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Original Research Communications |
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: We investigated whether aging influenced the secretion of CCK, GLP-1, and PYY and their effects on appetite and pyloric motility.
Design: Eight healthy older (65–80 y) and 7 younger (20–34 y) men received isoenergetic (12.1 kJ/min) intraduodenal infusions of lipid and glucose for 120 min on separate days. Plasma CCK, GLP-1, and PYY concentrations were measured.
Results: Plasma CCK concentrations were higher in older than in younger subjects (P = 0.004) as a result of higher baseline values (4.7 ± 0.2 compared with 3.2 ± 0.2 pmol/L; P < 0.0001) and a greater rise during lipid infusion (increase from baseline: 7.1 ± 0.5 compared with 5.3 ± 0.6 pmol/L; P = 0.048). Plasma GLP-1 and PYY concentrations were not significantly different between groups. The decrease in hunger during intraduodenal lipid infusion was inversely related to the increase in CCK, GLP-1, and PYY in younger but not older subjects. During intraduodenal lipid infusion, the increase in isolated pyloric pressure wave (IPPW) frequency was positively related to GLP-1 and PYY and the increase in IPPW amplitude was positively related to CCK in older but not younger subjects, whereas the increase in IPPW amplitude and pyloric tone was negatively related to GLP-1 and PYY in younger subjects.
Conclusions: Human aging is associated with increased CCK concentrations, which may contribute to the slowing of gastric emptying, mediated by increased pyloric motility. The role of increased plasma CCK concentrations in mediating the age-related decrease in appetite remains to be established.
Key Words: Cholecystokinin • CCK • glucagon-like peptide 1 • GLP-1 • peptide YY • PYY • appetite • pylorus • gastric emptying • small intestine • elderly • men • aging
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Appetite is controlled by a central system that is responsible for the initiation of eating and that is held in check by a peripheral satiety system, which is activated by the presence of food in the gastrointestinal tract (3). An important mediator of gastrointestinal satiety signals is thought to be the release of gastrointestinal satiety hormones, including cholecystokinin (CCK) (4, 5), bombesin, glucagon, and glucagon-like peptide 1 (GLP-1) (6), induced by interaction of nutrients with receptors in the small intestine (4).
Gastric emptying of nutrients is slightly slower in healthy elderly than in young adults (7, 8) and there is evidence that this may contribute to increased satiation, perhaps by prolonging gastric distension (7), and that this thus may be a cause of the decrease in appetite that accompanies normal aging. Nutrients in the small intestine exert feedback effects on the stomach to slow gastric emptying. This is associated with the stimulation of phasic isolated pyloric pressure waves (IPPWs) and basal pyloric pressure and suppression of antral pressure waves (9) and fundic tone (10). The release of gastrointestinal hormones, particularly CCK (11–13), GLP-1 (14), and peptide YY (PYY) (12), is probably important in mediating the slowing of gastric emptying induced by small-intestinal nutrients.
We showed that isoenergetic intraduodenal infusions of glucose and lipid exert nutrient- and age-specific effects on appetite and gastric motility. Intraduodenal infusion of both glucose and lipid suppresses hunger in young men, whereas infusion of neither does in older men; additionally, lipid is a more potent suppressor of hunger and food intake than glucose in younger but not older subjects (15). Intraduodenal lipid infusion stimulates phasic pyloric pressure waves in both younger and older subjects and this response is greater in older subjects, suggesting that enhanced pyloric pressure responses to intraduodenal fat may contribute to the slowing of gastric emptying in older persons.
