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Department of Nutrition, University of California, Davis, CA 95616-8669
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • collagen crosslinks • collagen-associated fluorescence • energy restriction • pentosidine • Fischer F344 rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Kristal and Yu 1992
,
Monnier 1989
). Crosslinks occur when reducing sugars
react with proteins to form reversible Amadori products. Given
sufficient time, the Amadori products spontaneously undergo further
nonenzymatic rearrangement to form irreversible crosslinks called
advanced glycation endproducts
(AGE).3
AGE, including pentosidine, are correlated strongly with cellular
dysfunction. In vivo, the rate of AGE accumulation is thought to
reflect serum glucose levels. Cerami and colleagues report that the
concentration of AGE in lens protein of adult-onset diabetics (Type
II) is related directly to the level of serum glucose (Cerami 1985
). In contrast, rodents calorically restricted over a
lifetime maintain lower serum glucose concentrations, have decreased
AGE accumulation, have a delayed or blunted onset of age-associated
disorders and have a longer life span than do animals given free access
to food (Masoro et al. 1989
, Miksik et al. 1991
, Reiser 1994
).
The results of several investigations suggest that diets high in mono-
or disaccharides may increase serum glucose concentrations and, in
turn, lead to a greater accumulation of AGE. The relevance of these
investigations to age-related dysfunction is unclear as the
majority of studies are of short duration and conducted in young
animals. In a recent review of studies using rodents and published in
the Journal of Nutrition from 1990–1995, McDonald (1997)
noted that ~9 out of 10 studies evaluating the impact
of diet on various outcomes used animals that were less than 12 wk of
age. In addition, 56% of the studies fed the experimental diet for
less than 12 wk. Twelve weeks is less than 7% of the average lifespan
for rats. It is likely that results from studies conducted in young
animals may reflect more closely events associated with rapid growth
and development rather than aging per se. This point is given emphasis
by results from investigations evaluating the effect of age and diet on
glucose homeostasis and insulin resistance. Several early studies
preformed in young rats (2–12 mo of age) suggested that glucose
intolerance and insulin resistance increase with age and when animals
are fed diets high in sucrose (Reaven et al. 1979
and
Reaven et al. 1983
, Reiser and Hallfrisch 1977
, Wright et al. 1983
). However,
when older rats (18–26 mo of age) were included, differences in
glucose intolerance were seen in the 26- and 12-mo-old rats only in
comparison to the 2-mo-old rats. There were no significant differences
in glucose tolerance or insulin secretion between the 12- and 26-mo-old
animals (Eiffert et al. 1991
, Hara et al. 1992
, McDonald 1990
, Ruhe et al. 1992
). These data suggest that to determine more precisely the
effect of diet on aging and/or adult-onset disease in animal models
for human aging (i.e., diabetic, cardiovascular disease, cancer, etc)
investigations should be carried out over a large portion of the
animal’s lifespan.
There exists a substantial need for data that describe the effects of macro- and micronutrient composition of diets on long-term feeding and the aging process. This investigation is part of a larger effort to describe generally the effects of a long-term feeding protocol on rodents. The specific purpose of the present study was to evaluate the long-term effects of dietary sugars and calorie restriction on serum and tissue markers of glycemic stress. To this end, serum glucose, fructosamine and glycated hemoglobin concentrations were measured as short-term markers of glycemic stress in rats given free access to food or 60% of the amount eaten by animals given free access to isocaloric diets that contained, as the carbohydrate source, cornstarch, sucrose, glucose, fructose or equimolar amounts of glucose and fructose. Collagen-associated fluorescence and pentosidine concentrations in skin, trachea, aorta and tail tendon collagen were also assessed as long-term markers of advanced glycation in these animals.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Briefly, 3-mo-old
rats were obtained from the National Institute of Aging animal colony
maintained by Harlan Sprague-Dawley Laboratories (Indianapolis,
IN). Upon arrival, rats were housed individually in hanging wire cages
(23.5 x 45.5 x 19 cm) and provided free access to
distilled, autoclaved water (pH 3.5). The rats were randomly assigned
to one of five isocaloric, semi-purified diets which differed only
in carbohydrate source (either cornstarch, sucrose, glucose, fructose
or equimolar amounts of fructose and glucose) and given free access to
food or restricted to 60% of the mean caloric intake of the
carbohydrate-matched rats that were given free access to food
(Table 1
).The mineral and vitamin mix was increased by 40% in the
caloric-restricted diet in order to ensure proper nutrient density.
