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Department of Integrative Physiology (P.P.J., D.R.S.), University of Colorado, Boulder, Colorado 80309; Division of Geriatric Medicine, Department of Medicine (R.E.V.P., D.R.S.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Department of Internal Medicine (D.G.J.), University of Arizona College of Medicine, Tucson, Arizona 85724
Address all correspondence and requests for reprints to: Douglas R. Seals, Ph.D., Department of Integrative Physiology, University of Colorado, UCB 354, Boulder, Colorado 80309-0354. E-mail: seals{at}colorado.edu.
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Abstract |
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Introduction |
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One of the determinants of total energy expenditure that contributes to its decline with aging is a reduction in the thermic effect of food (TEF) (3, 4). The TEF is the increase in energy expenditure that occurs in response to acute energy intake and represents approximately 10% of daily energy expenditure (6, 7). The facultative component of TEF (i.e. the energy expended in excess of the obligatory requirements for digestion, absorption, transport, and storage of nutrients) is mediated primarily by an increase in sympathetic nervous system (SNS) activity and resulting stimulation of the ß-adrenergic signaling pathway (8, 9, 10, 11). Skeletal muscle metabolism, stimulated by a robust increase in muscle sympathetic nerve activity (MSNA) (12, 13, 14), contributes importantly to the whole-body TEF in humans (8, 11, 15).
The mechanisms responsible for the age-associated decline in TEF have not been determined, but an inability to properly activate the SNS and, thus, provide an appropriate stimulus for ß-adrenergic receptor signaling has been hypothesized (16, 17, 18). The experimental results related to this postulate, however, are equivocal (19, 20, 21, 22), perhaps due in part to the use of indirect measures of SNA. Information from direct measurements of SNA is not available.
In contrast to aging, habitual aerobic endurance exercise is often associated with enhanced TEF, especially in middle-aged and older adults, i.e. a group with reduced baseline TEF (3). The mechanisms contributing to the augmented TEF observed in some exercise-trained adults are unknown (18). It is possible that exercising adults are able to generate a more robust SNS response to acute energy intake than their sedentary peers (23). However, no data from directly measured SNA are available on this issue.
Accordingly, the main experimental goals of the present study were to determine whether 1) the reduction in TEF with human aging is associated with an attenuated sympathetic neural response; and 2) whether the greater TEF observed in young and/or older habitually exercising adults is associated with a correspondingly augmented sympathetic neural response. To achieve these aims, MSNA was measured via peroneal microneurography before and for up to 4 h after acute energy intake in groups of young and older adults who were either sedentary or performing regular aerobic endurance exercise.
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Subjects and Methods |
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Forty-six healthy men aged 19–36 or 54–75 yr were studied: 16 young and 11 older sedentary men and nine young and 10 older habitually exercising men. The latter performed regular aerobic endurance exercise (
3 d/wk for a minimum of 30 min/d), whereas the sedentary subjects performed no regular physical activity. All subjects had been weight-stable (±2 kg) during the previous 6 months and were healthy as assessed by medical history. The older men were further evaluated for clinical evidence of cardiopulmonary disease with a physical examination and electrocardiograms during rest and maximal exercise. All subjects were nonsmokers, not using any medications, and were euthyroid as assessed by fasting levels of plasma thyroid hormones. The nature, purpose, and risks of the study were explained to each subject, and all subjects provided written informed consent to participate in the study. The experimental protocol was approved by the Human Research Committee at the University of Colorado at Boulder.
Experimental protocol
Subjects were studied after a 12-h overnight fast, and, for the exercising men, approximately 24 h after the last exercise session. Subjects reported to the laboratory between 0600 and 0800 h and rested in a semirecumbent position in a quiet, dimly lit room. An iv catheter was inserted into an antecubital vein, and subjects were instrumented for measurement of MSNA. After an acceptable neurogram was obtained, subjects rested quietly for 20 min before fasting blood samples were taken. Next, resting metabolic rate (RMR) was determined with simultaneous recording of MSNA. Subjects then consumed an oral glucose load of 2.5 g/kg fat-free mass in the form of an orange-flavored drink. This glucose load was based on fat-free mass to standardize the stimulus for each individual. The TEF (i.e. the increase in metabolic rate above preprandial baseline levels during the postprandial period) and MSNA were measured for up to 4 h after glucose intake. Indirect calorimetric measurements were made for 40 min each hour, allowing the subject relief from the ventilated hood for the first 10 min of each half hour, at which time postprandial blood samples were collected for measurement of plasma norepinephrine, leptin, and insulin concentrations. MSNA was recorded for 15-min periods ending at min 30, 60, 120, 180, and 240 after the glucose load. TEF and the MSNA response were calculated for each individual as the change from baseline across each time point and as the area under the response curve (trapezoidal rule).