The present study was performed to determine the effects of aging on plasma concentrations of CCK, GLP-1, and PYY. All 3 hormones slow gastric emptying; CCK and GLP-1 also suppress appetite and food intake (13, 16–18). We hypothesized that reduced hunger, increased satiety, and slower gastric emptying in the elderly are due in part to greater release of these satiety hormones in older than in younger persons. We assessed this by measuring plasma CCK, GLP-1, and PYY concentrations in response to intraduodenal lipid and glucose infusions and correlated these results with measures of appetite, food intake, and pyloric motility reported in a previous study (15). We were particularly interested in assessing the CCK response to intraduodenal lipid infusions because lipid is a more potent stimulator of endogenous CCK release than glucose (19) and there are conflicting reports about the effect of age on increases in plasma CCK concentrations produced by ingestion of lipid (20) or a mixed meal (21). We hypothesized that aging enhances the lipid-induced increase in CCK concentrations.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Protocol
The experimental protocol was described previously (15). On each of the 2 study days subjects arrived at the laboratory at 0900 after a 12-h overnight fast. On arrival, a silicone rubber manometric assembly (4-mm outer diameter) was inserted into the subject's stomach via an anaesthetized nostril. The tip of the tube was allowed to pass into the duodenum by peristalsis, which took between 20 and 180 min, and the position of the manometric assembly was monitored continuously by measurement of transmucosal potential difference (9). An intravenous cannula was placed in a left antecubital vein to enable blood sampling for the measurement of plasma CCK, GLP-1, PYY, and glucose. About 30 min after the manometric tube had been positioned correctly, at time 0, an intraduodenal infusion of either 25% glucose (Baxter Healthcare Pty Ltd, Old Toongabbie, Australia) at a rate of 3 mL/min or a triacylglycerol emulsion (10% Intralipid; Kabi Pharmacia AB Sweden, distributed by Baxter Healthcare Pty Ltd) at a rate of 2.6 mL/min was commenced via a port in the manometric tube and continued for 120 min. The rate of energy delivery of both infusions was 12.1 kJ/min and intraduodenal infusions were delivered 
10 cm distal to the pylorus.
At -15, -5, 0, 10, 20, 30, 45, 60, 75, 90, 105, and 120 min, visual analogue scales were used to measure subjective appetite ratings (23). These questionnaires consisted of a list of symptoms (that included hunger, fullness, desire to eat, somnolence, dizziness, indigestion, headache, and thirst) with a horizontal 10-cm scale for each; subjects were instructed to make a single vertical mark on the scale indicating assessment of their current feelings. The values at -15, -5, and 0 min were averaged to provide a baseline and the change in ratings from baseline during intraduodenal nutrient infusions was quantified (15, 22, 23).
At -15, 10, 20, 30, 45, 60, 75, 90, 105, and 120 min, venous blood was collected in ice-chilled EDTA dipotassium–treated tubes containing 400 x 106 IU aprotinin (Trasylol; Bayer Australia Ltd, Pymple, Australia)/L blood for measurement of CCK, GLP-1, and PYY. Plasma was separated by centrifugation (3200 rpm for 15 min at 4°C) within 30 min of collection and stored at -70°C until assayed.
Antropyloric motility was recorded during the intraduodenal lipid, but not glucose, infusion. The change in plasma hormone concentrations from baseline in response to each infusion was calculated as the difference between plasma hormone concentrations at each time point and those at -15 min.
At 120 min the intraduodenal infusion was stopped and the manometric catheter removed. Subjects were then presented with a standardized cold buffet-style meal prepared in excess of what they would normally eat and were invited to eat as much as they wished. The rate of ingestion and the total amount and macronutrient composition of the food consumed were quantified (4, 15). Antropyloric pressures were measured as described previously (15).
Measurement of plasma CCK
Plasma CCK was measured by a radioimmunoassay technique (24) with antibody T204, which binds to all biologically active CCK peptides containing the sulfated tyrosine region with almost equal affinity. The detection limit of the assay was between 0.5 and 1 pmol/L in plasma. The intraassay precision ranged from 4.6% to 11.5% in the steep part of the standard curve. All samples were assayed in the same run.
