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Results for “Caloric Restriction”

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PubMed2001

Aging and caloric restriction in nonhuman primates: behavioral and in vivo brain imaging studies.

In a long-term longitudinal study of aging in rhesus monkeys, a primary objective has been to determine the effects of aging and caloric restriction (CR) on behavioral and neural parameters. Through the use of automated devices, locomotor activity can be monitored in the home cages of the monkeys. Studies completed thus far indicate a clear age-related decline in activity consistent with such observations in many other species, including humans. However, no consistent effects of CR on activity have been observed. Selected groups of monkeys have also been involved in brain imaging studies, using magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI studies completed thus far reveal a clear age-related decline in the volumes of the basal ganglia, the putamen, and the caudate nucleus, with no change in total brain volume. PET analysis has revealed an age-related decline in the binding potential of dopamine D2 receptors in the same brain regions. These results are consistent with findings in humans. Although additional longitudinal analysis is needed to confirm the present results, it would appear that locomotor activity, volume of the basal ganglia, as well as dopamine D2 receptor binding potential provide reliable, noninvasive biomarkers of aging in rhesus monkeys.

Aging↗

PubMed1992

An in vitro pancreas acinar cell model for testing the modulating effects of caloric restriction and ageing on cellular proliferation and transformation.

Pancreatic acinar cells were isolated for culture from a young (Y) and an old (O) Brown-Norway or Fischer 344 rat fed an ad libitum (AL) or calorically restricted (CR) diet. The cells were cultured and cellular growth rates were determined as a function of passage number. An overall increase in cellular growth rate and transformation frequency with age and/or AL diet relative to youth as well as a decrease with CR diet were concordant with reported responses in vivo. Transformation frequency was measured in Brown-Norway cells and followed the same pattern as the growth response: AL/O > AL/Y = CR/Y > CR/O. The cellular model is shown to fit the general multistage requirements of the carcinogenic process as well as general age and diet characteristics of pancreatic cancer. This pancreatic acinar cell age-diet approach may prove to be a valuable tool for determining mechanisms of exocrine pancreatic carcinogenesis as well as other disease states; it may also be of utility in in vitro gerontological nutritional and pharmacological studies since some of the age and diet determinants of biological effects appear to be segregable. Propensity of cells from an old and/or AL diet animal for faster growth and for cellular transformation are programmed into the cells by the time of their excision from the animal (as late as 14 months), indicating a heritable component in the model or a mechanism that is dependent upon elements that control gene expression.

Aging↗

PubMed1995

Caloric restriction decreases age-dependent accumulation of the glycoxidation products, N epsilon-(carboxymethyl)lysine and pentosidine, in rat skin collagen.

Nonenzymatic glycation of body proteins and subsequent advanced glycation reactions have been implicated in the aging process, while caloric restriction (CR) in rodents results in an increase in both mean and maximum life span. We have evaluated the effect of chronic (25 months) CR on glycation of blood proteins and accumulation of advanced glycation and oxidation (glycoxidation) products, N epsilon-(carboxymethyl)lysine (CML), and pentosidine, in skin collagen. Brown-Norway rats, fed ad libitum (AL) from birth, were divided into two equal groups at 4 months of age and placed on AL or CR diets (CR = 60% of AL diet). Cohorts of animals were sacrificed at 7, 13, and 25 months after the initiation of CR. At necropsy glycated hemoglobin was measured by affinity HPLC and glycated plasma protein by the fructosamine assay; extracts of skin collagen were analyzed by gas chromatography-mass spectrometry for CML and by reversed-phase HPLC for pentosidine. Glycation of hemoglobin, plasma proteins, and skin collagen was decreased significantly (18-33%) by CR. Concentrations of CML and pentosidine increased significantly with age in skin collagen in both AL and CR animals; however, CR significantly reduced levels of CML (25%), pentosidine (50%), and fluorescence (15%) in collagen in the oldest rats. We conclude that CR reduces the extent of glycation of blood and tissue proteins and the age-related accumulation of glycoxidation products in skin collagen.

