antagonist (propranolol) due to decreases in heart rate below the Institutional Review Board predetermined lower limit of 40 beats/min. Accordingly, data on 10 older adults are presented (six males and four females).
Protocol
Subjects reported to the laboratory on four separate occasions. The first visit involved health history screening, a physical examination, measurement of blood pressure and heart rate via 12-lead electrocardiogram at rest and during incremental stationary cycle ergometry exercise (25 W·min–1) to exhaustion, determination of peak oxygen uptake (VO2peak), and body composition analysis. Baseline energy flux was determined in each subject over a 4-d period. This assessment confirmed that subjects were in energy balance and provided information regarding their total daily energy expenditure, the proportion of their total daily energy expenditure related to habitual exercise, and total daily dietary intake, including macronutrient composition. Energy flux was decreased over a 5-d period using methods established previously by Bullough et al. (9). Energy expenditure was decreased by having subjects abstain from exercise, and energy intake was reduced by feeding subjects a controlled diet designed to maintain energy balance. Breakfast was eaten at the laboratory, and all other food (lunch, dinner, and snacks) was sent home. Relative macronutrient composition was unchanged in the reduced compared with the baseline (high) energy flux condition. Before and during the reduced energy flux state, RMR, ß-AR support of RMR, skeletal muscle sympathetic nerve activity (MSNA), and blood chemistries were determined. The final visit to the laboratory involved a repeat determination of VO2peak.
Control group
To establish that changes in the primary outcome variables in response to the reduced energy flux condition were not the result of habituation to the measurements, seven older adults (two males and five females) underwent a time control condition. This involved the same pre- and postmeasurements as the experimental group without a change in energy flux. Subjects carried out their usual physical activities and consumed a controlled diet to maintain energy balance during this condition.
Measurements
Baseline energy flux, measured under conditions of regular daily exercise and usual energy intake, was determined over 4 consecutive days (3 weekdays and 1 weekend day). Dietary intake was estimated from food diaries. Subjects kept accurate and complete diet records and were provided with a diet scale (Scaleman; Target Corporation, Minneapolis, MN) to weigh all food. A registered dietitian subsequently analyzed all food diaries using standard computer-assisted procedures (The Food Processor, version 7.6; ESHA, Salem, OR). Energy expenditure was determined from a combination of measures. Subjects maintained a physical activity diary documenting all activities undertaken on a minute-by-minute basis. These activities were then assigned a metabolic equivalent score from previously published norms (14). Finally, these metabolic equivalent scores were converted to kilocalories using individual RMR data. To provide additional confirmation of reduced energy expenditure in the low energy flux state, accelerometer counts (counts·d–1) were compared during the high and reduced energy flux periods (Actigraph; CSA Inc., Shalimar, FL). Accelerometers were worn 24 h/d, and subjects were blinded as to the number of counts.
ß-AR support of RMR was determined using our previously described protocol (15). Briefly, all measurements were made in the morning after a 12-h fast and after a 24-h abstention from exercise. Subjects were studied under quiet resting conditions in the semirecumbent position. Measurements were performed between 0600–0900 h in a dimly lit room at a comfortable temperature (
23 C). RMR was measured before and during ß-AR blockade (iv infusion of propranolol: 0.25 mg·kg–1 bolus followed by continuous infusion at 0.006 mg·kg–1·min–1). A catheter was placed in an antecubital vein and was kept patent with heparin. After a 30-min rest period after instrumentation, baseline RMR was measured. The first 15 min were considered a habituation period, after which oxygen consumption and carbon dioxide production were averaged each minute for 30 min using a ventilated hood indirect calorimetry system (DeltaTrac Metabolic Monitor; SensorMedics Corp., Yorba Linda, CA). The system was calibrated each morning before data collection. Additional quality control included monthly pressure calibrations and gas calibrations together with biannual calibrations using an alcohol burn test. RMR was calculated from the average of the 30-min collection using the Weir formula (16). Then the hood was removed while an iv bolus of propranolol (0.25 ml·kg–1) was administered. After a 5-min habituation period, RMR was measured again during continuous infusion of propranolol (0.006 mg·kg–1·min–1). Heart rate (electrocardiogram) and blood pressure (Dinamap XL Vital Signs Monitor; Johnson & Johnson, Arlington, TX) were measured.
Recordings of multiunit MSNA were measured from the peroneal nerve using microneurography, as previously described (17, 18, 19). These measurements were made immediately after the pre-ß-AR blockade determination of RMR at each time point. Within-subject neurograms were analyzed by the same investigators (C.B. or P.P.J.), who were blind to the experimental condition during which the recordings were made.