At 9, 18 or 26 mo (n = 5 rats per diet group/age) blood
was collected from the tail vein of unanesthetized, 4-h
food-deprived rats and separated into serum for subsequent analysis
of glucose concentration. One week later, 4-h food-deprived rats
were anesthetized with halothane and killed by pneumothorax. Whole
blood was collected via cardiac puncture and various tissues were
removed. Blood was allowed to clot on ice for 2 h and serum was
separated via centrifugation. Serum was stored at -20°C for
subsequent analyses. Tissues collected included a section of skin
removed from the mid-dorsal region of the back (1 x 3 cm), a
3-cm section of the tail closest to the body of the rat, the trachea
and a 1–2-cm section of the descending aorta. The tissue samples were
immediately frozen in liquid nitrogen and stored at -70°C until
analysis was performed. The University of California-Davis Animal
Care and Use Committee approved all methods and procedure performed on
the rats.
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Fasting serum glucose concentration in 10 µL of the serum collected from tail-vein blood was determined using a quantitative, enzymatic method (Procedure No. 510; Sigma Diagnostics, St. Louis, MO). Total glycated hemoglobin concentration in 50 µL of whole blood collected during cardiac puncture was quantified colorimetrically (Shimadzu Model UV160, Kyoto, Japan) after being separated from unbound hemoglobin using an affinity resin (Procedure No. 442; Sigma Diagnostics, St. Louis, Mo). Total hemoglobin concentration in 20 µL of whole blood was determined using the Drabkin’s colorimetric assay (Procedure No. 525, Sigma Diagnostics). Fructosamine concentration in 100 µL of serum collected during cardiac puncture was determined using a colorimetric assay in which glycated proteins reduce nitroblue tetrazolium (Procedure No. 465, Sigma Diagnostics). Albumin concentration in 10 µL of serum was determined colorimetrically using a dye-binding procedure in which bromcresol purple binds albumin (Procedure No. 625, Sigma Diagnostics).
Collagen-associated fluorescence in tail tendon and skin.
Collagen-associated fluorescence was used to quantify the amount of
glycation-related crosslinking in skin and tail tendon samples.
Fluorescence was measured using a modification of the method developed
by Sell and Monnier (Sell and Monnier 1989a
).
Briefly, ~50 mg wet tail tendon or skin that had been scraped with a
razor blade to remove excess epidermis and subcutaneous fat was
homogenized in phosphate buffered saline (PBS), washed in a
chloroform/methanol solution and digested with 280 U of Type VII
collagenase (Sigma Diagnostics) at 37°C for 24 h and
centrifuged. The pellet and an aliquot of the supernatant were
hydrolyzed separately in 6 mol/L HCl, and hydroxyproline content was
measured using a colorimetric assay (Woessner 1961
). The
volume of the remaining supernatant was adjusted to 2 mL, and the
fluorescence spectra were measured using 330 ex/390 em wavelengths to
measure pentosidine-associated fluorescence and at 370 ex/440 em
wavelengths to measure general AGE-associated fluorescence (Perkin
and Elmer Model LS50B, Norwalk, CT).
Pentosidine analysis in trachea and tail tendon.
Synthesis and purification of pentosidine standard.
The method for the synthesis and purification of pentosidine was
similar to the methods described by Sell and Monnier (Sell and Monnier 1989b
), and Reiser (Reiser 1994
). Briefly, a pentosidine standard was synthesized by
heating equal amounts (500 mL each) of L-arginine, L-lysine, and
D-ribose (100 mmol/L each) at 80°C for 1 h. The mixture was
run through Dowex-50W ion exchange resin (Sigma Diagnostics, St. Louis,
MO). The resin was washed with 1 L of 1 mol/L pyridine and pentosidine
was eluted with 1 L of 2 mol/L NaOH. The elutant was collected,
adjusted to pH 7.4 with HCl, and concentrated via rotary evaporation.
