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Department of Medicine, University of Adelaide, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia
Address all correspondence and requests for reprints to: Dr. Ian Chapman, Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide 5000, Australia. E-mail: ian.chapman{at}adelaide.edu.au.
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Abstract |
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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The causes of the physiological anorexia of aging are largely unknown and likely to be multifactorial. Possible mechanisms include a reduction in the central (8) and peripheral feeding drive, and increased activity of central (9) and/or peripheral (10) satiety signals. Among the latter, the gut hormones glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) may be important (11, 12, 13). Healthy older subjects appear to retain their sensitivity to the satiating effects of CCK (13) and have higher fasting and postprandial plasma CCK concentrations than young adults (13, 14, 15). In one study CCK concentrations were higher in undernourished than in healthy elderly (16). Ghrelin is a hormone, predominantly produced and secreted by the gastric mucosa, that stimulates pituitary GH secretion (17), appetite, and food intake (18). Although circulating ghrelin concentrations apparently increase between early adulthood and middle age in humans (19), there is evidence that old age is associated with deceased ghrelin concentrations in rodents (20) and may be associated with decreased concentrations in humans (21). Enhanced effects of CCK and/or reduced effects of ghrelin may therefore contribute to the development of anorexia and in some cases PEM with aging. To examine this possibility we have evaluated the responses of healthy young and older subjects and undernourished older subjects to an oral mixed nutrient preload.
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Experimental Subjects |
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Undernourished older subjects (n = 8; mean age, 80.4 ± 2.6 yr; range, 69–87) were recruited from among 250 recipients of domiciliary care services in South Australia using previously described criteria (16): a body mass index (BMI) of 18.5 kg/m2 or less, and/or at least two of the following risk factors: 1) a food intake less than 1000 kCal/d (from a 3-d food diary completed in the week before the first study day), 2) serum albumin concentration less than 30 g/liter, and 3) weight loss greater than 10% in the previous 6 months.
Group 2
Well-nourished independently living older subjects (n = 8; mean age, 77 ± 0.9 yr; range, 72–80) were recruited by advertisement. All had a BMI greater than 18.5 kg/m2 and none of the three risk factors for malnutrition listed above.
Group 3
Well-nourished young subjects (n = 8; mean age, 22 ± 1.3 yr; range, 18–29) who met none of the above criteria for malnutrition were recruited by advertisement.
Subjects in groups 2 and 3 were no more than 5% below their ideal body weight (22). Exclusion criteria were alcohol abuse; significant gastrointestinal symptoms (pain, reflux, diarrhea, or constipation); previous gastrointestinal surgery (apart from uncomplicated appendectomy); abnormal plasma amylase, lipase, or TSH concentrations; active malignancy; diabetes mellitus; impaired cognitive function [score <25 on Mini Mental State (23)]; depression [groups 1 and 2; score >11 on the Geriatric Depression Questionnaire (24)]; and the use of medications known to potentially affect gastrointestinal motor function or appetite (e.g. prokinetic drugs and antidepressants). Nutritional status was assessed by measurement of anthropometric markers (BMI, midarm circumference, and calf circumference), biochemical markers (albumin, prealbumin, retinol-binding protein) (25) and the Mini Nutritional Assessment (MNA) (26). Mean energy intake was assessed by a food diary maintained for 3 successive days. All subjects were unrestrained eaters (score <11 for factor I cognitive restrained) on the Three-Factor Eating Questionnaire (27). The study protocol was approved by the ethics committee of the Royal Adelaide Hospital, and all subjects gave written, informed, consent.
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Materials and Methods |
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Measurements
Appetite. Sensations of hunger and fullness were rated by each subject at regular intervals using 10-cm visual analog scales (VAS) as previously described (13, 14, 28).
Food intake. The amount of food eaten and the macronutrient distribution of energy were quantified using Foodworks 2.10 (Xyris Software, Highgate Hill, Australia) (13, 14).
Blood glucose. Blood glucose concentrations were measured in venous whole blood by the glucose oxidase method using a portable blood glucose meter (MediSense Precision Q·I·D System, Abbott Laboratories, MediSense Products, Inc., Bedford, MA).