Fat mass and fat-free mass were measured using dual-energy x-ray absorptiometry (DXA-IQ, software version 4.1; Lunar Radiation corp., Madison, WI). VO2peak was measured using open-circuit spirometry, as described previously (20).
Plasma triiodothyronine concentrations are sensitive to changes in energy balance (21, 22) and thus were determined via RIA (9) to help determine the degree of success in maintaining energy balance during the manipulation of energy flux. Plasma leptin concentrations have been associated with MSNA among healthy young and older adults, independent of body fat (18, 23). Leptin may act as one humoral signal linking energy flux with central SNS outflow to peripheral tissues; thus, plasma leptin concentrations were determined via RIA (LINCO Research Inc., St. Charles, MO) (18).
Data analysis and statistics
A one-way ANOVA with repeated measures was used to identify changes in RMR and ß-AR support of RMR in response to the low energy flux state. Changes in secondary outcome measures (MSNA and blood chemistries) also were identified using one-way repeated-measures ANOVA. Relations of interest were examined using univariate correlations. It was not the purpose of this study to compare data from the older habitual endurance exercisers with data from the nonsex-, nonactivity-matched control subjects; thus, control data were analyzed separately using one-way repeated-measures ANOVA. The level of significance was set at P < 0.05. Data are expressed as mean ± SE.
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Results |
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Subject characteristics and energy flux.
Selected subject characteristics are shown in Table 1
, and data pertaining to energy flux are presented in Fig. 1. There were no differences in estimated energy balance (i.e. energy intake relative to energy expenditure) in the high (P = 0.77) and low energy flux conditions (P = 0.36), indicating that we successfully decreased energy intake to match the lower energy expenditure during the reduced energy flux state. Compared with high energy flux, plasma triiodothyronine concentration was unchanged in the low energy flux state (1.86 ± 0.12 vs. 1.83 ± 0.08 nmol·liter–1, P = 0.66), providing additional evidence that energy balance was maintained throughout the intervention.
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). Collectively, these data establish that the level of energy flux was reduced in these subjects.
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. In the high energy flux state, RMR decreased during acute ß-AR blockade (P = 0.04), providing evidence for tonic ß-AR support of RMR in these habitually active older adults. Compared with baseline, RMR was reduced in the low energy flux state (P = 0.03). Furthermore, in the low energy flux state, RMR did not decrease significantly (P = 0.15) during acute ß-AR blockade, indicating a loss of tonic ß-AR support of RMR. RMR during acute ß-AR blockade was not different in the baseline and low energy flux states (P = 0.14), demonstrating that when the influence of tonic ß-AR support of RMR is removed, energy flux is no longer associated with differences in RMR. Consistent with this observation, there was a strong, positive relation between the change in RMR and the change in ß-AR support of RMR (r = 0.77, P = 0.009). Finally, these metabolic responses to the low energy flux state were no different in the male and female subjects.
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Time control group responses
Control group data are presented in Tables 1
and 2 and Figs. 1–3. None of the variables was different at baseline vs. maintained energy flux, suggesting that the responses to the low energy flux state in the experimental group were not due to any systematic change in our measurements over time.
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Discussion |
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Mechanism(s) by which energy flux modulates ß-AR support of RMR
ß-AR support of RMR is determined by the combined effects of the level of SNS activity (the stimulus) and ß-AR tissue responsiveness to that stimulus. In the present study, transition from a high to a low energy flux state resulted in a loss of ß-AR support of RMR. Therefore, it follows that this change may have been mediated by a decrease in SNS activity, a decrease in ß-AR responsiveness, or both. MSNA, a direct measure of central SNS outflow to the periphery, was reduced in the low compared with the high energy flux state, suggesting that a decrease in SNS outflow to the periphery likely contributed to the reduction in ß-AR support of RMR. This is consistent with at least three previous observations. The first observation is the aforementioned finding that young habitually exercising adults demonstrate reductions in both RMR and plasma norepinephrine concentrations, an indirect measure of SNS activity, in response to a short-term (3 d) reduction in energy flux (9). The second is that MSNA may be greater in at least some endurance exercise-trained older adults compared with their sedentary peers (24). The third observation is that the endurance exercise-trained state is associated with both increased whole-body SNS activity (as estimated by total norepinephrine spillover) and RMR in some healthy older adults (25).
We did not perform measurements of ß-AR tissue responsiveness in the present study. However, previous findings provide some support for the possibility that this mechanism could have contributed to the decrease in ß-AR support of RMR in response to the low energy flux condition. For example, ß-AR metabolic responsiveness is greater in habitually exercising compared with sedentary adults (26, 27, 28) and is increased in response to vigorous aerobic exercise training (high energy flux state?) in previously sedentary adults (29, 30). Future studies need to establish the possible role of changes in ß-AR tissue responsiveness in the modulatory effects of energy flux on ß-AR support of RMR.
