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Department of Nutrition, University of California, Davis, California 95616-8669
2To whom correspondence should be addressed at 3135 Meyer Hall, University of California, Davis, Davis, CA 95616-8519.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • aging • body composition • calorie restriction • cholesterol • fructose • triglyceride • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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13% of total sugars in the food
supply in 1965 to 47% in 1985 (Glinsmann et al. 1986
).
The increase in the use of high fructose corn syrup parallels a decline
in the use of sucrose. The overall effect of this change is that the
mean consumption of fructose has increased 18% and that the
glucose-to-fructose ratio has decreased from 1.4 to 1.0 between 1977
and 1987 (Gibney et al. 1995
). Data from a recent
investigation that evaluated the food sources of added sweeteners in
the U.S. diet are consistent with these early observations and suggest
that the percentage of fructose in the diet continues to increase
(Guthrie and Morton 2000
). The potential health
importance of increased dietary fructose consumption has been a topic
of recent research.
Several investigations suggested that diets high in fructose, supplied
either as a monosaccharide or as a component of the disaccharide
sucrose, increases serum triglyceride concentrations (Albrink and Ullrich 1986
, Lock et al. 1980
,
Macdonald 1966
, Reaven et al. 1979 and 1990
, Reiser et al. 1979
, Waddell and Fallon 1973
), increases total cholesterol concentrations and
increases the LDL-to-HDL ratio (Albrink and Ullrich 1986
, Cybulska and Naruszewicz 1982
, Lock et al. 1980
, Macdonald 1966
, Reiser et al. 1981, 1979 and 1989
) and may promote adiposity
(Barnard et al. 1993
, Hallfrisch et al. 1981
, Reiser and Hallfrisch 1977
,
Rizkalla et al. 1992
). In vitro studies investigating
the effect of sucrose on lipogenic enzyme activity, hepatic synthesis
and secretion and the removal rates of triglycerides have offered
further support to the hypothesis that the consumption of a diet high
in sucrose or fructose has an effect on serum triglyceride and
cholesterol concentrations (Bacon et al. 1984
,
Kazumi et al. 1989 and 1991
, Kok et al. 1996a and 1996b
, Mamo et al. 1991
, Nassir et al. 1993
, Park et al. 1992
, Yoshino et al. 1989, 1992 and 1997
). Most of these investigations, however,
have been of relatively short duration, with the subjects or animals
being fed the experimental diets for only a few day or weeks. It is
unclear whether the results of these studies more closely reflect a
short-term feeding phenomenon. Moreover, studies in mice and rats
that investigate the lipogenic effects of dietary carbohydrates use
very young animals, typically <6 mo old. Because these animals are
still in the developmental stage of life, the results of these studies
may reflect more closely developmental changes rather than those
associated with the adult aging process.
Data describing the long-term effects of specific dietary components on normal aging are seriously limited. Understanding these effects is important, because the use of long-term feeding protocols in research to investigate the impact of nutrition on the aging process is becoming common. The purpose of this investigation was to describe the long-term effects of specific dietary carbohydrates on serum lipid concentrations and body composition. It was our specific aims to 1) establish baseline data on the effects of particular carbohydrates for use by other investigators who are interested in long-term feeding investigations in rats and 2) to evaluate the impact of long-term high fructose diets on lipogenesis. To this end, we measured serum triglyceride, total cholesterol, HDL cholesterol concentrations and the body composition of rats aged 9, 18 and 26 mo that had free access to or were restricted to 60% of mean intake of rats with free access to one of five diets that varied in carbohydrate source starting at the age of 3 mo.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Two-hundred-eighty male Fischer 344 rats (3 mo old) were obtained from
the National Institute on Aging animal colony maintained at Harlan
Sprague-Dawley Laboratory (Indianapolis, IN) and housed in clean
facilities, as described previously (McDonald et al. 1988
). Briefly, rats were housed individually in
wire-bottom hanging cages within laminar flow units (Duo-Flow;
Laboratory Products, Maywood, NJ). The rooms were maintained at a
temperature of 25–26°C with 50% humidity and a 12:12 light/dark
cycle (lights on at 0600, lights off at 1800). Rats had free access to
distilled, autoclaved water (pH 3.5). A periodic systemic necropsy was
performed on a rat chosen at random every 3 mo throughout the duration
of the experiment. On necropsy, the rats were evaluated for gross
lesions that might result from environmental contamination. Sera from
the animals were monitored for specific antibodies that would indicate
disease. All results were negative.
