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1 Department of Nutrition;
2 Section of Neurobiology, We previously reported that aging Fischer 344 (F344) rats
display a spontaneous, rapid loss in body weight associated with decreased food intake near the end of life. Here, we describe the
specific changes in feeding patterns underlying this reduced intake.
Nine male F344 rats, aged 25 mo, were monitored continuously until 7 days after the onset of spontaneous rapid weight loss (i.e.,
senescence). Regardless of age at death (25.5-32.5 mo), all
senescent rats demonstrated a similar pattern of decreased food intake.
They ate significantly smaller meals (g/meal) of shorter duration
during spontaneous rapid weight loss compared with their period of
weight stability (presenescence). However, no differences occurred in
the number of meals eaten per day. Rapid weight loss had no effect on
the rats' selection of preferred diets. Serum levels of the hormone
leptin were not higher in the senescent vs. age-matched presenescent
rats, nor was the incidence of common disease different in senescent
animals. Moreover, the area of the pituitary-hypothalamus interface,
measured to identify possible hypothalamic compression, was similar in
the senescent rats and an age-matched, presenescent control group
despite significantly greater pituitary size in the former. Our data
show that simultaneous with rapid spontaneous weight loss, aging rats
demonstrate significant changes in feeding patterns suggestive of
earlier satiation. These feeding alterations do not result from loss of
ability to select for palatable food, elevated serum leptin levels,
specific pathology, or hypothalamic compression.
anorexia of aging; feeding; senescence
FOOD INTAKE IS A BASIC physiological function of
animals, and its homeostatic regulation is vital. Aging, especially in
its advanced stages, is associated with declines in both food intake and body weight (7, 8). This decreased eating, called the "anorexia
of aging," appears to develop without definitive cause in healthy
elderly persons and has been proposed to constitute a prelude to
"natural" death (22). Although several investigators have
characterized changes in feeding behavior in the aged, the mechanisms
reflecting age-related alterations in food intake have yet to be
elucidated. Clarkston et al. (4) reported that older persons tended to
be more satiated after eating and less hungry during fasting compared
with younger subjects. Roberts et al. (32) observed that in response to
under- or overfeeding, healthy older men had substantially reduced
ability to maintain constant energy balance compared with young men.
Similarly, elderly subjects do not show appropriate energy compensation
after being given a premeal feeding (33). Together, these results
strongly suggest that aging is associated with a decline in the
homeostatic mechanisms that influence hunger, appetite, and food
intake. However, the etiology of these age-related alterations has been
difficult to ascertain, in part because declines in food intake are
often subtle and not recognized until secondary (confounding)
pathologies have developed.
We observe that near the end of their known life spans, Fischer 344 (F344) rats develop a syndrome characterized by decrements in a number
of homeostatic functions, including food intake, body weight
regulation, thermoregulation, and circadian rhythmicity (23, 24). This
syndrome, which does not appear to be related to any known disease
process, is followed by death within an average of 3 wk. We believe
that the syndrome seen in these animals provides an appropriate model
for determining possible factors involved in the pathogenesis of
age-related anorexia. By using this experimental approach to define the
relationship between age-related decreases in food intake and body
weight, we can work toward determining both the precise sequence of
these events, which aids in establishing the cause of weight loss
(e.g., weight loss preceding depressed food intake may suggest
disease-associated cachexia), and the specific alterations in feeding
behavior resulting in reduced food intake.
The purpose of this investigation was to test the hypothesis that the
decreased food intake observed in aging F344 rats near the end of their
life spans 1) begins at
approximately the same time as the onset of spontaneous rapid weight
loss and 2) is a reflection of
significant alterations in feeding behavior. To this end, aged rats (25 mo of age) were monitored continuously on a food intake analysis system
as they passed from their period of weight stability into spontaneous
rapid weight loss. For each rat, feeding behaviors between the periods
were compared. In addition, we evaluated possible factors contributing
to decreased food intake in these animals, including alterations in
food preferences, changes in serum levels of the hormone leptin,
pathology, and possible compression of the hypothalamus by the
pituitary.