Aging↗

PubMedDate not supplied

Plasma protein's glycation is decreased in Sprague Dawley rats under caloric restriction.

Different dietary regimens were applied to three cohorts of rats. The first was fed ad libitum every day (AL), the second was fed ad libitum every other day (EOD) and the third was fed a diet equivalent to 60% of the caloric intake (60% CI) of the AL cohort. Levels of stable early glycation products in plasma proteins were then measured according to two different methods. Glycation of plasma proteins progressively increased in AL animals belonging to the 2-12 month age interval, while it showed a less pronounced age-dependent increase in EOD and 60% CI animals. The lowest degree of glycation was detected 2-3 months after the beginning of caloric restriction. After 12 months of age a lower level of glycation was detected in 60% CI rats than in EOD animals. Body weight was lower in restricted animals than in AL animals and was lowest in 60% CI rats. During the life span, glycemia was lower in fasting 60% CI than in EOD or AL rats.

Journal Article↗

PubMed1995

Transforming growth factor-alpha and epidermal growth factor expression in the exocrine pancreas of azaserine-treated rats: modulation by cholecystokinin or a low fat, high fiber (caloric restricted) diet.

Expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) was studied in normal pancreatic tissue and in (pre)neoplastic pancreatic lesions of azaserine-treated rats. They were given either a low fat, high fiber (low caloric) diet, to inhibit carcinogenesis, or a low fat diet combined with injections of the cholecystokinin analog caerulein to enhance carcinogenesis. The control groups, maintained on a low fat diet, were injected with azaserine or were not treated at all. Autopsy was performed at 6 and 15 months after the last azaserine injection. After both 6 and 15 months immunohistochemistry revealed a weak expression of EGF and TGF-alpha peptides in the acinar cells, and a stronger expression in the ductular and centroacinar cells. TGF-alpha peptide expression was reduced in both putative preneoplastic and neoplastic acinar cell lesions, but no differences in EGF peptide expression were observed between the various stages of exocrine pancreatic carcinogenesis. After 16 months an increase in TGF-alpha mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF-alpha mRNA levels in macroscopically isolated tumors were significantly lower, but EGF mRNA levels were significantly higher, than in total pancreatic homogenates from azaserine-treated rats. Furthermore, EGF and TGF-alpha mRNA levels in isolated tumors did not differ significantly from mRNA levels in non-carcinogen-treated rats. Neither with immunohistochemistry nor with PCR were differences in EGF or TGF-alpha expression observed due to either inhibition or stimulation of carcinogenesis. It is concluded that putative preneoplastic acinar cell lesions induced in rat pancreas by azaserine may develop into acinar adenocarcinomas independently of TGF-alpha and EGF. The results suggest involvement of these growth factors at the early stage of the carcinogenic process, during the initiation of normal acinar cells into putative preneoplastic cells. However, modulation of azaserine-induced pancreatic carcinogenesis by cholecystokinin or a low fat, high fiber (caloric restricted) diet appeared not to be regulated by EGF or TGF-alpha.

Animals↗

PubMed2004

Age and caloric restriction diets are confounding factors that modify the response to lipopolysaccharide by peritoneal macrophages in C57BL/6 mice.

Aging is the result of several detrimental changes that lead to a decrease in homeostasis, an increase in the incidence of degenerative diseases, and death. A caloric-restricted diet (CR), which consists of a significant reduction in calorie intake (40%) without malnutrition, has been shown to delay the onset of age-related diseases and pathologies and to extend life span. The aims of this study were to assess the effects of aging and CR on lipopolysaccharide (LPS)-dependant cytokine production by peritoneal macrophages (PMphis). Resident naïve PMphis were isolated from 2- to 24-month-old male C57BL/6 mice and were stimulated with Escherichia coli LPS (100 ng/mL) for 1 to 5 h in culture conditions. A linear decrease in the production of LPS-induced tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 10 was observed with age. LPS-induced IL-6 and IL-1beta levels were also reduced with age, but in a nonlinear fashion. Expression of CD14, the major receptor for LPS, on the PMphi surface was also observed to decline with age. Moreover, TNF-alpha production by PMphis was reduced in mice undergoing the two different CR diets of limited daily feeding and intermittent fasting, as compared with ad libitum-fed mice. The results of this study add the new variables age and diet to the paradigm proposing that the response to LPS is modulated by multiple components, including genetic background and sex.

