Department of Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands
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ABSTRACT |
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The age-dependent
alterations in -adrenergically mediated thermogenesis were
investigated in 11 young (mean ± SE age: 21.9 ± 0.5 yr) and 9 older (52.9 ± 2.1 yr) men during intravenous infusion of the
nonselective
-agonist isoprenaline (Iso). The older men had higher
basal plasma norepinephrine (327.7 ± 35.8 vs. 159.0 ± 18.2 pg/ml, P < 0.001) and epinephrine
(75.1 ± 18.1 vs. 29.1 ± 5.3 pg/ml,
P < 0.05) concentrations than the
young. The
-adrenergically mediated thermogenesis was diminished in
the older men, as reflected by the significantly higher plasma Iso
concentration needed to increase resting energy expenditure by 15%
(236.1 ± 51.0 vs. 107.6 ± 11.4 pg/ml,
P < 0.05). Additionally, both dose
(39.4 ± 6.6 vs. 19.1 ± 1.5 ng · kg fat-free
mass
1 · min
1,
P < 0.01) and plasma concentration
(332.2 ± 59.1 vs. 119.3 ± 14.0 pg/ml,
P < 0.01) of Iso needed
to increase resting heart rate by 25 beats/min were higher in older
than in younger subjects, suggesting that the age-related decline in
-adrenergic sensitivity is a generalized defect not related to a
specific tissue or response. In conclusion, aging is associated with a
diminished
-adrenergically mediated thermogenesis. This blunted
thermogenic response may contribute to a positive energy balance and
thus promote increased fat storage and obesity.
energy expenditure; chronotropic response; age; sympathetic nervous system; isoprenaline
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INTRODUCTION |
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AGING is associated with an increased risk for several chronic diseases such as type 2 diabetes and cardiovascular disease. A factor involved in the increased prevalence of these diseases may be the age-related change in body composition that includes an increase in (abdominal) fat mass and obesity (6), since both body fat mass and abdominal fat distribution are risk factors in the development of type 2 diabetes and cardiovascular disease (11). To come to a more effective prevention or treatment of the age-related increase in body fat storage, more information is necessary on the responsible mechanisms.
Aging may be associated with altered patterns of energy expenditure
(21). Several studies have demonstrated that resting metabolic rate
declines with advancing age (8, 16-19, 25). In most cases, the
decrease in age-related decline in fat-free mass seems to be the best
available predictor of the decrease in resting metabolic rate.
Furthermore, diet-induced thermogenesis (DIT) may decline with aging.
It is possible that this decline plays a role in the increased
adiposity found with advancing age by promoting a positive energy
balance. Schwartz et al. (21) hypothesized that the reduction in DIT is
related to diminished activity of the sympathetic nervous system. This
is in accordance with numerous studies that reported that aging is
associated with alterations in sympathetic activity. Despite the
increased basal sympathetic activity (4, 9, 17, 20, 21), as reflected by a rise in circulating norepinephrine, there appear to be blunted sympathetically mediated metabolic responses with aging. Especially, a
decline in -adrenergically mediated heart rate response in older
persons is well established (3, 7, 9, 26). At present, it is, however,
not known whether the sympathetically mediated thermogenesis also
declines with aging. If so, this results in an increased efficiency of
energy expenditure, contributing thereby to the age-related increase in
body fat stores. Previous studies have shown that the
-adrenoceptors are mainly involved in the sympathetically
mediated thermogenesis (1). Thus, to obtain more information on the
mechanisms behind the age-related increase in obesity, the present
study was intended to investigate whether the
-adrenergically
mediated thermogenesis is altered with aging.
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METHODS |
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Subjects. Eleven young (21.9 ± 0.5 yr) and 9 older (52.9 ± 2.1 yr) men participated in this study after their written informed consent was obtained (Table 1). The study protocol was approved by the Ethics Committee of Maastricht University. The results of the young subjects have been previously published (2). All subjects were normotensive and generally in good health. Cardiovascular and/or respiratory diseases were excluded by a medical questionnaire and physical examination. Subjects participated no more than 3 h/wk in sports activities, and none of the subjects had a physically demanding job.
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Body composition. Body density was measured by hydrostatic weighing, with a correction for residual lung volume as determined by helium dilution (Volugraph 2000, Mijnhardt, The Netherlands). Body composition was calculated according to the formula of Siri (22).
Isoprenaline infusion test.
To determine -adrenergically mediated thermogenic and heart rate
(HR) responses, subjects fasted overnight and came to the laboratory by
car or bus. The experiments were done in the morning in a quiet room
with a temperature between 23 and 25°C. The subjects remained in a
supine position throughout the study. Intravenous catheters were
inserted into both arms, one for infusion of the nonselective
-agonist isoprenaline (Iso) and the other for blood sampling.
-Adrenergically mediated
thermogenic and HR responses.