Animals and animal care. Male F344
rats aged 25 mo (n = 13) and 8 mo
(n = 7) were obtained from the
National Institute on Aging colony maintained by Harlan Sprague Dawley
Laboratory (Indianapolis, IN). Experiments were approved by the
University of California Animal Care and Use Committee. On arrival,
animals were placed into a laminar flow unit (Duo-Flo; Lab Products,
Maywood, NJ) that circulates nonrecyclable air through high-efficiency
particle air filters at a constant rate, providing class 100 laminar
flow clean air. Animals were housed individually in hanging wire-bottom cages (20 × 25 × 18 cm) and maintained at 25-26°C
and 50% humidity on a 12:12-h light-dark cycle (lights on at 0600, off
at 1800). Rats were provided with ground NIH-31 laboratory chow (Teklad Research Diets, Indianapolis, IN) and distilled water ad libitum. Three
25- mo-old rats were excluded from the experiment because they began
spontaneous rapid weight loss before adequate weight-stable data could
be collected. Also excluded was one rat that developed a lipoma and
continued to gain weight despite decreased food intake. The final
number of these 25-mo-old rats used in data analysis was nine. In
addition, serologic analyses (for RCV/SDAV, Sendai, PVM, KRV,
Mycoplasma pulmonis, H-1, Reo-3, TMEV,
LCM, MAD, CAR bacillus) were performed on all animals used in the
study, and no active infection was found.
Experimental protocol.
After 7 days of acclimation to our facility, rats were individually
housed in polycarbonate metabolic cages designed so that the food cup,
which was connected to the main living area with a tunnel, rested on a
scale (Denver Instrument, Arvada, CO). The living area, tunnel, and
food cup were designed so that food spillage was collected onto the
scale. The scale's digital output of food measurements was sent to the
computer every 15 s, and changes of 100 mg were time-stamped and
recorded onto a spreadsheet (Microsoft Excel) using SoftwareWedge (TAL
Technologies, Philadelphia, PA). Food was replenished, and rats were
manually weighed and examined on a daily basis. For each animal, water
was measured at the beginning and end of every 3-day period, and the
difference was divided by three and expressed as average daily water
intake. Throughout the experiment, animal handling and cage cleaning
were performed at varying times in the day to minimize entrainment to a
schedule. Nontranslucent boards were placed between cages to reduce the influence of one rat's sleep/wake/eating patterns on those of its
neighbors.
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
70°C until analysis. An age-matched,
weight-stable rat not displaying rapid weight loss was killed following
the same protocol to serve as a control for the weight-loss (senescent)
rat. In addition, 5 wk of food intake data were collected from four
younger rats (8 mo old at the start of the measurements) to ensure that
the observed eating patterns of the weight-loss group did not reflect
peculiarities inherent to the environment of the food intake collection
system. At the end of this time, the young rats were anesthetized with halothane, and serum was collected as above. All young animals were
killed between 1000 and 1200 in the nonfasted state to match the
conditions for the old rats.
Food intake analysis. The primary objective of the present investigation was to determine whether changes in the pattern of food intake of aging rats occur at approximately the same time as the onset of the spontaneous rapid loss in body weight near the end of life. Because the loss in body weight is independent of the animal's age, data analysis using time as an independent variable was not possible. That is, the use of a biological marker for age (spontaneous rapid weight loss) precluded analysis of food intake at a specific chronological time point. Thus we divided the food intake data from each older rat into five separate time periods: early, middle, late, and immediate pretransition weight stable and rapid weight loss (Fig. 1). The early, middle, and late weight-stable periods were divided into equal one-thirds, and a continuous 7-day segment at the midpoint within each of the periods was selected for analysis. The immediate pretransition period represented a 7-day period just before the onset of spontaneous rapid weight loss in the aging rats. The weight-loss period extended for 7 days, during which rats lost, on average, 5% of their pretransition weight. Because the young rats did not undergo spontaneous rapid weight loss, food intake data were divided into early, middle, and late weight-stable periods as described above. The following feeding behaviors were examined: total intake (g) per day, total intake (g) per day per metabolic body weight (kg0.67) (17), meals per day, total intake (g) per meal, meal duration, intermeal interval, eating rate (g) per minute, and time of eating. A meal was defined as the consumption of at least 200 mg ground chow within 15 min, preceded and followed by at least 15 min of no feeding.
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Response of senescent rats to a palatable diet. We conducted a study to test the effect of rapid spontaneous weight loss on selection of a palatable diet. Six weight-stable male F344 rats, age 25 mo and differing from the rats used for meal pattern analysis, were maintained individually in hanging wire-bottom cages as described in Animals and animal care. They were given a choice between a basal semipurified diet [65% of total kcal = carbohydrate (32.5% cornstarch, 32.5% sucrose); 13% protein (casein); 22% fat (hydrogenated oil)] and a high-fat, high-sucrose diet (HFHS) [52% of total kcal = fat, 36% sucrose, 12% protein] over a 2-day period. The basal diet provided 4.1 kcal/g, and the HFHS diet contained 5.1 kcal/g. The HFHS diet was then removed, leaving only the basal diet until the rats began spontaneous rapid weight loss, at which time the HFHS diet was provided along with the basal diet until the time of death. Body weights and measurements of food intake (in/out weight of each separate food cup, accounting for spillage) were recorded every day between 0800 and 1000 until the animal died of natural causes or was euthanized because of moribundity.