Measurements
Body mass and composition. Total body mass was measured to the nearest 0.1 kg on a physician’s balance scale (Detecto, Webb City, MO). Body mass index was calculated from weight and height (kilograms per meter squared). Dual-energy x-ray absorptiometry (model DPX-IQ, software version 3.2; Lunar Radiation Corp., Madison, WI) was used to measure whole-body fat mass, fat-free mass, and bone mineral density as described in detail previously (24, 25).
Maximal aerobic exercise capacity. Maximal oxygen consumption was used as a measure of maximal aerobic exercise capacity and was determined during incremental treadmill exercise using online computer-assisted open-circuit spirometry as previously described (26).
Fasting baseline and postprandial metabolism. Metabolic rate was measured by indirect calorimetry using a ventilated hood system (DeltaTrac Metabolic Monitor; SensorMedics Corp., Yorba Linda, CA) as described previously (27).
MSNA. MSNA was determined via peroneal microneurography as described previously (28, 29, 30). The neural recording was amplified, filtered (bandwidth 700-2000 Hz), full-wave rectified, and integrated (time constant = 100 msec) to obtain a mean voltage neurogram determined to be acceptable using criteria previously described (31).
Circulating concentrations of catecholamines, leptin, thyroid hormones, and insulin. Plasma norepinephrine and epinephrine concentrations were determined by radioenzymatic assay (32). Plasma leptin and serum TSH and total T4 concentrations were measured using competitive binding RIAs (33, 34, 35). Plasma insulin was analyzed by RIA (36). Plasma insulin and leptin concentrations were measured to determine whether the postprandial changes in these hormones were associated with any group differences in the sympathetic responses because circulating leptin and insulin have been identified as humoral signals with probable sympathoexcitatory actions (34, 37, 38).
Statistical analysis.
Group differences for key variables were determined by ANOVA with repeated measures (age x physical activity level x time). Metabolic rates (RMR and TEF) are corrected for FFM using covariance. We were unable to obtain data for the entire 4-h postprandial period in some subjects due to loss of or significant change in the MSNA neurogram. Thus, two different sets of analyses were performed: 1) repeated-measures ANOVA using all subjects and 2 h of postprandial data [time points = min 0 (baseline), 30, 60 and 120] and 2) repeated-measures ANOVA using the subgroups of subjects with the complete 4 h of postprandial data (time points = min 0, 30, 60, 120, 180, and 240; n = 12 young and 8 older sedentary 9 young and 8 older exercising). Newman-Keuls post hoc tests for multiple comparisons were used. Group differences in the 2- and 4-h areas under the curve were determined by ANOVA. To determine the contribution of sympathetic stimulation to potential group differences in TEF, we performed analysis of covariance (ANCOVA) for 
metabolic rate using the respective areas under the curve for MSNA as the covariate. The level of statistical significance was set at P < 0.05. Values are mean ± SE.
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Results |
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There were no significant interactions related to aging and habitual exercise (TEF interactions, P = 0.25–0.44; MSNA interactions, P = 0.43–0.99; plasma norepinephrine interactions, P = 0.47–0.86). Thus, the results of the main effects of aging are presented with the sedentary and exercising groups combined.
Baseline subject characteristics.
Table 1
shows the baseline characteristics of the combined groups of young and older men. The two groups did not differ significantly in body mass; TSH; T4; fasting plasma insulin, norepinephrine, or epinephrine; or resting heart rate or blood pressure. The older men had a greater body mass index, body fat, and fasting leptin concentrations, and lower fat-free mass, RMR, and maximal oxygen consumption. The characteristics of the young and older subgroups with 4 h of postprandial data were similar to those in the overall groups.
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, top left) and 4-h (P < 0.05; Fig. 1, top right) responses. The area under the curve for the baseline to postprandial change in metabolic rate was approximately 50% greater in the young compared with the older men for the 2-h response (P < 0.01; Fig. 2, top left); slightly smaller (due to metabolic rate returning to preprandial baseline levels), but similar differences were observed for the 4-h response (P < 0.05; Fig. 2, top right).
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). The corresponding areas under the curve for the baseline to postprandial changes in MSNA and plasma norepinephrine and epinephrine concentrations also were similar in the young and older men (Fig. 2).
Adjusting for MSNA (ANCOVA) did not significantly influence the age-related difference in metabolic rate because the area under the curve remained lower in the older men for both 2 h (adjusted areas, 1070 vs. 716 U for young and older, respectively; P < 0.0001) and 4 h (adjusted areas, 1745 vs. 1322 U, P < 0.05).