Measurement of plasma GLP-1
Plasma GLP-1 7-36 was measured after ethanol extraction of plasma samples by a radioimmunoassay method similar to that used by Orskov et al (25). The antibody used in the method was provided by SR Bloom (Hammersmith Hospital, London) and had been raised in a rabbit immunized with GLP-1 7-36 conjugated to bovine serum albumin by carbodiimide. The antibody had 100% cross-reactivity with synthetic GLP-1 7-36 amide (from Peninsula Laboratories, Belmont, CA), but did not cross-react with GLP-1 7-37 amide, glucagon, gastric inhibitory polypeptide, or other gut or pancreatic peptides. The minimal detectable limit for the GLP-1 radioimmunoassay was 2 fmol/L. The interassay CV was 18%.
Measurement of plasma PYY
Plasma concentrations of PYY were measured by a radioimmunoassay technique (26) using antiserum raised in rabbits immunized to purified porcine or bovine PYY. The antiserum showed minimal to no cross-reactivity to bovine or porcine pancreatic polypeptide, neuropeptide Y, and neurotensin. The minimal detectable limit for the PYY radioimmunoassay was 0.3 pmol/L with intraassay CVs of 6–11% in the working range of the assay.
Statistical analyses
Results are given as means ± SEMs. Comparisons between the younger and older groups in the macronutrient content of the previous diet, fasting plasma albumin concentrations, basal hormone (CCK, GLP-1, PYY) concentrations, BMI, and baseline scores for hunger and fullness were performed by using Student's unpaired t tests because these data were normally distributed. The effects of the intraduodenal nutrient infusions on scores for hunger and fullness were analyzed by repeated-measures mixed-model analysis of variance (ANOVA). The effects of nutrient infusions on absolute plasma hormone concentrations were analyzed by using a repeated-measures three-way ANOVA with time, age (younger versus older), and treatment (glucose versus lipid) as the factors (plasma GLP-1 and PYY concentrations were log transformed before this analysis because these data were not normally distributed). To test the hypothesis that intraduodenal lipid produced a greater CCK response in the older than in the younger subjects, CCK data during the intraduodenal lipid infusion were expressed as change in CCK concentration from baseline and analyzed by using a repeated-measures two-way ANOVA with time and age as the factors. This ANOVA was performed by using SIGMASTAT statistical software for WINDOWS (version 1; Jandel Corporation, San Rafael, CA). Relations between the changes in plasma hormone concentrations and 1) changes in hunger, fullness, and pyloric tone and 2) the number and amplitude of IPPWs were evaluated by linear regression with robust variance estimation via mixed-model analysis to allow for repeated values in each subject (27). A generalized R2 for each relation was determined in this analysis by using ordinary maximum likelihood (28). Relations between basal hormone concentrations and changes in plasma hormone concentrations and 1) body weight (kg), 2) BMI (kg/m2), and 3) previous energy intake (kJ) were analyzed by using linear regression. Differences between means of regression lines were analyzed by Student's t test for unpaired observations. Differences between slopes of regression lines were analyzed by F tests. A P value <0.05 was considered significant in all analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Appetite
The sensation of hunger was significantly lower than at baseline during intraduodenal lipid infusion (P < 0.05) but not intraduodenal glucose infusion in the younger subjects. During both intraduodenal nutrient infusions, the sensation of fullness was higher than at baseline (P < 0.05), with no significant difference between intraduodenal glucose and lipid.
In older persons, neither intraduodenal nutrient infusion affected the sensation of hunger compared with baseline. In contrast, both intraduodenal glucose (P < 0.01) and intraduodenal lipid (P < 0.01) infusion increased the sensation of fullness from baseline, with no significant difference between the 2 nutrients.
Antropyloric pressures
As reported previously (15), intraduodenal lipid infusion stimulated an increase in the frequency (P < 0.01) and amplitude (P < 0.01) of IPPWs in both age groups. The overall mean frequency of IPPWs during the intraduodenal lipid infusion was greater in the older subjects than in the younger subjects (13.8 ± 2.2 compared with 8.1 ± 1.5 waves/2 h; P < 0.05). The amplitude of the IPPWs was also greater at every time point in the older subjects than in the younger subjects (55.5 ± 10.3 compared with 37.1 ± 3.3 mm Hg), but this difference was not significant when the whole curve was analyzed by ANOVA. However, the amplitude of the IPPWs was higher in the older subjects than in the younger subjects between 60 and 69 min (52 ± 6 compared with 25 ± 5 mm Hg; P < 0.05).