Gastrointestinal hormones. Plasma CCK-8 (picomoles per liter) was measured by RIA using an adaptation of the method described by Santangelo et al. (13, 29). Standards (synthetic sulfated CCK-8, Sigma-Aldrich Corp., St. Louis, MO) were prepared in charcoal-stripped plasma and extracted in 66% ethanol along with the samples. Extracts were dried down under N2 and resuspended in assay buffer (50 mM phosphate, 10 mM EDTA, and 2 g/liter gelatin, pH 7.4). A commercially available antibody (C2581, lot 105H4852, Sigma-Aldrich Corp.) raised in rabbits against synthetic sulfated CCK-8 was employed. This antibody binds to all CCK peptides containing the sulfated tyrosine residue in position 7 (13, 29) and has a 26% cross-reactivity with unsulfated CCK-8, less than 2% cross-reactivity with human gastrin 1, and no cross-reactivity with structurally unrelated peptides (13). Antibody was added at a dilution of 1:17,500, and 125I-labeled sulfated CCK-8 with Bolton-Hunter reagent (74 TBq/mmol; Amersham International, Little Chalfont, UK) was used as tracer. Incubation proceeded for 7 d at 4 C. The antibody-bound fraction was separated by the addition of dextran-coated charcoal containing gelatin (0.015 g gelatin, 0.09 g dextran, and 0.15 g charcoal in 30 ml assay buffer). The detection limit was 1 pmol/liter, and the intraassay coefficient of variation at 50 pmol/liter was 9.5%.
Plasma GLP-1(7–36) amide (picomoles per liter) was measured after ethanol extraction of plasma samples by RIA (14). The detection limit was 2 pmol/liter, and the interassay coefficient of variation was 18%.
Plasma ghrelin (picograms per milliliter) was measured in duplicate using a commercial competitive RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA) (30, 31, 32) that uses 125I-labeled bioactive ghrelin as a tracer and a rabbit polyclonal antibody raised against full-length octanoylated human ghrelin. The assay detects total ghrelin, including Ser3-octanoyl and Ser3-des-octanoyl ghrelins, and has no cross-reactivity with ghrelin (1, 2, 3, 4, 5), ghrelin (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), secretin, vasoactive intestinal peptide, galanin, GH-releasing factor, neuropeptide Y, orexin A and B, PRL-releasing peptide (kit data sheet), or leptin (32). The lower limit of detection of this assay was 20 pg/ml. Samples above the upper limit of detection of 1280 pg/ml were reassayed at dilutions up to 10-fold (31). Intra- and interassay coefficients of variation were 5.5–6.9% and 12.1–12.8%, respectively (30, 33).
Plasma insulin (milliunits per liter) was measured by ELISA (Diagnostics Systems Laboratories, Inc., Webster TX). The sensitivity of the assay was 0.26 mU/liter, and the coefficient of variation was 2.6% within assays and 6.2% between assays.
Serum albumin was measured by the bromocresol purple method, prealbumin was determined turbidimetrically using an antiprealbumin antibody (Tina-quant Prealbumin Kit, Roche, Basel Switzerland), retinol-binding protein was measured by immunonephelometry using a human retinol-binding protein antiserum (Behring, Marburg, Germany), and other analytes were determined by standard methods.
Statistical analyses
Results are the mean ± SEM (unless stated otherwise). Baseline measurements of appetite and blood glucose were the mean of -15 and -5 min values, whereas baseline gastrointestinal hormone concentrations were measured at -15 min. The premeal period was the interval between baseline and 90 min. Comparisons between single characteristics of the three groups (e.g. BMI, baseline appetite scores, percent reduction on food intake, and baseline blood hormone concentrations) were performed using one-way ANOVA. All were performed using SuperANOVA version 1.11 (Abacus Concepts, Inc., Berkeley, CA), except Kruskal-Wallis one-way ANOVA was used on ranks (when data were not normally distributed), followed by the Student-Newman-Keuls test, performed using SigmaStat version 1.0 (Jandel Corp., San Rafael, CA). When a significant difference was observed, contrasts were used, enabling comparisons among the three groups. Differences in mean energy intake and macronutrient content of the buffet meal were analyzed by repeated measures two-way ANOVA, with type and treatment as factors. Repeated measures, three-way ANOVA, with time, type, and treatment as the factors, was used to analyze absolute ratings of appetite, nausea, and hunger and plasma concentrations of GLP-1, CCK, ghrelin, and insulin (from -15 to 90 min). When a significant interaction between factors was observed, contrasts were used to test preplanned hypotheses of interest, enabling comparisons among the three groups at definite time points. Hormone data after the buffet meal (120, 135, and 150 min) were not analyzed because of substantial differences in the amount of food eaten at that meal. P < 0.05 was considered significant.