The concentrated pentosidine solution was further purified by
chromatography on a 1.5 cm x 85 cm Bio-Gel P2 column
(Bio-Rad, Richmond, CA) that had been equilibrated with 0.02 mol/L
HEPES buffer containing 0.15 mol/L NaCl. Elutant was collected in 10 mL
fractions. The presence of pentosidine in the fractions was determined
by UV absorbance (325 nm) and fluorescence (335 ex/385 em). Those
fractions with the greatest fluorescence were assumed to contain the
greatest concentration of pentosidine and were pooled. Pooled fractions
were adjusted to a pH of 8.5 with NaOH, dried via rotary evaporation,
washed with methanol, then lyophylized. The pentosidine sample was
reconstituted in 5 mL of HPLC-grade H2O and further
purified by reverse-phase HPLC on a Vydac C18 column
using a mobile phase of acetonitrile/water (13:87, v/v) that contained
0.01 mol/L n-heptafluorobutyric acid as a counterion at a
flow rate of 1 mL/min. The elutant was collected in 30-s fractions
between min 24–28 when the pentosidine peak was detected at 325 nm
using an online spectrophotometer (Fig. 1
).Fluorescence (335 ex/383 em) was measured, and the fractions with the
greatest fluorescence were pooled then analyzed by electrospray
ionization mass spectrometry (Quattro-BQ; VG Biotech, Altrinchain,
Greater Manchester, United Kingdom) to confirm that pentosidine was the
product. The results of the mass spectrometry analysis of the synthetic
pentosidine standard were identical (that is, within conditions and
machine variations) to the data reported by Sell and Monnier
(Sell and Monnier 1989b
). The corrected m/z
was 379.2 with fragments indicating loss of H2O
(m/z, 361), COOH (m/z, 334) and
H2N-CH-COOH (m/z, 304). The synthetic
pentosidine reported by Sell and Monnier was 379.6.
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). Hydrolysates were analyzed for pentosidine concentration using reverse-phase HPLC. The HP1100 system equipped with a Vydac C18 column and on-line fluorimeter was used. Tail hydrolysates were separated using a flow rate of 1.0 mL/min with an analysis time of 40 min. The initial mobile phase composition was held at acetonitrile/water (5:95, v/v) for 5 min followed by a 35-min gradient to acetonitrile/water (17:83, v/v). Trachea hydrolysates were separated using a flow rate of 1 mL/min with an analysis time of 19 min. A linear gradient from acetonitrile/water (10:90, v/v) to acetonitrile/water (13:87, v/v) was run over 15 min followed by a 4-min isocratic hold at (13:87, v/v). Aorta samples were run using a flow rate of 1 mL/min and a linear gradient from acetonitrile/water (10:90, v/v) to acetonitrile/water (17:83, v/v) for 35 min. In each sample, pyridoxamine was used as an internal standard. A purified pentosidine standard was run at the beginning and end of each day to verify proper calibration.
Statistical analysis.
Differences in the main effects and the interactions between effects were determined by a combination of ANOVA using dietary carbohydrate, calorie restriction and age as independent variables. Post-hoc comparison utilized Fisher’s Least Significant Difference. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Serum glucose concentration.
Calorie intake and age significantly affected serum glucose
concentrations (Table 2
).Calorie-restricted rats had significantly lower serum glucose
concentrations compared to carbohydrate-matched rats that were
given free access to food. Within both feeding groups (free access or
calorie-restricted), serum glucose concentrations were not different in
the 9- and 18-mo-old rats but significantly lower in the 26-mo-old
rats. There were no significant differences in serum glucose
concentrations among rats given free access to food vs.
calorie-restricted rats at 26 mo of age. Although there were some
individual differences in serum glucose concentrations among the
carbohydrate groups, there was no significant main effect of dietary
carbohydrate on serum glucose.
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).Dietary fructose did not have a significant effect on serum glucose
concentration in calorie-restricted rats.