If energy flux influences ß-AR support of RMR, at least in part, by modulating central SNS outflow to peripheral tissues, leptin may act as one humoral signal linking these events. Previously, we (18) and others (23) found a positive relation between plasma leptin concentrations and MSNA among healthy young and older adults, independent of body fat. In the present study, the low energy flux state was associated with a trend for a reduction in plasma leptin, directionally consistent with the change in MSNA. However, among individuals, the changes in leptin were not large or consistent enough to correlate significantly with the corresponding reductions in MSNA. This lack of relation could be explained by the fact that we measured total plasma leptin in the present study, whereas recent evidence suggests that SNS activity is most strongly related to the protein-bound component of leptin (31). In any case, the potential signals responsible for the reduction in central SNS outflow in response to a decrease in energy flux remain to be determined.
Alternative interpretations
We considered other explanations for the present results. Decreased body mass is associated with reduced RMR and SNS activity (32, 33). However, body mass and composition (measured in a subset of subjects) were not different at baseline and in the low energy flux state. Alternatively, plasma triiodothyronine concentrations are sensitive to changes in energy balance (21, 22) and can influence RMR (34, 35). Such an effect in the present study is unlikely, however, because circulating triiodothyronine concentrations were unchanged at baseline and during reduced energy flux. Finally, maximal aerobic capacity, which correlates with RMR in some groups (5), was unchanged in response to the low energy flux state based on measurements of VO2peak.
Experimental limitations
In the present study, we used a previously established experimental model for reducing energy flux in free-living habitually exercising adults (9). Nevertheless, we recognize the limitations inherent to this approach. For example, problems with under- and overreporting on diet and physical activity diaries have been well documented, as has the relative crudeness of the use of accelerometers to determine energy expenditure. We attempted to reduce the impact of limitations associated with dietary records by excluding subjects identified as under- or overreporters based on their ratio of dietary intake to RMR (12, 13). Moreover, rather than attempting to estimate energy expenditure from accelerometer data, we used the raw data (i.e. actual accelerometer counts) as a measure of the relative change in physical activity-related energy expenditure. The strong, positive correlation between change in energy expenditure and change in accelerometer counts from baseline to the low energy flux condition provides support for the validity of this approach. Despite these limitations, collectively, our results indicate that we were able to successfully manipulate energy flux without perturbing energy balance using these methods in the present study.
Clinical significance
Our findings have important clinical implications. Modest but progressive (e.g. 0.5–1.0 kg/yr) weight gain with advancing age is a major contributor to adult obesity (36). Reduced ß-AR support of energy metabolism and RMR may play an important role in adult weight gain by contributing to age-associated decreases in daily energy expenditure (4, 7, 15, 37, 38). In contrast, habitually exercising adults appear to demonstrate much smaller, if any, increases in body weight and adiposity with advancing age compared with their sedentary peers (36, 39, 40). This may be attributed in part to their elevated ß-AR support of energy metabolism and RMR. The results of the present study indicate that an elevated state of energy flux may be a key mechanism mediating these beneficial ß-AR/metabolic properties of regularly exercising older adults and, therefore, may play an important role in their lower levels of body weight and adiposity. This, in turn, may contribute to the lower prevalence of chronic disease and premature mortality observed in middle-aged and older physically active adults (41, 42).
Our findings also suggest that increasing energy flux via regular physical activity may be an effective strategy for maintaining daily energy expenditure and preventing age-associated obesity. Previously sedentary adults could not be expected, at least initially, to exercise at levels such as those performed by the trained subjects in the present study. However, regular aerobic exercise of progressively increasing intensity and duration over time could eventually achieve levels of energy flux sufficient to augment resting metabolism, increase daily energy expenditure, and help maintain energy balance with advancing age.
Conclusion
Our findings provide the first direct evidence that chronically elevated energy flux is a key physiological mechanism mediating the tonically augmented ß-AR support of energy metabolism and RMR in habitually exercising older adults. Our results also suggest that energy flux may exert its influence on ß-AR support of energy metabolism and RMR via modulation of central SNS outflow to peripheral tissues.
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Acknowledgments |
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Footnotes |
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Abbreviations: ß-AR, ß-Adrenergic receptor; MSNA, skeletal muscle sympathetic nerve activity; RMR, resting metabolic rate; SNS, sympathetic nervous system; VO2peak, peak oxygen uptake.
Received December 15, 2003.
Accepted March 29, 2004.
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