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Results |
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. All undernourished older subjects qualified as such on the basis of reduced BMI alone. Two subjects (both undernourished older) smoked. Appetite and food intake
Hunger ratings (Fig. 1a).
Fasting hunger ratings (mean of the study days) were significantly lower in the undernourished older subjects than in the young subjects (P = 0.006) and were not quite significantly lower in the well-nourished older subjects than in the young subjects (P = 0.06), with no significant difference between the two older groups (P = 0.3). The decrease in hunger ratings after preload ingestion was comparable in all groups (effect of type, P = 0.3). Premeal (baseline to 90 min) hunger ratings were higher in the young subjects than in both the undernourished (P = 0.007) and well-nourished (P = 0.04) older subjects, with no significant difference between the two older groups (P = 0.43).
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The undernourished older subjects had significantly higher fasting fullness ratings than the well-nourished older subjects (P = 0.008), with no significant differences between the other groups. The increase in fullness ratings after preload ingestion was comparable in all groups (effect of type, P = 0.8). Premeal fullness ratings were higher in the undernourished older group than in the other groups, but only on the preload day (treatment x type interaction, P = 0.04).
Energy intake at the buffet meal (Table 2 and Fig. 2).
Mean energy intake at the buffet meal (Table 2) was less in both the undernourished and well-nourished older subjects than in the young subjects (P = 0.0001 for both), without a significant difference between the older groups (P = 0.38). In the undernourished older subjects food intake was not suppressed by the preload [preload day intake 100.5% of control day intake (median)], whereas it was in the other groups [well-nourished older (69.7%) and young (89.1%); effect of type, P = 0.02; P < 0.05 for both vs. undernourished older; P > 0.05, young vs. well-nourished older; Fig. 2]. The undernourished older subjects consumed more fat and less carbohydrate than the other groups on both study days (Table 2), but there was no effect of treatment on the macronutrient composition of the food eaten.
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Blood glucose and insulin concentrations. Blood glucose concentrations were not significantly different between groups at baseline. They increased after the preload (effect of treatment, P = 0.0001), and the premeal levels were lower in the young subjects than in both older groups (treatment x type interaction, P = 0.008; time x type interaction, P = 0.006; treatment x time x type interaction, P = 0.0015), with no difference between the older groups. Fasting plasma insulin concentrations were higher at baseline in the well-nourished older (9.34 ± 2.59 mU/liter) than in both the undernourished older (2.94 ± 0.4 mU/liter; P = 0.007) and well nourished young (4.42 ± 0.47 mU/liter; P = 0.03) subjects (effect of type, P = 0.017), with no significant difference between the latter two groups (P = 0.5). Insulin levels increased after the preload (effect of treatment, P = 0.0001), and premeal insulin concentrations were not significantly different between the groups (effect of type, P = 0.09; treatment x time x type, P = 0.13).
Plasma CCK concentrations (Fig. 3a).
Plasma CCK concentrations were significantly higher in the well-nourished and undernourished older subjects than in the young subjects, both fasting (7.08 ± 1.6 vs. 4.95 ± 0.8 vs. 1.4 ± 0.2 pmol/liter; well-nourished older vs. young, P = 0.002; undernourished older vs. young, P = 0.01) and during the premeal period (well-nourished older vs. young, P = 0.008; undernourished older vs. young, P = 0.02), without significant differences between the older groups. The increase in plasma CCK after ingestion of the preload was comparable in all three groups (treatment x time x type interaction, P = 0.44).
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)Plasma ghrelin concentrations were higher in the undernourished older than in the well-nourished older and young subjects, both fasting (baseline; 1320 ± 348 vs. 552 ± 132 vs. 664 ± 83 pg/ml) and when the four premeal time points were combined for analysis (both analyses; undernourished older vs. young and vs. well-nourished older, P < 0.1). Mean ghrelin concentrations (baseline to 90 min) were approximately 20% lower in the well-nourished older than young subjects, but this difference was not statistically significant (P > 0.2; power = 0.1). Plasma ghrelin concentrations decreased from -15 to 90 min (845 ± 101 to 719 ± 82 pg/ml; effect of time, P = 0.001), mainly due to the decrease after preload ingestion (877 ± 134 to 654 ± 95 preload day, 814 ± 149 to 783 ± 133 non-preload day; treatment x time interaction, P = 0.001). Although the absolute decline in ghrelin concentrations after the preload was greatest in the undernourished older subjects (134 ± 39 young vs. 176 ± 59 well-nourished older vs. 361 ± 126 undernourished older, P = 0.15), and the percent declines were somewhat greater in both older groups that in the young subjects (18 ± 4% young vs. 26 ± 6% well-nourished older vs. 24 ± 4% undernourished older; P = 0.4), neither the absolute (type x treatment, P = 0.18; type x time, P = 0.31; type x treatment x time, P = 0.16) nor the percent declines were significantly different between groups.