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).In general, calorie-restricted rats had significantly lower
glycated hemoglobin levels than their carbohydrate and age-matched
counterparts given free access to food. The exception to this effect
was seen in the 26-mo-old rats in which percentage glycated hemoglobin
did not differ significantly between the calorie-restricted rats
and those given free access to food. The main effect of age reflected
primarily the significant decrease in glycated hemoglobin in the 26-
vs. 9- and 18-mo-old rats given free access to food. While other
individual differences existed, no consistent pattern was observed.
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).This effect of fructose was not observed in the age-matched,
calorie-restricted rats.
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Serum fructosamine.
Age significantly affected serum fructosamine concentrations. That is,
serum fructosamine concentrations decreased significantly with age
(Table 4
).No other main effects were noted. A significant, but weak correlation
between serum fructosamine and serum glucose concentrations was
observed in the rats allowed free access to food
(r2 = 0.097, P < 0.0074)
and in the calorie-restricted rats (r2
= 0.077, P < 0.0200).
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Collagen-associated fluorescence
Skin collagen.
Aging significantly affected the pentosidine- (330 ex/390 em) and
general AGE-related (370 ex/440 em) fluorescence in skin collagen
isolated from rats given free access to food (Fig. 4
).A significant age-related effect on skin collagen for general
AGE-related fluorescence was observed in calorie-restricted
rats. The source of dietary carbohydrate did not affect significantly
collagen-associated fluorescence in skin, although a few individual
differences were noted (e.g., 12- vs. 26-mo-old rats fed fructose).
There was no significant effect on skin collagen-associated
fluorescence when the data were grouped by diets containing fructose
and those that did not (data not shown).
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). There was a significant effect of age, but not dietary carbohydrate or
caloric intake, on general AGE-related fluorescence in collagen
isolated from tail tendon. There was no significant effect on tail
collagen-associated fluorescence when the data were group by diets
containing fructose and those that did not (data not shown).
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There were significant main effects of calorie restriction and age
on pentosidine concentration in collagen from tail tendon. In general,
an age-related increase in pentosidine concentration was delayed
with calorie restriction (Table 5
). That is, a significant increase in pentosidine concentration was
observed in the 18-mo-old rats given free access to food relative to
the levels observed in the 9-mo-old rats, whereas a significant
increase in pentosidine concentration was not observed until 26 mo of
age in the calorie-restricted rats. The source of carbohydrate in
the diet did not affect pentosidine concentrations in collagen from
tail tendon.
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). Within the group of rats allowed free access to food, a significant
effect of age was observed at both 18 and 26 mo. Within the
calorie-restricted group, an effect was only observed at 26 mo.
Within each age group, overall pentosidine concentrations were similar
between the rats given free access to food and the
calorie-restricted group. Dietary carbohydrate did not have an
effect on pentosidine concentrations. Those rats consuming a diet that
contained fructose had similar pentosidine concentrations compared to
those rats that were fed a diet that did not contain fructose.
Pentosidine was not quantifiable in aorta collagen collected from
individual rats. For each diet group, we pooled five aortas per age
group to increase the total amount of pentosidine but were unsuccessful
at isolating a distinguishable pentosidine peak.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The effects that specific dietary carbohydrates may have on serum
glucose concentration are controversial. Several investigations suggest
that diets high in sucrose or fructose increase serum glucose
concentrations as compared to diets containing complex carbohydrates.
For example, Hallfrisch and colleagues fed 3-wk-old rats isocaloric
diets that contained either 54% sucrose or cornstarch for 11 wk and
then evaluated the animals’ response to an intraperitoneal glucose
tolerance test (Hallfrisch et al. 1979
). Although
resting levels of serum glucose were slightly lower in the rats fed
cornstarch, the area under the curve for serum glucose following the
glucose tolerance test was significantly greater in rats given sucrose.
These investigators suggest that the greater serum glucose
concentrations reflect metabolism of the fructose moiety of the sucrose
molecule. That is, entry of fructose into the liver cell bypasses
glucokinase and thus has a greater potential of leaving the liver as
glucose. However, our previous investigations (Hara et al. 1992
, McDonald 1990
, Ruhe et al. 1996
) and the data presented here are not consistent with the
hypothesis that dietary simple sugars, sucrose and fructose, increase
serum glucose to a greater extent than do complex carbohydrates, i.e.,
cornstarch. In general, we find no significant differences in serum
glucose concentration within groups of rats given free access to food
or restricted to 60% of the free access group regardless of the
carbohydrate provided in the diet (Table 2
and Figure 2
).
