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Results for “Caloric Restriction”

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PubMed1990

The effect of long-term caloric restriction on function of T-cell subsets in old mice.

The effect of caloric restriction (from weaning to old age) on CD3-stimulated CD4+ and CD8+ lymphocyte proliferation and calcium mobilization was examined. Young ad libitum (ad lib) fed, old ad lib fed, old calorically restricted, and old calorically restricted mice which were fed ad lib during the last 6 weeks of their life (restricted/refed) were compared in both BDF1 [(C57BL/6 x DBA/2)F1] and C57BL/6 mice. Proliferation of CD4+ cells was lower in old ad lib animals than in young animals; this difference was not seen in CD8+ cells. Those CD4+ cells which did proliferate in old ad lib animals underwent similar cell cycle progression as young cells. In calorically restricted and calorically restricted/refed animals, CD4+ cell proliferation was similar to the young animals, and CD8+ cells showed a higher proliferative capacity than cells from either young or old ad lib mice. Differences in proliferative capacity were not correlated with alterations in transmembrane signaling efficiency as peak [Ca2+]i was reduced in both T-cell subsets in all groups of old mice relative to young mice. Additionally, reduced [Ca2+]i was observed in the CD8+ subset for which there was no deficit in proliferation, and the enhanced proliferation seen in old restricted and old restricted/refed mice did not manifest as increased [Ca2+]i mobilization. The percentage of CD4+ cells from both mouse strains was reduced in all groups of old mice compared with young mice, while the percentage of CD8+ cells was generally similar in young and all groups of old mice. Our studies would suggest that lifelong caloric restriction of mice prevents the age-associated decrease in T-cell proliferative capacity but that the enhanced proliferation of these cells is not due to increased efficiency of transmembrane signaling.

Aging↗

PubMed2007

Transient caloric restriction and cancer risk (The Netherlands).

Over the past century, many animal experiments have shown that caloric restriction can reduce the risk of cancer, a finding that proved to be highly reproducible. Many papers have been published on its potential for human health, but until know little evidence is available on its actual effects in humans. In Utrecht, The Netherlands, we have been investigating the effects of the 1944-1945 Dutch famine on breast cancer risk factors and breast cancer risk, and paradoxically the relatively short-term famine seemed to be related to increased breast cancer risk in later life. One of the differences between the famine situation and the large body of evidence from animal experiments is the duration of caloric restriction. Almost all animal experiments investigated sustained caloric restriction and information on the effects of short-term transient caloric restriction is very scarce. A search in the literature identified some animal experiments on short-term transient caloric restriction and these seemed to be at least supportive to the famine findings. Because caloric restriction in humans for preventive health measures would be mostly short-term, it is important to extend animal research on short-term caloric restriction.

Animals↗

PubMed1977

Effects of acute caloric restriction on cholesterol metabolism in man.

The effects of acute caloric restriction on cholesterol balance and kinetics of plasma cholesterol specific activity were investigated in five hyperlipemic subjects with varying degrees of obesity. Caloric restriction decreased plasma triglycerides by 41 +/- 12%, plasma cholesterol by 11 +/- 9%, and the ratio of esterified to free cholesterol by 12 +/- 7+. Immediately on institution of caloric restriction there appeared to be an influx of tissue cholesterol into plasma and a reduction in endogenous synthesis of cholesterol. The cholesterol balance decreased from 1,469 +/- 441 to 1,212 +/- 349 mg/day and the rate of decay of plasma cholesterol specific activity decreased 62 +/- 3%. The effect of caloric restriction on hepatic synthesis of bile acids was also very prompt. The total fecal bile acids were reduced immediately by 36 +/- 7%. Because the effect on fecal excretion of deoxycholic acid was greater than that on fecal lithocholic acid, it was suggested that hepatic synthesis of cholic acid was reduced more than the synthesis of chenodeoxycholic acid. Caloric restriction did not cause any change in the percentage of absorption of dietary cholesterol (40 +/- 2% versus 42 +/- 3%). These observations are in accord with our model relating cholesterol metabolism with the metabolism of plasma lipoproteins in man.