Because this study did not differentiate selection for caloric density from taste preference, we designed a second experiment to test more specifically the ability of senescent rats to respond to preferred tastes. Eight additional weight-stable male F344 rats, age 25 mo, were offered a choice between the basal semipurified diet (described above) flavored with vanilla (1.0% weight of diet) and the basal diet flavored with lemon (1.0%) (flavors in solution from McCormick, Hunt Valley, MD). Food coloring was added to the diets to differentiate spillage. To account for any site preference, the positions of the food cups were alternated every day. To control for possible color/wavelength preference, coloring of the diets was alternated every 4 wk. Food intake and body weights were measured as described for the HFHS diet study.Necropsy. Necropsies were performed on the senescent and age-matched, weight-stable animals by personnel at the School of Veterinary Medicine's Comparative Pathology Laboratory. The following tissues were collected for routine histopathology: kidneys, adrenal glands, liver, spleen, lungs, testicles, brain, and pituitary. Because pituitary cystic adenomas are a common observation in F344 rats older than 24 mo of age (21), the area of both the pituitary gland and the pituitary-hypothalamus interface was determined. The brain and pituitary gland were sectioned along the midline longitudinally. Images of hemotoxylin and eosin-stained sections of the hypothalamus and pituitary were captured at 748 × 548 pixels using a digital camera (ProgRes 3008, Kontron Elektron) that was mounted on a microscope (Zeiss Axioscope; Carl Zeiss, Thornwood, NY) connected to an IBM/PC computer. Images were analyzed on a Power Macintosh computer using NIH image 1.61 software (Research Service Branch of the National Institute of Mental Health, Bethesda, MD). Pituitary and pituitary-hypothalamus interface measurements from one senescent animal were excluded from analysis because the values exceeded two standard deviations from the mean. Remaining data collected from this animal were not markedly different from that of other senescent rats and thus were included in analysis.
Serum analysis. Serum leptin was measured by radioimmunoassay using a diagnostic kit from Linco Research (St. Charles, MO). Serum total and free thyroxine (T4) and triiodothyronine were measured by radioimmunoassay using diagnostic kits from INCSTAR (Stillwater, MN).
Statistics.
Data were analyzed using analysis of variance to evaluate possible
differences in the main effect. When differences in main effect were
found, Fisher's protected least-significant difference test was used
to evaluate differences between individual means. Differences were
considered significant at P 
0.05. All means are presented
±SE.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Body weight. The age at which spontaneous rapid weight loss began in the senescent rats varied from 778 to 975 days. Mean weight loss occurring during the 7-day weight-loss period was 5.2%, with the greatest being 7.3% and the least 3.4%. The average weight of the rats before rapid weight loss was 401 ± 1.7 g. This value was significantly higher than that of the age-matched, weight-stable controls measured at the same time (386 ± 3.8 g). The average weight of the young rats was 396 ± 7.4 g, which was not different from that of the other groups.
Food intake analysis. Food intake (g eaten/day and g eaten/day × kg0.67 body wt) and body weight in the old (25-32.5 mo) rats displayed two rates of decline. Before rapid weight loss, both variables showed relatively small incremental decreases among time periods, with an average 0.09 ± 0.02% body wt loss/day and an average decline of 0.13 ± 0.00% in g eaten/day occurring over the entire weight-stable period. The transition to the weight-loss period was marked by a sudden increase in the rates of decline (average 0.74 ± 0.09% body weight loss/day; average 5.04 ± 2.53% decrease in g eaten/day). To illustrate the relationship between body weight and daily food intake, data for three representative old rats (from a total of 9) are presented in Fig. 2. Although there was variation in the shape of curves for each animal, all exhibited a rapid decline in food intake (g eaten/day) at approximately the same time as the rapid loss in body weight. This concurrent decline in food intake and body weight occurred in senescent rats regardless of age (in Fig. 2, note the differences in experimental day at which decline occurred).