Although the reasons for differing results among investigations with
regard to the effect of dietary carbohydrates on serum glucose
concentration are unclear, we suggest that the differences reflect, in
part, the age of the animal used in the experiment and/or the length of
time the diet was given. The majority of investigations evaluating the
interactions between dietary carbohydrates and serum glucose
concentration have utilized young, developmentally immature animals fed
diets for short periods (usually less than 12 wk). This approach is
problematic for at least two reasons. First, developmentally immature
animals are rapidly growing and have yet to obtain their "maintenance
body weight," which occurs in most rats and mice about 4–5 mo of
age. Developmentally immature rodents have significantly different
endocrine profiles, many which affect glucose metabolism, than do
mature rodents that have established a relatively consistent body
weight. Second, short-term feeding does not allow sufficient time
for metabolic adaptation to the diet. This is particularly important
with regard to carbohydrate as previous investigations have
demonstrated that hepatic enzymes involved in glucose metabolism are
regulated, in part, by the level and type of portal vein-delivered
sugars (Mayes 1993
). The importance of using
developmentally mature rodents and long-term feeding protocols to
evaluate glucose metabolism in response to various carbohydrates has
been demonstrated. That is, young (2–3-mo-old) rats consistently show
greater serum glucose concentrations and glucose tolerance in response
to dietary sucrose as compared to older (6 to 26 mo of age) rats
(Eiffert et al. 1991
, Hallfrisch et al. 1979
, Hara et al. 1992
, McDonald 1990
, Reaven et al. 1979
and
1983
, Reiser and Hallfrisch 1977
,
Ruhe et al. 1992
, Wright et al. 1983
).
Differences in serum glucose concentrations are not generally observed
when comparing 6-, 12-, or 24–26-mo-old animals, a finding consistent
with the data presented here. Such observations suggest that future
investigations use feeding protocols longer than 12 wk and include
developmentally mature animals when evaluating the effect of diets high
in carbohydrate on age-related metabolic adaptations or specific
adult-onset disease.
Regarding the relationship between the age-related accumulation of AGE and diet, some investigations have suggested that diets high in fructose increase serum glucose concentration and thus increase AGE accumulation. The data presented do not support this suggestion. That is, the type of dietary carbohydrate does not significantly affect serum markers of glycemic stress, i.e., higher than physiological concentration of serum glucose, fructosamine and glycated hemoglobin. Moreover, collagen concentrations of pentosidine, a tissue marker of AGE, are not affected significantly by the type of dietary carbohydrate. However, the restriction of calories to 60% of that consumed by animals given free access to food results in a significant decrease in serum glucose, glycated hemoglobin and pentosidine concentrations in tail tendon collagen. These findings clearly suggest that caloric intake rather than specific dietary carbohydrate has greater influence on markers of glycemic stress.
Several previous investigations have directly or indirectly implicated
serum glucose as the primary factor affecting the age-related rate
of accumulation of pentosidine. For example, Masoro and colleagues
proposed that the serum glucose-lowering effect of calorie
restriction results in decreased AGE accumulation and is one factor
that may influence the greater life span of the calorie-restricted
animals (Masoro et al. 1989
). Additionally, the series
of investigations by Monnier, Sell and their colleagues have
consistently shown greater AGE accumulation in hyperglycemic and Type
II diabetic humans (Brownlee et al. 1988
, Cerami et al. 1988
, Kohn et al. 1984
, Monnier et al. 1984
and 1992
, Sell et al. 1992
, Vlassara et al. 1986
). Our data, however,
are not entirely consistent with the concept that serum glucose is the
primary factor accounting for AGE accumulation. We found that only in
tail tendon collagen was there an effect of calorie restriction on the
rate of AGE accumulation. Moreover, we did not observe a significant
correlation between serum glucose and pentosidine accumulation for any
of the tissue measured. The correlation between serum glucose and
glycated hemoglobin was significant, but weak. The idea that serum
glucose may not be a precise predictor of the age-related
accumulation of pentosidine is consistent with the recent work of Iqbal
et al. These investigators report that age-related pentosidine
accumulation in the skin of female broiler breeders is significantly
less than that observed in humans and rats despite the fact that the
serum glucose concentration is four times greater in the hens
(Iqbal et al. 1999
). They conclude that the formation of
pentosidine, and possibly other AGE as well, is not solely dependent on
the concentration of serum glucose. Although the reasons for the
differing results are not clear, we suggest that the relationship
between serum glucose and pentosidine concentrations may be important
only in individuals with above physiological concentrations of serum
glucose (i.e., greater than 6.9 mmol/L, resting). Since only 15–20%
of those over the age of 65 y display hyperglycemia and/or type II
diabetes, it is unlikely that pentosidine is a relevant marker of
biological aging.