EE and HR responses of the young and older men reached a steady state
after 10 min of Iso infusion, i.e., 5-min values were stable until the
end of the infusion period. Therefore, mean values over the last 20 min
were considered as representative for the administered doses. The
respiratory exchange ratio (RER) in both groups reached a steady state
after 20 min of infusion after a rapid increase within the first 5 min
of the Iso infusion that was most probably caused by a change in
ventilation (1). Therefore, RER values over the last 10 min of infusion
were averaged.
Statistical analysis. Values are presented as means ± SE. Differences between the young and older groups were analyzed by use of Student's unpaired t-test. The effects of Iso infusion on various parameters within each group and between both groups were analyzed by use, respectively, of one-factor and two-factor ANOVA for repeated measurements. Simple and multiple regression analyses were used to determine which variables contributed to variations in response between subjects. A value of P < 0.05 was considered significant.
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RESULTS |
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Physical characteristics of the subjects are given in Table 1. There is >30 yr of difference between the mean ages of the young (n = 11 subjects) and the older (n = 9 subjects) groups. Although weight and body mass index were similar in both groups, the older subjects had significantly higher percent body fat compared with the young (P < 0.05).
Figure 1 shows the changes in plasma Iso, NE, and Epi with infusion of stepwise increasing doses of Iso in young and older men. There were dose-dependent increases in plasma Iso in both groups (for young and older subjects: one-factor ANOVA for repeated measurements, P < 0.001), but the mean plasma concentrations with the increasing standardized doses were higher in the older than in the young subjects (two-factor ANOVA for repeated measurements, P < 0.05; Fig. 1A). Basal values of plasma NE and Epi were significantly different between young and older subjects (unpaired t-test: NE, 159.0 ± 18.2 vs. 327.7 ± 35.8 pg/ml, P < 0.001; Epi, 29.1 ± 5.3 vs. 75.1 ± 18.1 pg/ml, P < 0.05, respectively; Fig. 1, B and C). During Iso infusion, there was an increase in plasma NE (for young and older subjects, P < 0.001) and no significant change in plasma Epi in both groups as illustrated in Fig. 1, B and C. Moreover, the older men had higher mean plasma NE (P < 0.001) and Epi (P < 0.05) concentrations with increasing doses of Iso compared with the young subjects (Fig. 1, B and C).
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REE was not significantly different between young and older subjects
(Table 2). Figure
2 shows the changes in EE (as %change above baseline), RER, and HR (as %change) with infusion of stepwise increasing doses of Iso in young and older men. The young and the older
subjects showed Iso-induced increases in EE (for both groups,
P < 0.001). There were no
significant differences in the increases in EE with increasing doses of
Iso between the young and older groups, irrespective of whether
increases were expressed as percent increase above baseline (Fig.
2A, P = 0.30) or absolute increase (young vs. older men: change in EE, 6 ng,
0.44 ± 0.06 vs. 0.27 ± 0.10 kJ/min; 12 ng, 0.70 ± 0.08 vs.
0.51 ± 0.06 kJ/min; 24 ng, 1.10 ± 0.11 vs. 0.82 ± 0.12 kJ/min, respectively), although the absolute increases in EE tended to
be lower in the older men (P = 0.08).
In addition, doseEE=15% was
not significantly different between groups, as indicated in Table 2.
However, when responses were related to plasma concentrations of Iso,
concn
EE=15% was lower in the
young than the older men (Table 2), indicating a blunted
-adrenergically mediated thermogenic response in the older men.
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Resting values of the RER were similar in young and older subjects (0.81 ± 0.01 vs. 0.82 ± 0.01, respectively). The RER decreased with higher doses of Iso in the young (P < 0.001), whereas there was no significant change in the older subjects. However, there were no significant differences in the RER with Iso between young and older subjects (Fig. 2B).
The Iso-induced increases in HR of the young and older subjects (for
both groups, P < 0.001) were lower
in the older men than in the young (P < 0.01) when related to the dose of Iso, either expressed as absolute
increase above baseline (CD25, Table 2) or as percent change in HR
(Fig. 2C). Basal HR levels were
lower in the young than in the older men (Table 2). HR responses to Iso
expressed as CD25 and CC25 values are shown in Table 2. Both CD25 and
CC25 values were lower in the young than in the older men. Thus the
older men also seem to have blunted -adrenergically mediated HR
responses. Furthermore, there was a significant correlation between
Iso-induced thermogenic and HR response in both young (R = 0.80, P < 0.01) and older subjects
(R = 0.69, P < 0.05).