In both younger and older subjects there was an initial increase in pyloric tone during intraduodenal lipid infusion (P < 0.01 for both); the overall response was not significantly different between the 2 groups (mean change: 10.7 ± 6.4 mm Hg in the younger subjects compared with 7.0 ± 2.0 mm Hg in the older subjects). There were no antral pressure waves after the onset of intraduodenal lipid infusion in either group.
Plasma CCK
Before the intraduodenal glucose and lipid infusions, baseline fasting plasma CCK concentrations were higher in the older subjects than in the younger subjects (mean of both study days: 4.7 ± 0.3 compared with 3.2 ± 0.2 pmol/L; P < 0.001) (Figure 1
). The three-way ANOVA revealed a significant effect of age, with higher CCK concentrations in older subjects than in younger subjects throughout the nutrient infusions (mean for 0–120 min: 7.8 ± 0.5 compared with 5.7 ± 0.4; F[1,13] = 11.9, P < 0.01). There was also a significant effect of treatment (F[1,240] = 186.4, P < 0.001), with a greater CCK response to lipid than to glucose, and of time (F[9,240] = 17.7, P < 0.001). The age x time interaction was not significant (F[9,240] = 1.3, P = 0.27); however, there was a significant treatment x time effect (F[9,240] = 21.8, P < 0.001). There was no significant age x treatment x time interaction (F[9,240] = 1.13, P = 0.35), indicating that the timing of the increase in CCK concentrations was not significantly different between older and younger subjects. The age x treatment interaction was not significant (F[1,240] = 3.13, P = 0.078). However, analysis of the plasma CCK response to intraduodenal lipid infusion alone by two-way ANOVA indicated a significant effect of age as a result of a greater increase in CCK concentrations in older than in younger subjects (mean increase from baseline, 10–120 min: 7.1 ± 0.5 compared with 5.3 ± 0.6 pmol/L; P = 0.048; Figure 2). Neither the basal CCK concentrations nor the response to intraduodenal nutrients was related to body weight, BMI, or previous energy intake in either group (data not shown).
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). By three-way ANOVA, there was no significant effect of age (F[1,13] = 0.79, P = 0.39); however, there was a significant effect of treatment (F[1,240] = 14.1, P < 0.001), with higher GLP-1 concentrations during intraduodenal lipid infusion than during glucose infusion, and of time (F[9,240] = 93.5, P < 0.001). Age x treatment and age x time interactions were not significant (F[1,240] = 0.16, P = 0.69 and F[9,240] = 0.59, P = 0.80, respectively); however, there was a significant treatment x time effect (F[9,240] = 2.47, P < 0.05), with plasma GLP-1 concentrations peaking at 60 min during the lipid infusion but rising throughout the glucose infusion. There was no significant age x treatment x time interaction (F[9,240] = 0.60, P = 0.79), indicating that the timing of the increase in GLP-1 concentrations was not significantly different between the older and younger subjects. Basal GLP-1 concentrations were not related to body weight, BMI, or previous energy intake in either group (data not shown). However, the mean change in GLP-1 concentration during the intraduodenal glucose infusion was inversely related to BMI (F = 7.0, P = 0.046) and weight (F = 13.8, P = 0.014) in the younger subjects.