Plasma leptin concentrations did not change from baseline in response to glucose ingestion in either the young or the older men (P = 0.36). In contrast, plasma insulin levels increased in both groups after glucose ingestion (P < 0.01); the magnitude of increase was similar in the young and older men (2 h, P = 0.98; 4 h, P = 0.84; data not shown).
Effects of habitual exercise
As described above, because there were no significant interactions related to aging and habitual exercise status, the results of the main effects of habitual exercise are presented with the age groups combined.
Baseline subject characteristics.
Table 2 shows the characteristics of the sedentary and exercising men. As expected, the exercising men were leaner and had lower resting heart rates and higher maximal oxygen consumptions than the sedentary men (all P < 0.05). There were no significant exercise status-related differences in RMR or measures of sympathoadrenal activity, although RMR tended to be greater in the exercising compared with the sedentary men (P = 0.11). Fasting leptin and insulin concentrations and resting heart rate and diastolic blood pressure were or tended to be lower in the exercising compared with the sedentary men. The characteristics of the subgroups with 4 h of postprandial data were similar to those in these overall 2-h groups.
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). These differences were most apparent in the first 2 h after glucose intake. The area under the curve for the preprandial baseline to postprandial change in metabolic rate was approximately 20–25% greater in the exercising compared with the sedentary men for the 2- and 4-h responses (P < 0.05, Fig. 4).
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). As such, the corresponding areas under the curve for the changes in MSNA and plasma norepinephrine and epinephrine concentrations were not different among the groups (Fig. 4). Because the sedentary vs. exercising group differences in TEF were not as great as those between the young and older groups, and the mean increase in MSNA, although not significant, was slightly greater in the exercising men, we determined the contribution of sympathetic stimulation to exercise-group differences in TEF by covarying the postprandial increase in metabolic rate for the change in MSNA via ANCOVA. Adjusting for MSNA slightly reduced the habitual exercise status-related difference in area under the curve for metabolic rate for 2 h (adjusted areas, 828 vs. 1011 U for sedentary and exercising, respectively; P = 0.09) and 4 h (adjusted areas, 1388 vs. 1741 U; P = 0.05).
Plasma leptin concentrations did not change after glucose intake in either group (P = 0.23). Plasma insulin increased in both groups after glucose ingestion (P < 0.01); the magnitude of increase was smaller in the exercising compared with the sedentary men (P < 0.01 for both 2- and 4-h responses). However, the ratio of MSNA to insulin did not differ significantly between the two groups (2 h, P = 0.10; 4 h, P = 0.38) (data not shown).
Correlates of the postprandial sympathetic response
The 2- and 4-h postprandial MSNA and plasma norepinephrine and epinephrine responses were not significantly related to any baseline subject characteristic in either the overall pooled subject sample or any particular group of subjects. Similarly, there were no significant relations between the 2- and 4-h sympathoadrenal (MSNA and plasma norepinephrine and epinephrine) responses and the corresponding changes in metabolic rate (TEF), plasma leptin concentrations, or plasma insulin concentrations.
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Discussion |
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Effects of aging
The age-related difference in TEF in the present study is consistent with previous findings (19, 39, 40), suggesting that our sample was representative of healthy men in general. Our experimental approach to establishing the metabolic and sympathetic neural responses to acute food intake was designed to reduce potential confounds related to age-associated differences in habitual physical activity (3), appropriate duration of postprandial measurements (6), and indirect measures of sympathetic activity (20, 41). We attempted to control for these potential confounds, respectively, by 1) matching the young and older groups for, and separately determining the influence of, habitual aerobic exercise; 2) measuring metabolic and sympathoadrenal activity for a sufficient duration (i.e. up to 4 h) to establish the complete temporal responses and determine group differences at key common time points; and 3) directly measuring sympathetic nerve activity via microneurography.
The hypothesis that the reduced TEF observed in older men is associated with an attenuated sympathetic neural response is not supported by our data. Rather, we found that the postprandial adjustments for both MSNA and plasma catecholamines were well preserved in older healthy men. Moreover, there was no relation between the TEF and sympathoadrenal responses among the young and older men. The sympathetic ß-adrenergic component of the TEF is the product of the stimulus (the increase in SNS activity and consequent release of norepinephrine + secretion of epinephrine from the adrenal medulla) and the tissue responsiveness to that stimulus (receptor and postreceptor signaling). As such, our experimental results clearly establish that the mechanism responsible for the reduction in TEF with primary aging in humans does not involve an inadequate sympathetic stimulus, at least that provided to skeletal muscle. It is possible that sympathetic neural activation to other regions that contribute to TEF, including adipose tissue, was smaller in the older men.