The pattern of AGE accumulation among the tissues examined in this
investigation was not consistent. Trachea collagen had the greatest
concentration of pentosidine of the three tissues evaluated, yet did
not show a decrease in accumulation of this AGE benchmark as a result
of calorie restriction. Conversely, the pentosidine concentration of
tail tendon collagen was roughly half the amount of that found in
trachea collagen, and calorie restriction significantly reduced its
accumulation. We were unable to detect pentosidine for accurate
analyses in pooled (n = 5) aorta samples. We can only
speculate as to the reasons for differences in the apparent
susceptibility of specific tissues to the accumulation of AGE.
Differences among tissues in the amount of specific collagen types may
influence the pattern of crosslinking. Reiser proposed that the rate of
glycation may be influenced by the location of glycation sites, which
may differ among tissues due to differences in the structure of
collagen (Reiser et al. 1992
). Reiser did not observe an
effect of calorie restriction in reducing the accumulation of
pentosidine in aortic collagen from aging C57BL/6N NIA mice
(Reiser 1994
). Sell also observed that calorie
restriction does not affect the accumulation of pentosidine in tail
tendon, ear auricle or aorta collagen from C57BL/6N NIA mice
(Sell and Monnier 1997
). However, calorie restriction
did blunt the accumulation of pentosidine in tail tendon and ear
auricle in the shorter-lived DBA/2N NIA strain of mice. Cefalu
reported that calorie restriction reduces pentosidine content in skin
collagen in aging Brown Norway rats (Cefalu et al. 1995
). Novelli et al. reported that the age-related
increase in collagen-associated fluorescence measured in skin and
aortic collagen is not sensitive to calorie restriction in aging
Sprague-Dawley rats (Novelli et al. 1998
).
Discrepancies in the literature may reflect differences in the methods
used to prepare tissues and detect pentosidine, differences in the
animal models studied and/or differences in the susceptibility of
specific tissues to the accumulation of AGE. Nonetheless, it is clear
that the accumulation of pentosidine, as well as dietary effects on the
accumulation, is tissue-specific. Future investigations should
consider these factors in their interpretation of results.
The data presented here are consistent, in general, with the literature
describing the beneficial effects of calorie restriction in delaying
the physiological consequences of aging. We find that rats
calorie-restricted to 40% less than that of rats given free access
to food show significant delays in the accumulation of AGE (Fig. 5)
.
Although 40% restriction is commonly used among investigators who
evaluate possible mechanisms associated with the positive effect of
calorie restriction, it is a severe restriction and most likely does
not represent a protocol that could be tested in humans. There is no
substantial evidence, however, to suggest that milder restrictions
significantly delay age-related decline and specific pathology. For
example, Holloszy et al. found that 24–26-mo-old male Long-Evans
rats were able to maintain daily exercise (wheel running) when the
animals were restricted to 5% less than animals allowed free access to
food (Holloszy et al. 1985
). Weindruch and colleagues
have reported that mice restricted to 90% of the calories consumed by
animals allowed free access to food beginning early in life had a
significantly reduced incidence of tumors and other pathologies as well
as a significantly longer life span than did the free-access mice
(Weindruch 1995
). These investigators suggest that the
pathologies associated with free access feeding may confound results
and recommend that future long-term studies include a mild
calorie-restricted group in order to control for the effects of
disease. Our previous and current data support this suggestion.