Diet and feeding protocol.
After 1 wk of acclimation to the housing facility (i.e., light cycle,
temperature and so on), rats were assigned to be fed one of five
isocaloric semipurified diets that differed in carbohydrate source
(Table 1
). The carbohydrate source was either cornstarch, sucrose, glucose,
fructose or equimolar fructose plus glucose. Rats were assigned to
their diet group so that initially there were no significant
differences in mean body weight between diet groups. After 2 wk of free
access to the semipurified diets, half of the rats per carbohydrate
group (total of 28 per diet group) were restricted to 60% of the mean
caloric intake of their carbohydrate-matched free access–fed rats.
Vitamin and salt contents of the restricted diets were increased by
40% to ensure proper nutrient density. The average daily food intake
of rats fed with free access (n = 5/carbohydrate group)
was determined during a 7-d period 1 wk before the start of caloric
restriction, 1 wk after the initiation of calorie restriction and
periodically between wk 15 and 25. The food intake was measured as the
difference in the weight of the food cup, corrected for spillage, at
the beginning and end of a 24-h period. There was some variability
between the free access–fed carbohydrate groups in the first 2 wk,
with the glucose- and fructose plus glucose–fed rats being fed 3
g/d more than the fructose-fed rats. By wk 25, the variability
between carbohydrate groups decreased. All of the rats with free access
to food were fed a similar amount of grams of food per day. The amount
of food fed to the calorie-restricted rats was adjusted
accordingly. The body weight of each rat was measured once a week for
the first 10 wk of the experiment and then once a month for the
remainder of the life of the rat.
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). Nonetheless, it is important to show the effect of diet
composition on life-span characteristics. Thus, after removing a
total of 150 rats at 9, 18 and 26 mo of age (n = 5 per
age, carbohydrate and calorie-intake group), 112 rats (n
= 10–16 per diet group) were allowed to live out their natural
life span or were killed when they became moribund. The survival
analysis presented here is calculated for these 112 rats. To increase
the number of rats per group, we combined groups according to the
feeding paradigm (free access or calorie restricted) and whether the
diet contained fructose (fructose, sucrose or fructose plus glucose) or
did not contain fructose (glucose or starch). We recognize, however,
that a group size of 24–32 per group is insufficient for accurate
calculation of survival characteristics. Thus, these data are presented
only to demonstrate that trends in survival characteristics in our rat
population are similar to accepted norms previously reported
(Murtagh-Mark et al. 1995
, Yu et al. 1982
). In general, the calorie-restricted rats lived
significantly longer than did the rats with free access to food
(Table 2
), as indicated by greater mean, median and upper 10% survival rates
for the calorie-restricted group. Survival characteristics were not
significantly affected by the source of dietary carbohydrate when rats
had free access to food. However, when calories were restricted, the
rats fed a diet containing fructose had a significantly greater maximum
life span than did the calorie-restricted rats fed a diet that did
not contain fructose.
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Food was removed at 0800 h, and 500 µL of blood was taken from
the tail at 1100 h in rats aged 9, 18 or 26 mo (n
= 5 rats per diet group/age). The serum was separated by allowing
the blood to clot at room temperature and then frozen at -20°C until
analysis of glucose concentration. One week after the collection of
tail blood, 3-h food-deprived, halothane-anesthetized rats were
killed by pneumothorax. Approximately 5 mL of whole blood was collected
via cardiac puncture and allowed to clot on ice. An additional 100 µL
of cardiac blood was collected in heparinized tubes for analysis of
hemoglobin and glycated hemoglobin concentration. After blood
collection, the carcass was eviscerated, weighed and stored at -20°C
until analysis of body composition was performed. The data for serum
glucose, hemoglobin and glycated hemoglobin are reported elsewhere
(Lingelbach et al. 2000
).