Plasma PYY
Before the intraduodenal glucose and lipid infusions, there was no significant difference in fasting plasma PYY concentrations between older and younger subjects (11.3 ± 0.6 compared with 10.5 ± 0.6 pmol/L; P = 0.13; Figure 1). By three-way ANOVA, there was no significant effect of age (F[1,13] = 0.01, P = 0.94); however, there was a significant effect of treatment (F[1,240] = 491.5, P < 0.001), with greater plasma PYY concentrations during intraduodenal lipid infusion than during glucose infusion, and of time (F[9,240] = 78.9, P < 0.001). Age x treatment and age x time interactions were not significant (F[1,240] = 0.11, P = 0.74, and F[9,240] = 1.03, P = 0.41, respectively), but there was a significant treatment x time effect (F[9,240] = 23.6, P < 0.001), with plasma PYY concentrations peaking earlier during intraduodenal lipid infusion than during glucose infusion. There was no significant age x treatment x time interaction (F[9,240] = 0.60, P = 0.793), indicating that the timing of the increase in PYY concentrations was not significantly different between older and younger subjects. Neither the basal PYY concentrations nor the response to intraduodenal nutrients was related to body weight, BMI, or previous energy intake in either group (data not shown).
Relations between appetite and plasma concentrations of CCK, GLP-1, and PYY
During intraduodenal lipid infusion, the change in hunger ratings from baseline was inversely related to the change in plasma CCK concentrations from baseline in the younger (R2 = 0.064, P = 0.030) but not the older (P = 0.71) subjects. In contrast, there was no significant relation between the change in fullness ratings and the change in plasma CCK concentrations during lipid infusion in either the younger (P = 0.32) or older (P = 0.095) subjects. During intraduodenal glucose infusion, there was no significant relation between the change in plasma CCK concentrations and the change in either hunger (younger subjects: P = 0.73; older subjects: P = 0.60) or fullness (younger subjects: P = 0.90; older subjects: P = 0.51) ratings.
During intraduodenal lipid infusion, the change in hunger ratings was inversely related to the change in plasma GLP-1 concentrations in the younger (R2 = 0.16, P = 0.0004) but not the older (P = 0.58) subjects. There was also a significant relation between the change in fullness ratings and the change in plasma GLP-1 concentrations during intraduodenal lipid infusion in both the younger (R2 = 0.22, P = 0.0001) and the older (R2 = 0.21, P = 0.0001) subjects. During intraduodenal glucose infusion, there was no significant relation between the change in hunger ratings and the change in plasma GLP-1 concentrations in either the younger (P = 0.15) or the older (P = 0.19) subjects. There was, however, a significant relation between the change in fullness ratings and the change in plasma GLP-1 concentrations in the older (R2 = 0.17, P = 0.0004) but not the younger (P = 0.23) subjects.
During intraduodenal lipid infusion, the change in hunger ratings from baseline was inversely related to the change in plasma PYY concentrations from baseline in the younger (R2 = 0.27, P = 0.0001) but not the older (P = 0.81) subjects. There was also a significant relation between the change in fullness ratings and the change in plasma PYY concentrations during intraduodenal lipid infusion in both the younger (R2 = 0.29, P = 0.0001) and the older (R2 = 0.29, P = 0.0001) subjects. During intraduodenal glucose infusion, there was a significant inverse relation between the change in hunger ratings and the change in plasma PYY concentrations in the younger (R2 = 0.12, P = 0.003) but not the older (P = 0.84) subjects. There was also a significant relation between the change in fullness ratings and the change in plasma PYY concentrations in both the younger (R2 = 0.15, P = 0.0005) and the older (R2 = 0.24, P = 0.0001) subjects.
Relations between pyloric pressures and plasma concentrations of CCK, GLP-1, and PYY
There was no significant relation between the increase in frequency of IPPWs and the increase in plasma CCK concentrations during intraduodenal lipid infusion in either the younger (P = 0.99) or the older subjects (P = 0.31). There was, however, a positive relation between the increase in amplitude of IPPWs and the increase in plasma CCK concentrations in the older subjects, although this was not significant (R2 = 0.04, P = 0.052). In contrast, there was a nonsignificant inverse relation in the younger subjects (P = 0.15). There was also a significant inverse relation between the increase in pyloric tone and the increase in plasma CCK concentrations during intraduodenal lipid infusion in the younger (R2 = 0.076, P = 0.020) but not in the older (P = 0.63) subjects.