In conclusion, these data suggest that specific dietary carbohydrates do not affect the aging process by altering serum glucose concentrations or the accumulation of AGE in specific tissues. We find that AGE accumulation reflects more closely calorie intake rather than dietary carbohydrate. Moreover, the inhibitory action of calorie restriction on age-associated accumulation of pentosidine differs between tissues from the same animals. The present data as well as previous investigations demonstrate that long-term feeding protocols should include developmentally mature animals that are subject to a mild calorie restriction in order to evaluate more precisely the effect of diet on mechanisms underlying age-related metabolic adaptation or adult-onset disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AGE, advanced glycation
endproducts; PBS, phosphate buffered saline.
Manuscript received August 26, 1999. Initial review completed October 5, 1999. Revision accepted January 18, 2000.
|
REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1. Brownlee M., Cerami A., Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N. Engl. J. Med. 1988;318:1315-1321[Medline]
2. Cefalu W. T., Bell-Farrow A. D., Wang Z. Q., Sonntag W. E., Fu M. X., Baynes J. W., Thorpe S. R. Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N(carboxymethyl)lysine and pentosidine, in rat skin collagen. J. Gerontol.:BS 1995;50A:B337-B341
3. Cerami A. Hypothesis. Glucose as a mediator of aging. J. Am. Geriatr. Soc. 1985;33:626-634
4. Cerami A., Vlassara H., Brownlee M. Role of advanced glycosylation products in complications of diabetes. Diabetes Care 1988;11(Suppl 1):73-79
5. Eiffert K. C., McDonald R. B., Stern J. S. High sucrose diet and exercise: effects on insulin-receptor function of 12- and 24-mo-old Sprague-Dawley rats. J. Nutr. 1991;121:1081-1089
6.
Hallfrisch J., Lazar F., Jorgensen C., Reiser S. Insulin and glucose responses in rats fed sucrose or starch. Am. J. Clin. Nutr. 1979;32:787-793
7. Hara S. L., Ruhe R. C., Curry D. L., McDonald R. B. Dietary sucrose enhances insulin secretion of aging Fischer 344 rats. J. Nutr. 1992;122:2196-2203
8.
Holloszy J. O., Smith E. K., Vining M., Adams S. Effect of voluntary exercise on longevity of rats. J. Appl. Physiol. 1985;59:826-831
9. Iqbal M., Probert L. L., Alhumadi N. H., Klandorf H. Protein glycosylation and advanced glycosylated endproducts (AGEs) accumulation: an avian solution?. J. Gerontol.:BS 1999;54:B171-B176
10. Kohn R. R., Cerami A., Monnier V. M. Collagen aging in vitro by nonenzymatic glycosylation and browning. Diabetes 1984;33:57-59[Abstract]
11. Kristal B. S., Yu B. P. An emerging hypothesis: synergistic induction of aging by free radicals and Maillard reactions. J. Gerontol. 1992;47:B107-B141[Abstract]
12. Masoro E. J., Katz M. S., McMahan C. A. Evidence for the glycation hypothesis of aging from the food-restricted rodent model. J. Gerontol. 1989;44:B20-B22[Abstract]
13.
Mayes P. A. Intermediary metabolism of fructose. Am. J. Clin. Nutr. 1993;58:754S-765S
14. McDonald R. B. Effect of age and diet on glucose tolerance in Sprague-Dawley rats. J. Nutr. 1990;120:598-601
15. McDonald R. B. Some considerations for the development of diets for mature rodents used in long-term investigations. J. Nutr. 1997;127:847S-850S[Medline]
16. McDonald R. B., Carlson K., Day C., Stern J. S., Horwitz B. A. Effect of gender on the response to a high fat diet in aging Fischer 344 rats. J. Nutr. 1989;119:1472-1477
17.