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Response of senescent rats to a palatable diet. All animals preferred the HFHS to the basal diet during both their weight-stable and rapid-weight-loss periods (data not shown). Similarly, rapid weight loss had no effect on rats' selection for a palatable isocaloric diet. Between the weight-stable and weight-loss periods, the percentage of daily food intake of the lemon- vs. vanilla-flavored diets did not significantly differ (6.82 ± 2.50 and 93.17 ± 2.50% lemon and vanilla diet, respectively, during weight loss; 10.96 ± 3.09 and 89.04 ± 3.09%, lemon and vanilla diet, respectively, during weight stability) (Fig. 3).
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Serum leptin. As shown in Table 2, both the senescent and age-matched weight-stable groups had significantly lower leptin levels than did the young rats. The senescent rats displayed the broadest range of leptin values (1.5-13.2 ng/ml), which contributed to the large standard error for this group. Although two of the nine senescent rats displayed leptin levels similar to those found in young animals, there was no basis on which to discard these high values, and thus they were included in the analysis. The other seven senescent rats tended to have low leptin levels (average 3.10 ± 0.53 ng/ml).
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Serum thyroid hormones. There was a significant main effect of physiological state (senescence, age-matched weight stability, youth) on total and free T4, which was reflected in a general decline moving from the young to age-matched, weight-stable to the senescent groups (Table 2). Total serum T4 concentrations were significantly lower in the senescent vs. young rats, and free T4 was significantly lower in the senescent and age-matched, weight-stable versus the young rats. There were no significant differences in total or free triiodothyronine among the groups.
Necropsy. Overall, there was a greater incidence of disease in the senescent vs. age-matched, weight-stable rats. However, the occurrence of pathology common to animals within the senescent and age-matched, weight-stable groups did not differ. All senescent and age-matched, weight-stable rats displayed testicular adenomas, adrenal capsular fibrosis, and some degree of renal disease (Table 3), findings consistent with literature describing pathologies of the F344 strain (5, 21). Pituitary gland pathology was observed in both groups, with two of the nine senescent rats displaying pituitary cystic adenomas. Pituitary area for senescent rats was significantly greater than that for age-matched, weight-stable rats; however, the average area of the pituitary-hypothalamus interface for both groups of animals was not significantly different (Table 4).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Our previous investigations suggest that spontaneous rapid weight loss in aging male F344 rats is associated with decreased food intake (23). In the present study we found significant alterations in feeding patterns that occurred near the time of onset of the spontaneous rapid weight loss. Specifically, rats ate meals of smaller size and shorter duration during spontaneous rapid weight loss than they did during their weight-stable period. However, the number of meals eaten per day and the eating rate of these rats generally did not differ between their rapid weight-loss and weight-stable periods. We suggest that early satiation, rather than a significant loss in food-seeking drive, is a factor underlying the reduced food intake observed during spontaneous rapid weight loss.
Palatability/reward is proposed to contribute to continued eating of a meal rather than to meal initiation (20). It is possible that early meal termination in senescent rats reflects a loss in the pleasure response to food. We tested this possibility by comparing food preferences displayed by rats during their weight-stable vs. weight-loss periods. Whether selecting between diets of differing macronutrient/kilocalorie content or of varying flavors, rats demonstrated the same preferences before and during spontaneous rapid weight loss. This implies that taste (broadly defined as the chemical senses of taste and olfaction) and the pleasure response to palatable foods are generally conserved in the senescent rats and function well enough to maintain selection for specific macronutrients and flavors. The reward response that results in selecting particular foods may be mediated by hypothalamic endogenous opioids (27). There has been reported a reduced effectiveness of the opioid feeding pathway in aging rodents (11, 19), but whether the attenuation is great enough to affect food intake is not known. In humans, age-related changes in taste and pleasantness of food have not shown causal relationships with altered eating (34) and are thought to have minimal effects on overall energy intake (26).
Another factor regulating food intake is the adipose hormone leptin, which is thought to act within the hypothalamus to reduce food intake when body fat stores are replete (3). We considered the possibility that inappropriately elevated leptin concentrations were contributing to decreased feeding in the senescent rats. However, serum leptin levels were significantly lower in the senescent versus young rats, reflecting the loss of body fat in the former and providing evidence that the suppression of food intake in the senescent rats was not due to high circulating levels of leptin. Interestingly, we found that serum leptin concentrations in senescent and age-matched, weight-stable animals were not significantly different. This was unexpected because we had previously shown a significantly higher body fat percentage in weight-stable versus senescent rats (23), and studies have demonstrated a positive correlation between adiposity and serum leptin levels (16). In our prior study (23), we allowed senescent rats to lose an average 10.5% body weight before euthanasia, which is nearly twice the amount of weight loss in senescent animals in the present experiment. It is possible that a significant reduction in circulating leptin levels is not seen until body fat loss exceeds that experienced by the senescent rats in this study. However, recent data from our laboratory (unpublished data) suggest that the positive correlation between adiposity and serum leptin levels observed in young and aged presenescent rats remains in the senescent animal.