Aging↗

PubMed1980

Type IV hyperlipoproteinemia: effects of a caloric restricted type IV diet versus physical training plus isocaloric type IV diet.

Serum lipids, plasma insulin and glucagon, aerobic capacity, and body composition were examined in middle-aged men (X age = 44.2 years) with type IV hyperlipoproteinemia to determine the relative effectiveness of a caloric restricted type IV hyperlipoproteinemia diet (group A) versus physical training plus an isocaloric type IV diet (group B). After 9 weeks of the above interventions, reductions (P less than 0.01) in mean cholesterol levels from 213 to 186 (12% change) and from 205 to 185 mg/dl (9% change), and in triglyceride levels from 332 to 211 (29% change) and from 263 to 138 mg/dl (42% change) were found for groups A and B, respectively. A small reduction in mean fasting insulin level was found only in group B; this reduction appeared inversely associated with increases in aerobic capacity in group B (r = -0.66). Both interventions were without effect on fasting glucagon levels. The physical training program prescribed resulted in a 12% increase in aerobic capacity (group B). Significant mean body weight reductions of 7.7 lb (P less than 0.01) and 2.9 lb (P less than 0.01) were seen for groups A and B, respectively; these absolute body weight reductions differed significantly (P less than 0.05) between groups. Both groups significantly lost body fatness (P less than 0.01). These reductions in body weight and body fatness appeared independent of changes in lipid levels. These results demonstrate that both interventions reduce serum lipids in men with type IV hyperlipoproteinemia but that physical training plus an isocaloric type IV diet may be the more advantageous of the two regimens, since a greater percentage decrease and a more sustained reduction in serum triglyceride levels, and a greater reduction of fasting hyperinsulinemia were observed in group B.

Adult↗

PubMed1994

The homology of a novel polypeptide with stress protein characteristics in embryonic mice brain and in the hypothalamus of caloric restricted rats as determined by ultramicro western blotting.

A novel protein (p34) was observed in polyacrylamide gel fluorographs of gestation day 13 embryonic mouse brain following retinoic acid dosing of dams. Another p34 polypeptide with identical gel migratory characteristics was seen in the hypothalamus of old caloric restricted rats after "food deprivation stress". Western blotting, employing an ultramicro trans-blot cell developed in our laboratory, detected identical immunochemical determinants between these proteins, verifying their homology. Peptide mapping and Western blotting further validated the uniqueness of p34 compared with other stress proteins including heme oxygenase.

Animals↗

PubMed2001

Dietary caloric restriction prevents the age-related decline in plasma melatonin levels of rhesus monkeys.

Rhesus monkeys exhibit an age-associated decrease in peak plasma melatonin levels analogous to that reported for humans. This decrease is essentially abolished in monkeys subjected to a 30% reduction in caloric intake over a 12-yr period. The caloric restriction (CR) effect does not seem to be a reversal, but rather a long-term prevention, of the age-related decline in hormone concentrations. The age effect does not seem to be due to a phase shift in the peak of melatonin secretions, as has been observed in some populations of aged humans. It is also extremely unlikely that the CR effect simply reflects a phase shift, since old monkeys on the diet have nocturnal melatonin levels equal to or greater than adult fully fed controls. Thus, if peak times (approximately 0200 h) were actually shifted, maximal levels in old CR monkeys would be even higher. These findings, coupled with previous observations in humans, suggest that peak plasma melatonin levels may represent a possible candidate "biomarker of aging" in primates. Moreover, this index of age-associated physiological decrement seems to be inhibited by dietary CR.