Plasma GLP-1 concentrations (Fig. 3c).
Plasma GLP-1 concentrations were similar in all three groups, both at baseline (effect of type, P = 0.13) and premeal (effect of type, P = 0.7). GLP-1 levels increased comparably in all groups after the preload.
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Discussion |
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There is no consensus about the best method of diagnosing mal/undernutrition in older people. Various criteria have been used (16, 37, 38). We used previously described criteria based on weight loss and reduced BMI, food intake, and serum albumin concentration (16). Although all subjects in the undernourished groups qualified on the basis of a low BMI alone, they also had other indicators of reduced nutrition, with significantly lower calf and midarm circumferences, dairy food intake, and MNA scores (with and without allowance for body weight) than the other groups. The MNA is a screening tool for undernutrition in older people that involves anthropometric measurements and a questionnaire assessing such factors as food intake (type and frequency), weight loss, and medications, but not blood sampling (26). A score of less than 24 out of 30, present in 6 of 8 undernourished subjects in this study, but in none of the other subjects, is associated with subsequent adverse outcomes, such as increased rates and durations of hospitalizations and falls over the following year (39). Serum albumin concentrations were significantly lower in the undernourished older than young subjects, suggesting protein deficiency, but prealbumin and retinol-binding protein were not reduced, making severe malnutrition unlikely. The undernourished older subjects in this study are therefore likely to be representative of older, community-dwelling people at risk of developing severe protein energy malnutrition and its complications, who should perhaps be targeted for some form of nutritional intervention.
A possible limitation of this study is that we only studied women. This was largely for ease of recruitment. Nevertheless, women make up the majority of elderly people, and we have found previously no difference between men and women in the proportion of community-dwelling older people who are undernourished (39). The number of subjects studied was relatively small. A type 2 error would not seem to account for the failure to detect higher plasma CCK concentrations in undernourished than well-nourished older subjects (they were nonsignificantly lower) or reduced food intake after the preload in the undernourished subjects (it increased nonsignificantly), but may account for the failure to detect a significant reduction in plasma ghrelin concentrations and baseline (fasting) hunger ratings in healthy older compared with young subjects. Plasma ghrelin concentrations were 20% lower in the older than in the young well-nourished subjects. This difference was not statistically significant, but the study was underpowered to examine this issue; we would have had to study 136 subjects/group for this difference to achieve significance. Rigamonti et al. (21) studied a similar number of well-nourished subjects (7 older and 12 young) using the same ghrelin RIA and reported that plasma ghrelin concentrations were significantly (
35%) lower in the older than the young subjects. However, the lower ghrelin concentrations in both studies may have been an effect of body size rather than age. The older subjects had higher BMIs than the young subjects in both our study (3.2 kg/m2 greater) and that by Rigamonti et al. (3.8 kg/m2 greater), and plasma ghrelin levels were inversely related to body size and BMI (21, 40). Larger studies that take into account body composition and size are required to determine the effect of aging on ghrelin metabolism and plasma concentrations.
The finding of reduced food intake in older subjects is consistent with previous observations (1, 2, 13, 14, 34, 35, 41, 42), as is equivalent suppression of food intake by ingestion of a nutrient preload in well-nourished older and young subjects (35). In contrast, Rolls et al. (34), using a larger preload than ours and a shorter time between preload and test meal, reported greater suppression of food intake in young than older healthy subjects. This may reflect different study designs; the extent of suppression of subsequent food intake by a nutrient preload is dependent on preload size and the time between preload and test meal (43, 44).