McDonald R. B., Horwitz B. A., Stern J. S. Cold-induced thermogenesis in younger and older Fischer 344 rats following exercise training. Am. J. Physiol. 1988;254(Regulatory Integrative Comp. Physiol. 23):R908-R916
18. Miksik I., Struzinsky R., Deyl Z. Change with age of UV absorbance and fluorescence of collagen and accumulation of epsilon-hexosyllysine in collagen from Wistar rats living on different food-restriction regimes. Mech. Ageing Dev. 1991;57:163-174[Medline]
19. Monnier V. M. Toward a Maillard reaction theory of aging. Prog. Clin. Biol. Res. 1989;304:1-22
20.
Monnier V. M., Kohn R. R., Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc. Natl. Acad. Sci. USA 1984;81:583-587
21. Monnier V. M., Sell D. R., Nagaraj R. H., Miyata S., Grandhee S., Odetti P., Ibrahim S. A. Maillard reaction-mediated molecular damage to extracellular matrix and other tissue proteins in diabetes, aging and uremia. Diabetes 1992;41(Suppl 1):36-41
22. Novelli M., Masiello P., Bombara M., Bergamini E. Protein glycation in the aging male Sprague-Dawley rat: effects of antiaging diet restrictions. J. Gerontol.:BS 1998;53A:B94-B101
23. Reaven E. P., Gold G., Reaven G. M. Effect of age on glucose-stimulated insulin release by the beta-cell of the rat. J. Clin. Invest. 1979;64:591-599
24. Reaven E., Wright D., Mondon C. E., Solomon R., Ho H., Reaven G. M. Effect of age and diet on insulin secretion and insulin action in the rat. Diabetes 1983;32:175-180[Abstract]
25. Reiser K. M. Influence of age and long-term dietary restriction on enzymatically mediated crosslinks and nonenzymatic glycation of collagen in mice. J. Gerontol. 1994;49:B71-B79[Abstract]
26.
Reiser K. M., Amigable M., Last J. A. Nonenzymatic glycation of type 1 collagen: The effects of aging on preferential glycation sites. J. Biol. Chem. 1992;267:24207-24216
27. Reiser S., Hallfrisch J. Insulin sensitivity and adipose tissue weight of rats fed starch or sucrose diets ad libitum or in meals. J. Nutr. 1977;107:147-155
28. Ruhe R. C., Coordt M. C., McDonald R. B. Effects of caloric restriction and source of dietary carbohydrate on glycemic status of the Fischer 344 rat. Aging 1996;8:287-291[Medline]
29.
Ruhe R. C., Curry D. L., Herrmann S., McDonald R. B. Age and gender effects on insulin secretion and glucose sensitivity of the endocrine pancreas. Am. J. Physiol. 1992;262(Regulatory Integrative Comp. Physiol. 31):R671-R676
30. Sell D. R., Lapolla A., Odetti P., Fogarty J., Monnier V. M. Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes 1992;41:1286-1292[Abstract]
31. Sell D. R., Monnier V. M. Isolation, purification and partial characterization of novel fluorophores from aging human insoluble collagen-rich tissue. Connect. Tissue Res. 1989a;19:77-92[Medline]
32. Sell D. R., Monnier V. M. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J. Biol. Chem. 1989b;264:21597-21602
33. Sell D. R., Monnier V. M. Age-related association of tail tendon break tie with tissue pentosidine in DBA/2 vs. C57BL/6 mice: the effect of dietary restriction. J. Gerontol.:BS 1997;52:B277-B284
34. Vlassara H., Brownlee M., Cerami A. Nonenzymatic glycosylation: role in the pathogenesis of diabetic complications. Clin. Chem. 1986;32:B37-B41
35. Weindruch R. Animal models. Masoro E. J. eds. Handbook of Physiology: Aging 1995:37-52 Oxford University Press New York.
36. Woessner J. F. The determination of hydroxyproline in tissue and protein samples containing small proportions of this amino acid. Arch. Biochem. Biophys. 1961;93:440-447[Medline]
37.
Wright D. W., Hansen R. I., Mondon C. E., Reaven G. M. Sucrose-induced insulin resistance in the rat: modulation by exercise and diet. Am. J. Clin. Nutr. 1983;38:879-883
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0.05. Values are means
± SEM, n = 3–5.