Aging↗

PubMed2001

Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

We present genome-wide microarray expression analysis of 11,000 genes in an aging potentially mitotic tissue, the liver. This organ has a major impact on health and homeostasis during aging. The effects of life- and health-span-extending caloric restriction (CR) on gene expression among young and old mice and between long-term CR (LT-CR) and short-term CR (ST-CR) were examined. This experimental design allowed us to accurately distinguish the effects of aging from those of CR on gene expression. Aging was accompanied by changes in gene expression associated with increased inflammation, cellular stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic metabolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks of ST-CR reversed the majority of these changes. LT-CR produced in young mice a pattern of gene expression that is a subset of the changes found in old LT-CR mice. It is possible that the early changes in gene expression, which extend into old age, are key to the life- and health-span-extending effects of CR. Further, ST-CR substantially shifted the "normo-aging" genomic profile of old control mice toward the "slow-aging" profile associated with LT-CR. Therefore, many of the genomic effects of CR are established rapidly. Thus, expression profiling should prove useful in quickly identifying CR- mimetic drugs and treatments.

Aging↗

PubMed1985

Effects of severe caloric restriction on the degree of sialylation of apoprotein C-III in obese women.

Alterations in the relative proportions of very low density lipoprotein (VLDL) apoprotein C-III (apoC-III) isoforms have been previously observed under various dietary and metabolic states. This study was designed to evaluate the effects of a very high caloric restriction on plasma triglycerides and on the relative proportions of VLDL apoprotein C-II (apoC-II) and apoC-III isoforms in obese subjects. VLDL were isolated by preparative ultra-centrifugation from 12 obese women. ApoC-II and apoC-III subspecies were separated by analytical ultrathin-layer isoelectrofocusing. The mean body weight decreased significantly from 96.2 +/- 8.7 to 90.6 +/- 7.6 kg (p less than 0.01). Mean total and VLDL triglycerides did not vary significantly. Apoprotein C-III2 (apoC-III2) as percentage of total apoprotein C increased (p less than 0.01) and apoprotein CIII0 (apoC-III0) decreased (p less than 0.01). Apoprotein C-III1 (apoC-III1) did not vary significantly. An inverse correlation was found between the percentage variation of apoC-III2 and that of apoC-III1 (r = -0.94; p less than 0.01). The variations of apoC-III2 correlated positively (r = 0.83; p less than 0.01), while those of apoC-III1 correlated inversely (r = -0.65, p less than 0.025) with the changes of VLDL triglycerides. The apoC-III1 to apoC-III2 ratio as well as the apoC-III0 to apoC-III2 and apo C-III1 ratios decreased after diet (p from less than 0.01 to less than 0.001). Total apoC-III as well as apoC-III2 and apoC-III1 to apoC-II ratios did not vary.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

Management of multifactorial idiopathic epilepsy in EL mice with caloric restriction and the ketogenic diet: role of glucose and ketone bodies.

BACKGROUND: The high fat, low carbohydrate ketogenic diet (KD) was developed as an alternative to fasting for seizure management. While the mechanisms by which fasting and the KD inhibit seizures remain speculative, alterations in brain energy metabolism are likely involved. We previously showed that caloric restriction (CR) inhibits seizure susceptibility by reducing blood glucose in the epileptic EL mouse, a natural model for human multifactorial idiopathic epilepsy. In this study, we compared the antiepileptic and anticonvulsant efficacy of the KD with that of CR in adult EL mice with active epilepsy. EL mice that experienced at least 15 recurrent complex partial seizures were fed either a standard diet unrestricted (SD-UR) or restricted (SD-R), and either a KD unrestricted (KD-UR) or restricted (KD-R). All mice were fasted for 14 hrs prior to diet initiation. A new experimental design was used where each mouse in the diet-restricted groups served as its own control to achieve a 20-23% body weight reduction. Seizure susceptibility, body weights, and the levels of plasma glucose and beta-hydroxybutyrate were measured once/week over a nine-week treatment period. RESULTS: Body weights and blood glucose levels remained high over the testing period in the SD-UR and the KD-UR groups, but were significantly (p < 0.001) reduced in the SD-R and KD-R groups. Plasma beta-hydroxybutyrate levels were significantly (p < 0.001) increased in the SD-R and KD-R groups compared to their respective UR groups. Seizure susceptibility remained high in both UR-fed groups throughout the study, but was significantly reduced after three weeks in both R-fed groups. CONCLUSIONS: The results indicate that seizure susceptibility in EL mice is dependent on plasma glucose levels and that seizure control is more associated with the amount than with the origin of dietary calories. Also, CR underlies the antiepileptic and anticonvulsant action of the KD in EL mice. A transition from glucose to ketone bodies for energy is predicted to manage EL epileptic seizures through multiple integrated changes of inhibitory and excitatory neural systems.