Postmeal suppression of appetite and subsequent food intake is mediated in part by the meal-induced release of gut peptides, including CCK. Intravenous infusion of CCK decreases (13, 45, 46) and infusion of the CCK-A receptor antagonist loxiglumide increases (47) food intake in humans. Plasma CCK concentrations are higher in healthy older than in young adult subjects (13, 14, 15). We have shown that sensitivity to the satiating effect of exogenous CCK is at least retained and may even be increased in healthy older adults (13), suggesting that increased CCK-mediated satiety may be a mediator of the anorexia of aging. Berthelemy et al. (16), using the same criteria for malnutrition as in this study, reported higher plasma CCK concentrations in malnourished than in well-nourished older subjects. In contrast, we found no difference in plasma CCK concentrations between undernourished and well-nourished older subjects, although they were significantly higher in both groups of older subjects than in the young adults. Furthermore, the undernourished subjects did not have a greater reduction in voluntary food intake after ingestion of the nutrient preload, as we had hypothesized. Indeed, they failed to suppress at all, in contrast to both older and young well-nourished subjects. This finding and the equivalent CCK concentrations in both older groups are evidence against postprandial satiety mediated by increased meal-induced CCK activity as a major contributor to anorexia in the elderly.
Although ghrelin stimulates hunger and food intake (17, 18), by far the highest circulating ghrelin concentrations in this study were in the underweight, undernourished, older subjects. We cannot exclude the possibility that ghrelin activity is reduced in undernourished, older subjects, for example, due to marked ghrelin resistance or increased concentrations of bioinactive ghrelin. Nevertheless, the finding of raised ghrelin concentrations in the undernourished, older subjects suggests that reduced ghrelin activity is not the cause of the anorexia of aging. It is more likely that increased plasma ghrelin concentrations represent a compensatory response to undernutrition at any age, as they are consistent with the rise in circulating ghrelin concentrations that occurs with fasting in normal weight individuals (19), with diet-induced weight loss in the obese (30), and with anorexia nervosa in young adults (32) and with the decrease in ghrelin concentrations that acutely follows food ingestion (19) and occurs in patients with anorexia nervosa as they increase their food intake and body weight (32). The failure of nutrient ingestion to suppress subsequent voluntary food intake in the undernourished subjects cannot be attributed to failure to suppress plasma ghrelin concentrations. Ghrelin levels fell at least as much in the undernourished as in the well-nourished older and young subjects, suggesting that the suppressive effects of food ingestion on ghrelin concentrations do not diminish with aging or undernutrition.
We used VAS to assess appetite ratings. They are often used in feeding studies in healthy young and older adults (13, 14, 28, 34, 35, 36, 41, 42, 43, 44). In young adults they are reproducible, and the hunger ratings correlate significantly with food intake at subsequent test meals (48, 49). We have recently found similar and stronger relations between VAS ratings and food intake in healthy older subjects (50). Using these scales, healthy older people consistently rate themselves as less hungry than healthy young adults (13, 34, 41, 42). This age-related reduction in hunger appears to be enhanced in undernourished older subjects, who were less hungry in the fasted state in this study than both other groups, although only significantly less than the young subjects. Reduced basal hunger and appetite may therefore be a more important contributor to age-related undernutrition than increased (meal-induced) satiety.
The cause(s) of this reduced appetite is unknown. It is apparently not due to increased circulating CCK concentrations, as these were nonsignificantly higher in the well-nourished compared with the undernourished older subjects despite their higher hunger ratings. Similarly, age-related reductions in ghrelin concentrations do not provide an explanation; these were much higher in the undernourished older women than in the young women. GLP-1 is another putative suppressor of appetite and food intake (11), but there was no difference in plasma GLP-1 concentrations between older and young subjects or between undernourished and well-nourished older subjects. Numerous other hormones and neurotransmitters are now known to affect appetite and food intake. Altered activity of or sensitivity to one or more of these agents could contribute to the reduction in appetite that accompanies normal aging and its apparent amplification in the undernourished elderly.
In conclusion, the undernourished older women in this study were less hungry, more full, and had higher plasma ghrelin concentrations than the other groups and had equivalent increases in CCK and decreases in ghrelin plasma concentrations as the well-nourished older subjects in response to the nutrient preload. Unlike both the well-nourished older and young subjects, however, subsequent voluntary food intake was not suppressed by ingestion of the oral nutrient preload in the undernourished older subjects. This suggests that reduced basal hunger and appetite may be a more important cause of the anorexia of aging than increased meal-induced satiety.
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Footnotes |
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Abbreviations: BMI, Body mass index; CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; MNA, Mini Nutritional Assessment; PEM, protein energy malnutrition; VAS, visual analog scales.
Received October 24, 2002.
Accepted April 10, 2003.
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, P < 0.05). Baseline fullness was greater in undernourished older subjects than in both other groups (#, P < 0.05). Premeal fullness was greater on the preload than the control day (