Body composition.
The composition of eviscerated carcasses was assessed using the method
developed by Bell and Stern (1977)
. Briefly, carcasses
were freeze dried, and the water content was determined as the
difference between wet weight and the weight after freeze drying. Fat
was extracted from the freeze-dried carcasses via ether/methanol
extraction. The fat mass was calculated as the difference between the
dried carcass and the postextraction weight. Carcasses were then
incinerated at 260°F, and the remaining ash weight was recorded. We
could not calculate carcass protein and ash weight because the
incinerated carcasses were accidentally discarded before post-ashing
weight was determined.
Serum analysis.
Serum triglyceride concentration was measured in 20 µL of serum according to an enzymatic procedure (procedure 334-UV; Sigma Diagnostics, St. Louis, MO). Total serum cholesterol concentration was measured in 10 µL of serum according to an enzymatic method (procedure 352; Sigma Diagnostics). HDL cholesterol concentration was isolated from 500 µL of serum using HDL ISOSPIN reagents that precipitate the LDL fraction of the sera (procedure 352-5; Sigma Diagnostics). The HDL concentration in the resulting supernatant was then measured with the same method used to measure total cholesterol concentration.
Statistical analysis.
Repeated measures ANOVA was used to determine possible differences in
mean body weights. Differences in the main effects and the interactions
between effects were determined by ANOVA using dietary fructose,
calorie restriction and age as independent variables. Possible
differences in mean body composition variables and triglyceride, total
cholesterol and HDL concentrations were determined from post hoc
comparison with Fisher’s PLSD. Differences were considered significant
at P < 0.05. Possible differences in survival
characteristics (median and percentile groups) attributed to dietary
fructose and/or calorie restriction were analyzed with a
2 test to determine whether the groups were from the
same distribution. Survival means were compared by one-way ANOVA
with post hoc comparison with Fisher’s PLSD.
A specific aim of this study was to establish baseline data on the effects of particular carbohydrates for use by other investigators who are interested in long-term feeding investigations in rats. This investigation is primarily a descriptive evaluation. With this specific aim, we provided means and SEM in the tables, with post hoc comparisons, and results of the higher order three-way design described in the text.
Another specific aim of this research was to determine whether dietary fructose alters lipid metabolism. The means of all five carbohydrate groups that are given in the tables do not, we believe, provide an adequate portrayal of the impact that dietary fructose has on measures of lipid metabolism. To more clearly illustrate the effect of dietary fructose on the measured variables, we also performed analyses after the diets were grouped into those that contained fructose (sucrose, fructose and fructose plus glucose) and those that did not (starch and glucose).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Rats with free access to food were significantly heavier than their
carbohydrate-matched, calorie-restricted counterparts (Fig. 1
). There was, however, a significant interaction (P = 0.0046) between the source of dietary carbohydrate and the amount of
calories consumed. Calorie-restricted rats fed a diet that
contained fructose (sucrose, fructose and fructose plus glucose) were
significantly heavier than calorie-restricted rats fed a diet that
did not contain fructose (cornstarch and glucose) (Fig. 2
). Conversely, the mean body weight of rats with free access to diets
containing fructose was significantly less than that of rats with free
access to diets that did not contain fructose.
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, 2
). Mean
maximal body weight of the cornstarch-, glucose-, sucrose-, fructose-
and fructose plus glucose–fed rats was achieved at 83, 81, 78, 76 and
76% of the group maximal life span, respectively. Carcass composition.
In general, mean values for total carcass water, fat and fat-free
weight
(FFW)3were a function of total carcass weight (Table 3
); significant differences in the total amounts of carcass water, fat
and FFW reflected differences in carcass weight. Although several
significant differences were noted among the age and carbohydrate
groups for total carcass water, fat and FFW, no consistent general
pattern was observed. The notable exception to this was the observation
that FFW declined significantly in all 26- versus 9- and 18-mo-old rats
that were calorie restricted. FFW of 26-mo-old rats that had free
access to food significantly increased (cornstarch), did not differ
(sucrose, glucose and glucose plus fructose) or declined significantly
(fructose) compared with the 9- and 18-mo-old rats.