An alternative reason for the lack of significant differences in leptin concentrations between senescent and age-matched, weight-stable rats may involve our study design, which allowed rats on the meal pattern analysis system free access to food. We sought to determine serum leptin levels as they exist during the normal feeding routine of the rats. Yet serum leptin levels vary with short-term (24 h) fasting as well as glucose infusion (12). Thus, if varying states of feeding/fasting existed between the animal groups, leptin assay results may have been affected. However, because seven of the nine senescent rats ate a meal within 3 h of the time when food was last accessible to animals before euthanasia, the mean leptin value for the senescent rats reflects the fed state. Because this mean was not higher than that of the age-matched, weight-stable rats, we cannot attribute the decline in food intake in the senescent rats to abnormally elevated leptin levels.
Although circulating levels of leptin do not appear abnormal in senescent rats, there may exist an alteration in the proposed interactions within the brain between leptin and hypothalamic neuropeptide Y (NPY). Energy balance is thought to be achieved, in part, by a homeostatic loop in which leptin-mediated suppression of food intake involving reduced NPY expression and release is balanced by NPY-mediated stimulation of food intake (41). Because age-associated reductions in hypothalamic NPY levels have been reported (13, 18), senescent weight-loss rats may have inappropriately low NPY levels, reflecting an altered relationship between NPY release and circulating levels of leptin. Thus a primary defect in energy imbalance in the senescent rats may reside in the NPY part of the feedback loop. We are currently investigating this possibility.
It has been commonly accepted that rats eat most of their 24-h food intake during the night. Our results show, however, a relatively equal distribution of feeding between the 12-h light and dark cycles. In 20 published papers on this topic, the majority used rats aged 6 mo or less, and nearly one-half chose the Sprague-Dawley strain. It has been reported that the night/day distribution of food intake is affected by age, with older rats eating 44-51% (30) to 55-60% (6) of their food during the dark phase. In addition, there is an influence of strain differences on dark/light meal distribution and consistency of eating schedule (6, 10). It seems reasonable that laboratory animals with continuous access to food might develop feeding schedules that are not tightly coupled to light-dark cycles. The reason for the significantly greater percentage of dark cycle food intake in the old animals during their early weight-stable compared with other time periods is not clear. That the young animals did not display this pattern suggests that a peculiarity in the food analysis system was not the cause. The old rats could have been exhibiting residual eating patterns during the early part of our study, which reflected a feeding schedule entrained before their arrival at our facility.
The lower levels of total and free T4 in the senescent versus young animals are consistent with a metabolic adaptation to conserve energy as food intake declines. Reduced food intake is associated with low serum thyroid hormone (36, 40), and the progressive decline in total and free T4 concentrations moving from the young to age-matched, weight-stable to the senescent rats generally corresponds with the differences in grams eaten per day per metabolic body weight between young and old rats and between weight-stable and weight-loss time periods in old rats (Tables 1 and 2).
Histopathological analysis showing similar rates of common disease incidence in senescent and age-matched, weight-stable groups supports our premise that the spontaneous rapid weight loss does not reflect disease-associated cachexia. Whereas senescent animals showed a higher overall incidence of pathology, there was no disease specific to this group that could account for the spontaneous rapid loss in body weight. As shown in Table 3, pathology common to the senescent rats (involving kidneys, adrenals, and testes) was also common to age-matched, weight-stable controls. Disease-induced functional changes in these tissues could affect feeding [e.g., via changes in glucocorticoid secretion from the adrenals (38), through impaired hepatic neural output and glucose metabolism (28), by uremia resulting from decreased kidney function (1), or from cytokines released from testicular tumors (31)]. However, this is not likely the cause of the rapid decline in food intake in senescent rats in light of the fact that the weight-stable group, which exhibited similar pathology, maintained its level of feeding. We have previously shown that senescent rats do not exhibit symptoms of cachexia, such as increased resting metabolic rates, decreased serum total protein or albumin, or increased urinary creatinine or urea nitrogen (23).