There was a positive relation between the increase in frequency of IPPWs and the increase in plasma GLP-1 concentrations during intraduodenal lipid infusion in the older (R2 = 0.087, P = 0.009) but not the younger (P = 0.60) subjects. In contrast, there was a significant inverse relation between the increase in amplitude of IPPWs and the increase in plasma GLP-1 concentrations in the younger (R2 = 0.14, P = 0.0001) but not the older (P = 0.28) subjects. There was also a significant inverse relation between the increase in pyloric tone and the increase in plasma GLP-1 concentrations in the younger (R2 = 0.044, P = 0.023) but not the older (P = 0.093) subjects.
There was a positive relation between the change in frequency of IPPWs and the increase in plasma PYY concentrations during intraduodenal lipid infusion in the older (R2 = 0.090, P = 0.009) but not the younger (P = 0.25) subjects. There was an inverse relation between the increase in amplitude of IPPWs and the increase in plasma PYY concentration in the younger (R2 = 0.10, P = 0.001) but not in the older (P = 0.88) subjects. Similarly, there was a inverse correlation between the increase in pyloric tone and the increase in plasma PYY concentration in the younger (R2 = 0.070, P = 0.020) but not the older (P = 0.51) subjects. None of the intercepts or slopes of the lines for these regression calculations of plasma CCK, GLP-1, and PYY versus appetite or pyloric motility were significantly different between younger and older subjects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Previous studies of the effect of aging on plasma CCK concentrations produced conflicting results. Masclee et al (20) found higher CCK concentrations in older than in younger subjects after intraduodenal fat infusion, but no significant difference in fasting CCK concentrations between the 2 age groups. Berthelemy et al (21) reported no significant difference in CCK concentrations, either in a fasting state or after a liquid meal, between well-nourished younger and older people, but did report that postprandial CCK concentrations were higher in malnourished older subjects than in well-nourished young and well-nourished older subjects. This is consistent with evidence that suboptimal energy intake, reduced body weight, or both may be associated with increased plasma CCK concentrations (29–31).
Differences in body weight were not responsible for the increased CCK concentrations in our older subjects because the mean BMIs of the age groups did not differ. Qualitative and quantitative differences in the subjects' previous diets are also unlikely to have contributed to the differences in CCK concentrations for 3 reasons. First, carbohydrate composition of the diet of the older subjects was only slightly lower than that of the younger subjects (43.4 ± 1.4% compared with 48.3 ± 1.8% of energy), whereas the percentages of fat and protein were similar. Second, no subjects were malnourished according to the criteria of Berthelemy et al (21), ie, energy intake <4184 kJ/d and body weight >20% below ideal or plasma albumin concentrations <20 g/L. Third, although the average total daily energy intake of the older subjects, as assessed by their food diaries, was less than that of the younger subjects, there was no relation between plasma CCK concentrations and daily energy intake.
There is circumstantial evidence that CCK is a physiologic satiety factor. Administration of exogenous CCK to healthy adults increases sensations of fullness and reduces sensations of hunger and subsequent food intake (13, 32–34). Most reports of CCK-induced satiety involve studies in which CCK is administered in doses that increase plasma CCK concentrations above physiologic postprandial concentrations. In one study, however, Lieverse et al (16) reported suppression of food intake by an exogenous dose of CCK that produced physiologic postprandial plasma CCK concentrations. Additionally, food intake is suppressed in both rats (35, 36) and humans (37) by administration of an inhibitor of trypsin, a compound that inhibits the release of endogenous CCK. Our finding that plasma CCK concentrations were higher in older subjects than in younger subjects therefore suggests that increased endogenous CCK activity may be a cause of the anorexia of aging. For this to be so, sensitivity to the satiating effects of CCK must be maintained or increased with advancing age. Of note, food intake is suppressed more in older than in younger rodents by intraperitoneal CCK administration (6). Although our study did not directly address sensitivity to the satiating effects of CCK, the suppression of hunger ratings and the significant inverse correlation between plasma CCK concentrations and hunger ratings in the younger men [consistent with the findings of French et al (38)] but not the older men during intraduodenal lipid infusion provide indirect evidence that human aging may be associated with reduced sensitivity to the satiating effects of CCK.