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). Rats with free access to food had significantly greater percentages
of carcass fat than did calorie-restricted rats. The main effect of
age reflected a primarily significantly greater percent fat of the
18-mo-old rats with free access to food compared with similarly fed 9-
and 26-mo-old rats. Percent carcass fat of 26-mo-old rats with free
access to diets containing fructose was significantly less than that of
the other age and carbohydrate groups with free access to food. Percent
carcass fat of 26-mo-old, calorie-restricted rats was significantly
less than similarly fed 9- and 18-mo-old rats regardless of the type of
carbohydrate in the diet. Percent carcass fat did not differ between
calorie-restricted 9- and 18-mo-old rats in either the
fructose-containing or fructose-free groups. Percent carcass
fat of the 9-mo-old calorie-restricted rats fed diets containing
fructose was significantly greater than their age-matched
counterparts not fed fructose. Due to the two-compartmental model
for body composition (i.e., fat and FFW), significant differences among
the groups in percent carcass FFW weight were identical to those
observed for percent carcass fat. The percentage of total body water in
FFW, a measure of dehydration, did not differ significantly among the
age, feeding and carbohydrate groups (mean 69.2–70.1%).
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There was a significant main effect on triglyceride concentrations of
consumed calories and a significant interaction between age and
consumed calories (Table 4
). In all carbohydrate groups and at all ages, calorie restriction was
associated with significantly lower serum triglyceride concentrations.
The significant interaction between age and consumed calories reflected
the observation that serum triglyceride concentration increased
significantly with age in the calorie-restricted rats, but no trend
was evident in the rats with free access to food. Several individual
differences among the age and carbohydrate groups in rats with free
access to food were observed, but no consistent trend was noted.
Conversely, serum triglyceride concentration of calorie-restricted
rats was significantly greater in 26- versus 9-mo-old rats regardless
of the carbohydrate source.
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). This effect was most apparent in the calorie-restricted animals,
in which serum triglyceride concentrations of 9-, 18- and 26-mo-old
rats fed fructose are significantly greater than those of their
age-matched fructose-free counterparts.
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). In all groups, there was a significant age-associated increase in
serum cholesterol concentrations. Calorie-restricted rats had
cholesterol concentrations similar to those of diet-matched rats
with free access to food at 9 and 18 mo of age, but at 26 mo of age,
calorie restriction was associated with significantly lower cholesterol
concentrations. In the groups with free access to food, but not the
calorie-restricted group, a diet that contained fructose was
associated with significantly greater cholesterol concentrations in the
26-mo-old rats compared with age-matched rats fed diets that did
not contain fructose.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Previous investigations in humans and mice and rats that evaluated the
effect of dietary carbohydrates on serum triglyceride concentrations
suggest that diets high in fructose significantly increase serum
triglyceride levels (Albrink and Ullrich 1986
,
Lock et al. 1980
, Macdonald 1966
,
Reaven et al. 1979 and 1990
, Reiser et al. 1979
, Waddell and Fallon 1973
). Although these
investigations provide a general consensus that increasing levels of
dietary fructose result in elevated serum triglyceride levels, all of
these studies used young animals that were fed the various diets for a
specific period of the life span, usually 3–12 wk. No previous
investigation evaluated the effect of dietary fructose on indices of
lipogenesis throughout the life span. This fact is important because
some of these investigations found that serum triglyceride
concentration increases during the first few days of the diet and then
plateaus and declines after 2–3 wk. Moreover, the interaction between
dietary fructose and the energy content of the diet remains unclear
because previous investigations of the effect of carbohydrate on serum
triglyceride concentration provided the study animals with free access
to food.
Our data clearly show that diets high in fructose increase serum triglyceride concentrations in male Fischer 344 rats and that this effect is evident after 6, 15 or 23 mo of feeding (i.e., the effect is not transitory). Most important, however, is our finding that calorie-restricted rats fed diets containing fructose had significantly greater serum triglyceride concentrations than did rats not fed dietary fructose. We found that fructose per se rather than the interaction between energy intake and fructose is the factor responsible for the increase in serum triglyceride concentration.