The implications of pituitary gland enlargement on brain function are uncertain, partly due to the observation that rats with massive pituitary tumors causing destruction of surrounding tissue can maintain normal behavior and the appearance of health (37). Although only two senescent animals displayed pituitary cystic adenomas, average pituitary gland area of the senescent rats was significantly greater than that for age-matched, weight-stable controls. This expansion of the pituitary did not, however, result in a significant difference in the area of the pituitary-hypothalamus interface between the groups. Therefore, although altered feeding in senescent rats is not likely the result of hypothalamic physical damage secondary to pituitary enlargement, we cannot rule out an effect of pituitary gland dysfunction. Food intake has been shown to be affected by pituitary hormones such as oxytocin (25), vasopressin (14), prolactin, somatostatin, and growth hormone (2). We plan to evaluate pituitary secretory function in senescent rats by measuring circulating hormone levels.
In conclusion, we found that the decline in food intake that occurs concurrently with spontaneous rapid weight loss near the end of life in the rat reflects significant alterations in feeding patterns that are characteristic of early satiation. These alterations are not caused by an inability to select palatable food, increased serum leptin levels, common disease, or hypothalamic compression. Other potential mechanisms that may explain these changes are under study in our laboratory.
Perspectives
Our data suggest that the decline in food intake that occurs simultaneously with spontaneous rapid weight loss involves significant changes in feeding patterns. The particular changes observed (smaller meal size and shorter meal duration) imply that satiation is accelerated. Such eating behavior in the face of rapid weight loss indicates disruption of the normal regulation of energy balance and may involve the central nervous system, specifically the hypothalamus. This interpretation stems from our working hypothesis, which implicates the hypothalamus in the transition from gradual aging to rapid senescence. Our findings in the present study suggest that one or more hypothalamic neurochemicals that mediate satiation and hunger are involved in spontaneous rapid weight loss near the end of life. NPY is one such candidate, considering both its potent ability to stimulate food intake and the findings from numerous laboratories of age-associated declines in NPY concentrations. Other potential effectors are cholecystokinin (29), orexin (35), and serotonin (9). In future investigations we plan to evaluate levels of and responsiveness to these peptides in aged rats undergoing spontaneous rapid weight loss.The findings that changes in food intake and body weight occur at various times in the rat's life span and display different rates of decline are suggestive of two or more rates of age-associated functional loss. The negative energy balance during presenescence that progresses gradually may reflect compensatory action of some components of the food intake regulatory system that partially offset impairments in other components. Senescence, which is characterized by markedly greater rates of decline in food intake and body weight, could represent functional loss beyond the point where compensatory mechanisms are effective.
It is premature to conclude that the rapid losses in food intake and body weight in the senescent rat can serve as markers of change in rates of aging in other mammals. Nonetheless, it is noteworthy that strains of other rodents as well as humans demonstrate similar age-related changes in eating and/or body weight. In humans, the gradual decline in food intake and body weight (15, 26) is, in some cases, followed by pronounced, unexplained anorexia and weight loss leading to death. These declines, which define part of the "geriatric failure to thrive" syndrome (39), may represent processes with underlying mechanisms common to those mediating reduced feeding and spontaneous rapid weight loss in our rat model. By gaining a better understanding of how physiological processes, such as energy balance, are altered with aging, we seek to offer insights into the biology of aging and contribute to the development of efficacious clinical approaches to debilitating age-related changes.
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ACKNOWLEDGEMENTS |
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We thank Eduardo Hernandez, Annette Gabaldon, Teresa Hutsell, and Robyn Parks for technical assistance and Jock Hamilton for insightful comments.
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FOOTNOTES |
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This work was supported by National Institute of Aging Grant AG-06665, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-35747, and a gift from the California Age Research Institute.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: C. A. Blanton, Dept. of Nutrition, One Shields Ave., Univ. of California, Davis, CA 95616.
Received 8 May 1998; accepted in final form 21 July 1998.
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REFERENCES |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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1.
Anderstam, B.,
A. H. Mamoun,
P. Sodersten,
and
J. Bergstrom.
Middle-sized molecule fractions isolated from uremic ultrafiltrate and normal urine inhibit ingestive behavior in the rat.
J. Am. Soc. Nephrol.
11:
2453-2460,
1996.
2.
Bray, G. A.
Nutrient intake is modulated by peripheral peptide administraiton.
Obesity Res., Suppl.
4:
569S-572S,
1995.
3.