Journal Article↗

PubMed1990

Effect of chronic caloric restriction on the circadian regulation of physiological and behavioral variables in old male B6C3F1 mice.

The circadian rhythms of food and water consumption, the number of feeding and drinking episodes, oxygen consumption, carbon dioxide production, respiratory quotient, gross motor activity, and body temperature were measured in male B6C3F1 mice that were fed ad libitum (AL) or fed a caloric-restricted diet (CR). The CR regimen (60% of the normal AL consumption) was fed to mice during the daytime (5 hr after lights on). CR animals exhibited fewer feeding episodes but consumed more food per feeding bout and spent more total time feeding than AL mice. It appears that CR caused mice to change from their normal "nibbling behavior" to meal feeding. Compared to AL animals, the mean body temperature was reduced in CR animals, while the amplitude of the body temperature rhythm was increased. Spans of reduced activity, metabolism, and body temperature (torpor) occurred in CR mice for several hours immediately before feeding, during times of high fatty acid metabolism (low RQ). The acute availability of exogenous substrates (energy supplies) seemed to modulate metabolism shifting metabolic pathways to promote energy efficiency. CR was also associated with lower DNA damage, higher DNA repair, and decreased proto-oncogene expression. Most of the circadian rhythms studied seemed to be synchronized primarily to the feeding rather than the photoperiod cycle. Night-time CR feeding was found to be better than daytime feeding because the circadian rhythms for AL and AR animals were highly synchronized when this regimen was used.

Aging↗

PubMed1981

Relative role of caloric restriction and exercise training upon susceptibility to isoproterenol-induced myocardial infarction in male rats.

To determine the relative effect of body weight and physical inactivity on susceptibility to drug-induced myocardial infarction, randomly selected groups of 100-day-old male Sprague-Dawley rats were subjected to a 10-wk program of exercise training and (or) to caloric restriction followed by two subcutaneous injections of L-isoproterenol. Two groups of rats were fed a restricted diet consisting of minimum calories to maintain body weight and were either exercised (R-Ex) or remained sedentary (R-C), one group was fed ad libitum and subjected to exercise (Ex), and one group remained sedentary (C), but was provided only enough food to maintain body weight in a range similar to Ex rats. Initially, there was no difference between group body weights, but Ex and C rats exhibited a significantly greater final body weight. All Ex, R-Ex, and R-C rats survived the isoproterenol injections, but 50% of C rats died. Group C rats exhibited significantly greater activity of total plasma lactate dehydrogenase (LDH), whereas R-Ex rats had the lowest total LDH activity (p less than 0.05). R-Ex and R-C rats had a significantly lower activity of plasma LDH-1, the heart isozyme, than did the heavier Ex and C rats. More specifically, R-C rats exhibited a significantly decreased amount of plasma LDH-1 activity when compared with Ex rats, indicating that smaller, untrained rats had less myocardial damage than the heavier, exercise-trained rats. These data suggest that either exercise or maintenance of body weight is beneficial toward prevention of the drug-induced myocardial infarction, but when weight maintenance is combined with exercise additional protection is provided.

Animals↗

PubMed2006

Caloric restriction and human longevity: what can we learn from the Okinawans?