This investigation was designed simply to describe the long-term
feeding effects of various dietary carbohydrates on variables of
lipogenesis to establish some baseline data for other investigators who
are interested in long-term feeding studies. An evaluation of
mechanisms that underlie the effect of fructose on variables of
lipogenesis was not our intent, and thus our discussion on such
mechanisms is speculative. Nonetheless, it is interesting to note that
there was no significant difference in serum triglyceride
concentrations among rats fed the high fructose diet and rats fed the
sucrose or fructose plus glucose diet, despite the fact that the high
fructose diet contained twice the amount of fructose. This observation
is in contrast to the dose response observed by others in humans
(Hallfrisch et al. 1983
, Reiser et al. 1981
). It has been proposed that the lipogenic effect of
fructose reflects differences in the hepatic metabolism of fructose and
glucose. Glucose metabolism in the liver has the potential to produce
glucose or fatty acids, whereas the metabolism of fructose has the
potential to produce glucose and both fatty acids and glycerol, the two
components of triglycerides. In a crossover design study in which male
and female subjects ingested controlled diets containing 44% of total
energy as carbohydrate with increasing proportions provided as sucrose
(2, 15 and 30% of total energy), Reiser et al. (1979)
observed a positive correlation between serum
triglyceride concentrations and the amount of sucrose in the diet in
the male but not in the female subjects after 6 wk on the experimental
diets. A similar dose response was observed in hyperlipidemic men who
ingested for a 5-wk period diets that contained increasing amounts of
fructose (0, 7.5 and 15% of total energy) and 43% of total calories
as carbohydrate (Hallfrisch et al. 1983
). Our data
indicate that there is no dose response when rats are fed a specific
carbohydrate diet for a prolonged period. We believe that the dose
response of fructose previously reported by others may be more closely
related to a short-term feeding phenomenon than to fructose per se.
Age and energy content of the diet, but not dietary fructose, were
associated with an increase in total cholesterol. An age-related
increase in total cholesterol concentration in rats with free access to
food was observed in both male and female Fischer 344 and
Sprague-Dawley rats fed nonpurified diets (Carlson et al. 1968
, Dupont et al. 1972
, Lacko and Davis 1979
, Liepa et al. 1980
, Masoro et al. 1983
, Story et al. 1976
). Fructose enhances the
increase in total cholesterol in older rats when with free access to
food. This effect of fructose was not observed in the restricted rats.
Restricted calorie intake blunted the age-related increase in total
cholesterol in the oldest group observed. This effect of calorie
restriction was also observed in diet-fed rats (Liepa et al. 1980
, Masoro et al. 1983
). Masoro et al. (1983)
reported that the age-related increase in total
cholesterol reflected an increase in HDL cholesterol. We observed that
the age-related changes in total cholesterol concentrations reflect
changes in the HDL cholesterol fraction. HDL cholesterol was
significantly lower in the 18-mo-old rats than in the younger 9-mo-old
rats. Overall, dietary fructose did not affect the total amount or
composition of serum cholesterol.
Several investigations in mice and rats fed experimental diets for a
period of several weeks suggest that free access to dietary sucrose
promotes the deposition of body fat (Barnard et al. 1993
, Hallfrisch et al. 1981
, Reiser and Hallfrisch 1977
, Rizkalla et al. 1992
). For
example, rats with free access to diets containing 40% (by weight) fat
and 30% sucrose for 8–9 wk had greater body weights and greater
epididymal and perirenal fat pad weights than rats fed an isocaloric
cornstarch diet (Hallfrisch et al. 1981
). A similar
effect was observed in rats fed a 16% fat and 54% sucrose or starch
diet for 7–11 wk, suggesting that the greater fat gain was due to the
high fat content of the diet (Reiser and Hallfrisch 1977
). The current investigation does not support the
hypothesis that diets high in fructose content promote the deposition
of body fat in rats. We found that 18- and 26-mo-old rats with free
access to diets containing fructose had a similar percent body fat as
rats fed fructose-free diets. This effect was not due to
differences in the amount of calories consumed, because similar results
were noted in the calorie-restricted animals. We did find, however,
that 9-mo-old calorie-restricted rats fed fructose had a slight but
significantly greater percent body fat than did age-matched
restricted rats fed the diets without fructose. This finding supports
our suggestion that an increase in body fat associated with dietary
fructose previously reported reflects more closely a short-term
feeding phenomenon in young animals.