Caro, J. F.,
M. K. Sinha,
J. W. Kolaczynski,
P. I. Zhang,
and
R. V. Considine.
Leptin: the tale of an obesity gene.
Diabetes
45:
1455-1463,
1996[Medline].
4.
Clarkston, W. K.,
M. M. Pantano,
J. E. Morley,
M. Horowitz,
J. M. Littlefield,
and
F. R. Burton.
Evidence for the anorexia of aging: gastrointestinal transit and hunger in healthy elderly vs. young adults.
Am. J. Physiol.
272 (Regulatory Integrative Comp. Physiol. 41):
R243-R248,
1997
5.
Coleman, G. L.,
S. W. Barthold,
G. W. Osbaldiston,
S. J. Foster,
and
A. M. Jonas.
Pathological changes during aging in barrier-reared Fischer 344 male rats.
J. Gerontol.
32:
258-278,
1997.
6.
Del Prete, E.,
and
E. Scharrer.
Influence of age and hepatic branch vagotomy on the night/day distribution of food intake in rats.
Z. Ernahrungswiss.
32:
316-320,
1993[Medline].
7.
Elahi, V. K.,
D. Elahi,
and
R. Andres.
A longitudinal study of nutritional intake in men.
J. Gerontol.
38:
162-180,
1983
8.
Fischer, J.,
and
M. A. Johnson.
Low body weight and weight loss in the aged.
J. Am. Diet. Assoc.
90:
1697-1706,
1990[Medline].
9.
Garrattini, S., A. Bizzi, and S. Caccia. Progress in
assessing the role of serotonin in the control of food intake.
Clin. Neuropharmacol. 11, Suppl.: S8-S32, 1988.
10.
Glendinning, J. I.,
and
J. C. Smith.
Consistency of meal patterns in laboratory rats.
Physiol. Behav.
56:
7-16,
1994[Medline].
11.
Gosnell, B. A.,
A. S. Levine,
and
J. E. Morley.
The effects of aging on opioid modulation of feeding in rats.
Life Sci.
32:
2793-2799,
1983[Medline].
12.
Grinspoon, S. K.,
H. Askari,
M. L. Landt,
D. M. Nathan,
D. A. Schoenfeld,
D. L. Hayden,
M. Laposata,
J. Hubbard,
and
A. Klibanski.
Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women.
Am. J. Clin. Nutr.
66:
1352-1356,
1997
13.
Gruenewald, D. A.,
B. T. Marck,
and
A. M. Matsumoto.
Fasting-induced increases in food intake and neuropeptide Y gene expression are attenuated in aging male Brown Norway rats.
Endocrinology
137:
4460-4467,
1996[Abstract].
14.
Gulati, K.,
and
A. Ray.
Effects of intrahypothalamic morphine and its interactions with oxytocin and vasopressin during food intake in rats.
Brain Res.
690:
99-103,
1995[Medline].
15.
Hallfrisch, J.,
D. Muller,
and
D. Drinkwater.
Continuing trends in men: the Baltimore Longitudinal Study of Aging (1961-1987).
J. Gerontol.
45:
186-191,
1990.
16.
Havel, P. J.,
S. Kasim-Karakas,
W. Mueller,
P. R. Johnson,
R. L. Gingerich,
and
J. S. Stern.
Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss.
J. Clin. Endocrinol. Metab.
81:
4406-4413,
1996[Abstract].
17.
Heusner, A. A.
Body size and metabolism.
Annu. Rev. Nutr.
5:
267-293,
1985[Medline].
18.
Huguet, F.,
E. Comoy,
A. Piriou,
and
C. Bohuon.
Age-related changes of noradrenergic-neuropeptide Y (NPY) interactions in rat brain: norepinephrine, NPY levels and alpha-adrenoceptors.
Brain Res.
625:
256-260,
1993[Medline].
19.
Kavaliers, M.,
and
M. Hirst.
The influence of opiate agonists on day-night feeding rhythms in young and old mice.
Brain Res.
326:
160-167,
1985[Medline].
20.
Levine, A. S.,
and
C. J. Billington.
Why do we eat? A neural systems approach.
Annu. Rev. Nutr.
17:
597-619,
1997[Medline].
21.
MacKenzie, W. F.,
and
G. A. Boorman.
Pituitary gland.
In: Pathology of the Fischer Rat, edited by S. L. E. G. A. Boorman,
M. R. Elwell,
C. A. Montgomery,
and W. R. MacKenzie. San Diego, CA: Academic, 1990, p. 485-500.
22.
McCue, J. D.