Caloric (or dietary) restriction (CR) extends lifespan and lowers risk for age associated diseases in a phylogenetically diverse group of species. Whether prolonged CR increases average or maximum lifespan or promotes a more youthful physiology in humans at advanced ages is not yet known. However, available epidemiological evidence indicates that CR may already have contributed to an extension of average and maximum life span in one human population and appears to have lowered risk for age associated chronic diseases in other human populations. We review the human studies in the context of a special human population, older Okinawans, who appear to have undergone a mild form of prolonged CR for about half their adult lives.

Aging↗

PubMed2002

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts.

To provide a global analysis of gene expression in the aging heart, we monitored the expression of 9,977 genes simultaneously in 5- and 30-month-old male B6C3F(1) mice by using high-density oligonucleotide microarrays and several statistical techniques. Aging was associated with transcriptional alterations consistent with a metabolic shift from fatty acid to carbohydrate metabolism, increased expression of extracellular matrix genes, and reduced protein synthesis. Caloric restriction (CR) started at 14 months of age resulted in a 19% global inhibition of age-related changes in gene expression. Interestingly, CR also resulted in alterations in gene expression consistent with preserved fatty acid metabolism, reduced endogenous DNA damage, decreased innate immune activity, apoptosis modulation, and a marked cytoskeletal reorganization. These observations provide evidence that aging of the heart is associated with specific transcriptional alterations, and that CR initiated in middle age may retard heart aging by inducing a profound transcriptional reprogramming.

Aging↗

PubMed1992

The high mobility group of nuclear proteins as biomarkers of age and caloric restriction in rats.

The quantitative levels and phosphorylation states of the high mobility group (HMG) of proteins were investigated in bone marrow, brain, heart, kidney, liver, pancreas, spleen, testis and thymus of three groups of male Fischer 344 rats. Two groups of rats, young ad libitum (Y/AL - 1 1/2 mo.) and old ad libitum (O/AL - 28 mo.), had free access to rat chow, and a third group of old rats were maintained on a caloric restricted intake (O/CR - 28 mo.). The quantities of HMGs 1,2,14 and 17 were significantly reduced in O/AL rats compared with Y/AL rats in all tissues examined, and in many cases, the amount of HMGs of O/CR rats were increased by varying degrees from O/AL animals. In G2-phase nuclei of bone marrow, spleen and testis, phosphorylation of HMG proteins was reduced significantly in O/AL rats, but was enhanced in O/CR animals (especially HMG14). These levels of HMGs in O/CR animals, altered by age and diet dependent factors, reflect a condition which is more reminiscent of Y/AL than O/AL animals.

Aging↗

PubMed1995

Caloric restriction in obese pre-diabetic rats prevents beta-cell depletion, loss of beta-cell GLUT 2 and glucose incompetence.

Pre-diabetic male Zucker diabetic fatty rats (ZDF) become diabetic between 8 and 10 weeks of age. At that time their beta cells exhibit high basal insulin secretion, absent insulin response to glucose and loss of GLUT 2 glucose transporter. Beta-cell volume, which is increased at the onset of non-insulin-dependent diabetes, declines precipitously by age 18 weeks. To determine if expression of this diabetic phenotype was dependent upon the increased food intake of these rats, they were diet-matched to lean littermates for 12 weeks beginning at 6 weeks of age. Untreated control ZDF rats received an unrestricted diet for 3 months. All of the controls became hyperglycaemic by 8 weeks of age, whereas all diet-matched rats remained euglycaemic throughout the 3 months, despite the fact that at 18 weeks of age their mean body weight equaled that of obese rats on an unrestricted diet. In the former rats glucose-stimulated insulin secretion was absent at 12 weeks of age and GLUT-2-positive beta cells had fallen below 30%. The volume fraction of their beta cells was 2.6 times normal at this age but by 18 weeks of age it had declined by 75%. Diet restriction for 3 months prevented the loss of glucose-stimulated insulin secretion and the reduction of beta-cell GLUT-2 and beta-cell volume fraction. However, neither the elevated basal insulin secretion nor the exaggerated arginine-stimulated insulin secretion of the obese rats was reversed or prevented by caloric restriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