Previous investigations have described a significant decline in the
body weight of rats near the end of life, usually beginning at 70–90%
of the life span. We have shown than this decline in body weight is
concomitant with a significant reduction in food intake (Blanton et al. 1998
). The data presented here are consistent with this
age-related anorexia/hypophagia. Although the mechanisms causing
the body weight loss near the end of life have not been elucidated, it
is clear from this and previous investigations that the decline more
closely reflects a starvation-like state rather than a wasting
disorder such as disease-associated cachexia (Table 3)
. This
suggestion is substantiated by the observation that total FFW (g) of
rats with free access to food is conserved or only slightly decreased
during weight loss. The decline in carcass weight between 18- and
26-mo-old rats with free access to food primarily reflects a loss in
fat weight. That the end-of-life body weight loss is not associated
directly with a disease process is supported by the observation that a
similar pattern of fat weight loss was observed in the
calorie-restricted rats (Fig. 1
, Table 3
). Calorie-restricted
rats have significantly less definable disease at death yet still show
a significant loss in body weight near the end of life.
It is interesting to note, however, that the conservation of FFW during
body weight loss seen in the rats with free access to food was not
observed in the calorie-restricted rats. Although a significant
decline in fat weight accounted for the majority of carcass weight loss
in the calorie-restricted rats, significant declines in FFW also
occurred in all calorie-restricted groups. Mechanisms accounting
for the reduction in FFW seen in the 26-mo-old calorie-restricted
rats are not known, and we can only offer a speculative proposal. We
contend that the calorie-restricted animals did not have sufficient
fat reserves available to provide the energy needed for soma
maintenance when the inevitable age-related anorexia began. Thus,
these animals must turn to protein as an energy substrate. This
suggestion is supported by the observation that the percent carcass fat
in the 26-mo-old calorie-restricted rat was undoubtedly close to
the essential level (i.e., lipid associated with cellular function, not
storage, and considered to be <5%; Fig. 3
). Moreover, the only rats
with free access to food and to show a decline in FFW were the
fructose-fed rats, the group that also had the greatest loss in fat
weight.
The significant decline in FFW of the oldest calorie-restricted
rats is part of a growing body of evidence indicating that although
calorie restriction can extend life span and delay or prevent many
age-associated diseases, there may be some detrimental consequences
in old age. Our current and previous data suggest that at least one of
these detrimental consequences is related to protein metabolism. For
example, we previously found that wound healing is significantly
blunted in calorie-restricted versus rats with free access to food
and reflects diminished collagen synthesis at the wound (Reiser et al. 1995
). It is possible that as the older
calorie-restricted animal enters a period of altered energy
balance, such as that seen in age-related anorexia, the total
protein content of the diet may fall below levels needed for
maintenance of tissue (i.e., protein synthesis). The protein content of
the diet used here was 13.9%, an amount that is consistent with
helping to reduce kidney disease during long-term feeding
experiments. Our data suggest that the protein requirements of the
calorie-restricted animal may have to be increased in old age.
Regardless, investigators considering studies with
calorie-restricted animals should be aware of the reduction in FFW
in the oldest rats and how this reduction may influence their study
results.
In summary, the data presented here suggest that feeding rats diets that contain fructose elevates serum triglyceride concentrations and that this effect is consistent over the life span. Moreover, the increased serum triglyceride concentration reflects fructose per se and is not associated with the energy content of the diet. Conversely, dietary fructose did not enhance fat deposition in the rats that either had free access to food or were calorie restricted to 60% of free access.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviation used: FFW, fat-free weight.
Manuscript received March 8, 2000. Initial review completed May 11, 2000. Revision accepted August 22, 2000.
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|
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