The naturalness of dying.
JAMA
273:
1039-1043,
1995
23.
McDonald, R. B.,
M. Florez-Duquet,
C. Murtagh-Mark,
and
B. A. Horwitz.
Relationship between cold-induced thermoregulation and spontaneous rapid body weight loss of aging F344 rats.
Am. J. Physiol.
271 (Regulatory Integrative Comp. Physiol. 40):
R1115-R1122,
1996
24.
McDonald, R. B.,
C. A. Fuller,
T. M. Hoban-Higgins,
and
B. A. Horwitz.
Relationship between circadian rhythm of body temperature and weight loss in aging rats (Abstract).
FASEB J.
10:
A409,
1996.
25.
Merali, A.,
and
H. Plamondon.
Pharmaco-ontogenic modulation by feeding by oxytocin, bombesin, and their antagonists.
Peptides
17:
1119-1126,
1996[Medline].
26.
Morley, J. E.
Anorexia of aging: physiologic and pathologic.
Am. J. Clin. Nutr.
66:
760-773,
1997
27.
Morley, J. E.,
and
A. S. Levine.
Involvement of dynorphin and the kappa opioid receptor in feeding.
Peptides
4:
797-800,
1983[Medline].
28.
Niijima, A.
Glucose-sensitive afferent nerve fibers in the liver and their role in food intake and blood glucose regulation.
J. Auton. Nerv. Syst.
9:
207-220,
1983[Medline].
29.
Peikin, S. R.
Role of cholecystokinin in the control of food intake.
Gastrointest. Endocrinol.
18:
757-775,
1989.
30.
Peng, M. T.,
and
M. Kang.
Circadian rhythms and patterns of running-wheel activity, feeding and drinking behaviors of old male rats.
Physiol. Behav.
33:
615-620,
1984[Medline].
31.
Plata-Salaman, C. R.,
Y. Oomura,
and
Y. Kai.
Tumor necrosis factor and interleukin 1-beta: suppression of food intake by direct action in the central nervous system.
Brain Res.
448:
106-114,
1988[Medline].
32.
Roberts, S.,
P. Fuss,
and
M. Heyman.
Control of food intake in older men.
JAMA
272:
1601-1606,
1994
33.
Rolls, B.,
K. Dimeo,
and
D. Shide.
Age-related impairments in the regulation of food intake.
Am. J. Clin. Nutr.
62:
923-931,
1995
34.
Rolls, B. J.,
and
A. Drewnowski.
Nutrition and aging.
In: Encyclopedia of Gerontology. New York: Academic, 1997, p. 429-440.
35.
Sakurai, T.,
A. Amemiya,
M. Ishii,
I. Matsuzaki,
R. M. Chumelli,
H. Tanaka,
S. C. Williams,
J. A. Richardson,
G. P. Kozlowski,
and
S. Wilson.
Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.
Cell
92:
573-585,
1998[Medline].
36.
Schalch, D. S.,
and
T. C. Cree.
Protein utilization in growth effect of calorie deficiency on serum growth hormone, somatomedins, total thyroxine (T4) and triiodothyronine (T3), free T4 index, and total corticosterone.
Endocrinology
117:
2307-2312,
1985
37.
Stein, D. G.,
and
E. J. Mufson.
Tumor induced brain damage in rats: implications for behavioral and anatomical studies with aging animals.
Exp. Aging Res.
5:
537-546,
1979[Medline].
38.
Strack, A. M.,
R. J. Sebastian,
M. W. Schwartz,
and
M. F. Dallman.
Glucocorticoids and insulin: reciprocal signals for energy balance.
Am. J. Physiol.
268 (Regulatory Integrative Comp. Physiol. 37):
R142-R149,
1995
39.
Verdery, R. B.
Failure to thrive in the elderly.
Clin. Geriatr. Med.
11:
653-658,
1995[Medline].
40.
Visser, T. J.,
G. A. van Haasteren,
E. Linkels,
E. Kaptein,
H. van Toor,
and
W. T. de Greef.
Gender-specific changes in thyroid hormone-glucuronidating enzymes in rat liver during short-term fasting and long-term food restriction.
Eur. J. Endocrinol.
135:
489-497,
1996
41.
Wang, Q.,
C. Bing,
K. Al-Barazanji,
D. E. Mossakowaska,
X. M. Wang,
D. L. McBay,
W. A. Neville,
M. Taddayon,
L. Pickavance,
and
S. Dryden.
Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat.
Diabetes
46:
335-341,
1997[Abstract].
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