Our data provide no direct insight into the possible contribution of reductions in tissue ß-adrenergic signaling to the lower TEF observed in the older men. However, Kerckhoffs et al. (42) have shown smaller increases in metabolic rate in response to intravenous infusion of isoproterenol, a nonselective ß-adrenergic receptor agonist, in older compared with young healthy adults. The markedly reduced metabolic rate/MSNA of the older men in the present study is consistent with their finding, although nonsympathetic ß-adrenergic influences also could contribute to the lower metabolic rate/MSNA observed. Nevertheless, taken together, the latter results and those of Kerckhoffs et al. (42) support a possible role for decreased ß-adrenergic signaling in the age-associated reduction in TEF.
Effects of habitual exercise
Our findings of a greater TEF in the habitually physically active group are consistent with previous observations in both young (43) and middle-aged and older (3) healthy men. Importantly, our sedentary and habitually exercising groups did not differ in fat-free mass, and the glucose stimulus also was adjusted for that factor. Thus, our results demonstrate that the greater TEF in the exercising men was independent of fat-free mass.
The present results extend these findings by demonstrating that the mechanism mediating this enhanced TEF is not an augmented sympathetic neural response (again, at least that directed to skeletal muscle), nor can it be linked to a greater increase in circulating catecholamines. This indicates that the greater TEF in regularly exercising adults is mediated by greater peripheral tissue ß-adrenergic responsiveness to the same sympathetic stimulus or to nonsympathetic ß-adrenergic influences. In the present study, the ratio of metabolic rate to MSNA was not different in the sedentary and physically active men. Although not a direct measure, this observation does not support a clear difference in ß-adrenergic responsiveness between the two groups. Previous reports of greater lipolytic responses to ß-adrenergic stimulation in endurance exercise-trained compared with sedentary humans (44, 45) are consistent with the possibility of greater ß-adrenergic responsiveness in exercising adults. However, to our knowledge, no direct information exists on the relation between habitual aerobic exercise status and responsiveness of metabolic rate to ß-adrenergic stimulation. Thus, it is unclear whether the differences in TEF between our sedentary and exercising men were the result of differences in ß-adrenergic responsiveness, in the non-SNS component of TEF, or both.
Age-habitual exercise interactions
An important question is whether the greater TEF observed in regularly exercising middle-aged and older humans represents a smaller or even absent age-associated reduction compared with that occurring in sedentary adults or the same age-associated reduction from higher baseline levels as young adults? In the present study, the lack of any statistically significant interactions between age and habitual exercise status indicates that although the latter was associated with a greater TEF in both our young and older men, habitual exercise status did not significantly influence the age-related decline in TEF. Thus, our results agree with an earlier report (43), together demonstrating that that age-associated reduction in TEF is not obviously different in sedentary and regularly exercising healthy men. Rather, the higher absolute TEF in older men appears to be the result of a similar decline from greater baseline levels as young adults. Nevertheless, it is important to appreciate that compared with their sedentary peers, the greater TEF at any age in habitually exercising adults may contribute to more effective regulation of body weight and fat storage by enhancing daily energy expenditure (25, 46).
Experimental considerations
We should emphasize that the thermogenic stimulus used in the present investigation, i.e. glucose ingestion, evokes a greater postprandial metabolic response than a conventional (mixed) meal. As such, results from the present and other studies that have used oral glucose as an experimental model to simulate postprandial metabolic responsiveness to energy intake likely overestimate the potential absolute caloric contribution of the age-related decline in TEF to the weight gain observed with adult aging in real life.
Clinical significance
Our findings have potentially important clinical implications. Although the TEF comprises a relatively small percentage of total daily energy expenditure, the decline with age could theoretically account for the small mean positive energy balance responsible for the progressive weight gain observed with age in adults living in industrialized societies (1, 2). Therefore, understanding the mechanisms by which aging reduces (and habitual exercise enhances) TEF is an important step in developing strategies by which energy balance can be more effectively maintained throughout adulthood. The present results provide the most definitive experimental evidence to date that differences in sympathetic neural responsiveness or circulating catecholamines are not a key mechanism involved in explaining the differential modulatory effects of aging and regular aerobic exercise on TEF in healthy humans. Instead, our findings suggest that differences in ß-adrenergic tissue responsiveness and/or nonsympathetic ß-adrenergic influences are responsible for the contrasting effects of age and exercise status on TEF.
Conclusions
In conclusion, the present study provides the first direct evidence refuting the long-standing hypothesis that differences in sympathetic neural responsiveness are responsible for the reduced TEF with aging and the augmented TEF associated with habitual aerobic exercise. Our results also suggest that TEF declines similarly with age in regularly exercising and sedentary adults.
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Footnotes |
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Abbreviations: ANCOVA, Analysis of covariance; MSNA, muscle sympathetic nerve activity; RMR, resting metabolic rate; SNS, sympathetic nervous system; TEF, thermic effect of food.
Received January 21, 2004.
Accepted May 26, 2004.
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