A multiple regression analysis with age and percent body fat as
independent variables and
concnEE=15% and CC25 as
dependent variables showed that age was the only factor significantly contributing to the variation in
concn
EE=15% (multiple R = 0.55, P < 0.05) and CC25 (multiple
R = 0.66, P < 0.01). This is confirmed in the
observation that exclusion of the lowest values of percent body fat in
the young and the highest values in the older men resulted in two
groups with comparable percent body fat [young men
(n = 9) 13.2 ± 0.9 vs. older men
(n = 6) 13.6 ± 1.4%] and a
still lowered thermogenesis in the older men
(concn
EE=15%: young men 111.9 ± 12.0 vs. older men 201.7 ± 45.9 pg/ml;
P = 0.052).
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DISCUSSION |
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The present study was undertaken to obtain more information on the
underlying mechanisms for the age-related increase in body fat mass by
investigating whether the -adrenergically mediated thermogenesis was
altered with aging. The main finding of the present study was that the
-adrenergically mediated thermogenic response was diminished in the
older men, as reflected by the significantly higher
concn
EE=15%. This blunted
thermogenic response in the older men was not statistically significant
when the thermogenic response was related to the administered
standardized dose of Iso per fat-free mass. In accordance with several
studies (2, 10, 13), the above findings indicate that using individual venous plasma Iso concentration-response curves instead of
dose-response curves increases the precision of the Iso-infusion test,
as interindividual variations of plasma Iso pharmacokinetics between
individuals are taken into account. This is of special importance in
the comparison of groups with differences in age, since aging is
associated with a reduced clearance of drugs within the body, as also
reflected by the higher Iso concentrations in older men in the present
study during infusion of doses standardized for fat-free mass. The
diminished clearance has been reported to be caused by decreases in
hepatic metabolism and renal elimination capacity (15).
Our data of a blunted thermogenic response with advancing age seem to
correspond with a previous study of Schwartz et al. (21), who showed a
reduced DIT in older men. Our study is, however, the first to
demonstrate that a diminished -adrenergic sensitivity may be
responsible for this blunted response. Because of the fact that in the
present study, percent body fat in the older group was already slightly
higher than in the younger subjects, we cannot make a definite
statement on whether the impaired thermogenesis is a cause or a
consequence of the increased percent body fat. However, multiple
regression analysis with age and percent body fat as independent
variables indicated that only age significantly contributed to the
variations in thermogenic response, strongly indicating that in these
nonobese older men, the blunted thermogenesis is a consequence of aging
per se. This seems to correspond to previous data showing that the
Iso-induced thermogenesis is only blunted in obese subjects with a
percent body fat >30 (2). The age-related decrease in thermogenesis
may contribute to the elevated percent body fat in the older men and
may thereby play an important role in the increased risk for chronic
diseases such as type 2 diabetes and coronary heart disease.
The exact mechanism for the decline in -adrenergic sensitivity
remains to be determined. Basal plasma NE concentrations were significantly higher in the older subjects, reflecting an increase in
basal sympathetic activity, as previously reported (4, 9, 17, 20, 21).
It is possible that this increased basal plasma NE concentration in the
older men may lead to a downregulation (24) and decreased agonist
binding of adrenoceptors (14, 24). Additionally, alterations in
adrenoceptor density (7, 9, 24) and postreceptor defects, such as
changes in G protein-mediated signal transduction (4, 5, 24) or in
activity of hormone-sensitive lipase (12), may probably contribute to
the blunted responses in the older men. It is noteworthy that besides
the decreased
-adrenergically mediated thermogenesis with aging, HR
response was also significantly blunted in the older men, as reported
before (3, 7, 9, 26). Moreover, there was a significant positive relationship between
-adrenergically mediated thermogenic and HR
responses in both groups. These data suggest that the age-related decrease in
-adrenergic sensitivity is a generalized defect not related to a specific organ or response. It remains, however, to be
elucidated whether the decrease in
-adrenergic sensitivity is caused
by a decrease in sensitivity of all
-adrenoceptor subtypes or is
caused by a
-adrenoceptor subtype-specific decrease in sensitivity.
During -adrenergic stimulation, there was a significant decrease in
the RER in young but not in older men, which may indicate a higher
increase in fat oxidation during
-adrenergic stimulation in the
young subjects. However, differences in the changes in RER with Iso
infusion between the two groups did not reach statistical significance.
In conclusion, -adrenergically mediated thermogenic and HR responses
are blunted in older persons (45-62 yr) compared with a younger
control group (20-25 yr). The exact mechanism for this decrease in
sensitivity remains to be determined. The reduction in the Iso-induced
thermogenic response with age may contribute to the increased percent
body fat in the older men and the related risk for chronic diseases
such as type 2 diabetes and cardiovascular disease. Further studies are
necessary to elucidate the responsible mechanisms for the age-related
blunting of the thermogenic response.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Dutch Diabetes Funds.
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FOOTNOTES |
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Address for reprint requests: E. E. Blaak, Dept. of Human Biology, Faculty of Health Sciences, Maastricht Univ., PO Box 616, 6200 MD Maastricht, The Netherlands.
Received 17 September 1997; accepted in final form 26 February 1998.
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