GLP-1 may also function as a satiety factor. Central and peripheral administration of GLP-1 suppresses food intake in rats (17) and humans (18), respectively. In humans, GLP-1 administration also enhances feelings of fullness and satiety (18). In contrast with previous findings (39), in the present study, GLP-1 concentrations increased more during lipid infusion than during glucose infusion in both the younger and older subjects. The lack of a significant difference in plasma GLP-1 concentrations between the younger and older subjects under any study condition makes it unlikely that changes in circulating GLP-1 concentrations contribute to the reduced appetite accompanying normal aging.
Fat or unabsorbed nutrients in the intestine stimulate PYY release by luminal cells (26). In experimental animals, feeding is stimulated by central PYY administration (40) but is unaffected by intraperitoneal administration (35). The role, if any, of PYY in the control of human feeding is unknown. The effects of aging on plasma PYY concentrations have hitherto not been reported. Plasma PYY concentrations did not differ significantly between older and younger subjects in the present study, however, indicating that changes in circulating PYY concentrations are unlikely to contribute to the anorexia of aging.
Previous studies showed that CCK (13, 41), GLP-1 (11, 14), and PYY (42, 43) slow gastric emptying: CCK (44) and GLP-1 (14) by stimulating IPPWs and inhibiting distal gastric (antral) contractions and PYY by inhibiting interdigestive migrating contractions in the small intestine (12). During intraduodenal lipid infusion, there was a greater increase in plasma concentrations of all 3 hormones in both the younger and older subjects than during glucose infusion. This finding is consistent with that of Raybould and Lloyd (19) for CCK, but contrasts with previous reports that plasma GLP-1 (39) and PYY (45) concentrations increase equally in healthy men after ingestion of high-carbohydrate or high-fat meals. This discrepancy could reflect orosensory or gastric mechanisms involved in the release of PYY. The greater release of these hormones during intraduodenal lipid infusion than during glucose infusion may contribute to the more powerful stimulatory effect of intraduodenal lipid on pyloric motility, as observed previously in young adults (22).
Intraduodenal lipid infusion stimulated IPPWs and abolished all antral contractions. The increase in frequency and amplitude of IPPWs during lipid infusion was greater in older than in younger subjects. The increases in plasma CCK concentrations were positively related to the increases in amplitude of the IPPWs (or phasic response) in the older subjects, although this relation was not significant. In contrast, there was a nonsignificant, inverse relation in the younger subjects. There was also a significant positive relation between lipid-induced plasma GLP-1 and PYY concentrations and frequency of IPPWs in older subjects but a significant inverse relation between these hormones and amplitude of IPPWs as well as pyloric tone in younger subjects. The relatively small subject number of subjects in our study makes it difficult to draw strong conclusions from these relations and it is not known whether the tonic or the phasic pressure response is more important in slowing gastric emptying (46). Nevertheless, these results suggest that the enhanced stimulation of pyloric motility induced in the older subjects by intraduodenal lipid infusion may have been due to increased secretion of CCK or increased sensitivity to the stimulating effects of CCK, GLP-1, and PYY and may in turn be a cause of the slower gastric emptying observed in older people.
In summary, human aging is associated with increased fasting and lipid-induced plasma CCK concentrations. We found no clear evidence, however, that increased secretion of this putative satiety hormone is a cause of the reduced appetite and food intake that accompanies normal aging. Indeed, resistance to the appetite-suppressing effects of CCK may be a feature of aging. In contrast, we found indirect evidence that delayed gastric emptying in older persons may be due to enhanced stimulatory effects of CCK, GLP-1, and PYY on pyloric motility.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Address reprint requests to IM Chapman, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, Australia, 5000. E-mail: ichapman{at}medicine.adelaide.edu.au.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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 K. L. Feltrin, T. J. Little, J. H. Meyer, M. Horowitz, T. Rades, J. Wishart, and C. Feinle-Bisset Effects of lauric acid on upper gut motility, plasma cholecystokinin and peptide YY, and energy intake are load, but not concentration, dependent in humans J. Physiol., June 1, 2007; 581(2): 767 - 777. [Abstract] [Full Text] [PDF]
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V. Di Francesco, M. Zamboni, E. Zoico, G. Mazzali, A. Dioli, F. Omizzolo, L. Bissoli, F. Fantin, P. Rizzotti, S. B Solerte, et al. Unbalanced serum leptin and ghrelin dynamics prolong postprandial satiety and inhibit hunger in healthy elderly: another reason for the "anorexia of aging" Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1149 - 1152. [Abstract] [Full Text] [PDF]
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 S. B. Roberts and I. Rosenberg Nutrition and Aging: Changes in the Regulation of Energy Metabolism With Aging Physiol Rev, April 1, 2006; 86(2): 651 - 667. [Abstract] [Full Text] [PDF]
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A. N. Pilichiewicz, T. J. Little, I. M. Brennan, J. H. Meyer, J. M. Wishart, B. Otto, M. Horowitz, and C. Feinle-Bisset Effects of load, and duration, of duodenal lipid on antropyloroduodenal motility, plasma CCK and PYY, and energy intake in healthy men Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2006; 290(3): R668 - R677. [Abstract] [Full Text] [PDF]
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 V. Di Francesco, M. Zamboni, A. Dioli, E. Zoico, G. Mazzali, F. Omizzolo, L. Bissoli, S. B. Solerte, L. Benini, and O. Bosello Delayed Postprandial Gastric Emptying and Impaired Gallbladder Contraction Together With Elevated Cholecystokinin and Peptide YY Serum Levels Sustain Satiety and Inhibit Hunger in Healthy Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1581 - 1585. [Abstract] [Full Text] [PDF]
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C. Feinle-Bisset, M. Patterson, M. A. Ghatei, S. R. Bloom, and M. Horowitz Fat digestion is required for suppression of ghrelin and stimulation of peptide YY and pancreatic polypeptide secretion by intraduodenal lipid Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E948 - E953. [Abstract] [Full Text] [PDF]
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 M Chapman, R Fraser, R Vozzo, L Bryant, W Tam, N Nguyen, B Zacharakis, R Butler, G Davidson, and M Horowitz Antro-pyloro-duodenal motor responses to gastric and duodenal nutrient in critically ill patients Gut, October 1, 2005; 54(10): 1384 - 1390. [Abstract] [Full Text] [PDF]
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I. M. Brennan, K. L. Feltrin, M. Horowitz, A. J. P. M. Smout, J. H. Meyer, J. Wishart, and C. Feinle-Bisset Evaluation of interactions between CCK and GLP-1 in their effects on appetite, energy intake, and antropyloroduodenal motility in healthy men Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1477 - R1485. [Abstract] [Full Text] [PDF]
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 R. G. Smith, L. Betancourt, and Y. Sun Molecular Endocrinology and Physiology of the Aging Central Nervous System Endocr. Rev., April 1, 2005; 26(2): 203 - 250. [Abstract] [Full Text] [PDF]
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K. Sturm, B. Parker, J. Wishart, C. Feinle-Bisset, K. L Jones, I. Chapman, and M. Horowitz Energy intake and appetite are related to antral area in healthy young and older subjects Am. J. Clinical Nutrition, September 1, 2004; 80(3): 656 - 667. [Abstract] [Full Text] [PDF]
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K. L. Feltrin, T. J. Little, J. H. Meyer, M. Horowitz, A. J. P. M. Smout, J. Wishart, A. N. Pilichiewicz, T. Rades, I. M. Chapman, and C. Feinle-Bisset Effects of intraduodenal fatty acids on appetite, antropyloroduodenal motility, and plasma CCK and GLP-1 in humans vary with their chain length Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R524 - R533. [Abstract] [Full Text] [PDF]
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J.-P. Gutzwiller, L. Degen, D. Matzinger, S. Prestin, and C. Beglinger Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R562 - R567. [Abstract] [Full Text] [PDF] |