Adult↗

PubMed1995

Role of caloric restriction in the prolongation of life.

Restriction of caloric intake increases longevity, slows the rate of functional decline, and reduces incidence of age-related disease in a variety of species. Most laboratory rodent studies have initiated restriction before puberty, whereas ongoing studies in nonhuman primates utilize restriction in adulthood. The mechanism of action of caloric restriction remains unknown; however, data suggest that cellular functions are altered in such a way that destructive by-products of metabolism are reduced, and defense or repair systems are enhanced by this nutritional manipulation.

Aging↗

PubMed2006

Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection.

Caloric restriction (CR) decreases aging rate and mitochondrial ROS (MitROS) production and oxidative stress in rat postmitotic tissues. Low levels of these parameters are also typical traits of long-lived mammals and birds. However, it is not known what dietary components are responsible for these changes during CR. It was recently observed that 40% protein restriction without strong CR also decreases MitROS generation and oxidative stress. This is interesting because protein restriction also increases maximum longevity (although to a lower extent than CR) and is a much more practicable intervention for humans than CR. Moreover, it was recently found that 80% methionine restriction substituting it for l-glutamate in the diet also decreases MitROS generation in rat liver. Thus, methionine restriction seems to be responsible for the decrease in ROS production observed in caloric restriction. This is interesting because it is known that exactly that procedure of methionine restriction also increases maximum longevity. Moreover, recent data show that methionine levels in tissue proteins negatively correlate with maximum longevity in mammals and birds. All these suggest that lowering of methionine levels is involved in the control of mitochondrial oxidative stress and vertebrate longevity by at least two different mechanisms: decreasing the sensitivity of proteins to oxidative damage, and lowering of the rate of ROS generation at mitochondria.

Aging↗

PubMed2003

Mitochondrion-mediated apoptosis is enhanced in long-lived alphaMUPA transgenic mice and calorically restricted wild-type mice.

Caloric restriction (CR) can extend the life-span of multiple species and is the only intervention known to attenuate aging in mammals. Mechanisms mediating the CR influence are as yet unclear. To get insight into these mechanisms we took advantage of alphaMUPA transgenic mice that have previously been reported to spontaneously eat less and live longer compared with their wild-type (WT) control. Here we report that mitochondria isolated from young adult alphaMUPA livers showed increased susceptibility to calcium-induced high-amplitude swelling, increased cytochrome c release and enhanced glutathione levels. Furthermore, young adult alphaMUPA mice showed significantly enhanced caspase-3 activity in liver homogenates, increased fraction of apoptotic hepatocytes, and a lower level of serum IGF-1. In addition, alphaMUPA mice showed a decreased rate of spontaneously occurring lung tumors at an old age. Short-term (8 weeks) calorically restricted WT mice also showed an increase of mitochondrial swelling and caspase-3 activity compared with ad libitum (AL) fed WT mice. These results provide the first indication that CR can enhance mitochondrion-mediated apoptotic capacity. Collectively, the results are consistent with the possibility that long lasting, moderately increased apoptotic capacity, possibly linked in part to IGF-1 and GSH modulation, could play a role in the CR-induced anti-aging influence in mice.

Aging↗

PubMed2004

Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

Aging↗

PubMed1995

Persistent lipolytic effect of exogenous growth hormone during caloric restriction.

PURPOSE: In previous studies in which obese volunteers were calorically restricted to 24, 18, or 12 kcal/kg of ideal body weight (IBW) per day, we observed that the growth-hormone-induced acceleration of body fat loss was variable and that the severity of caloric restriction modulated the magnitude of fat loss and the anabolic response to growth hormone. The present study was undertaken to characterize the effects of caloric restriction to 15 kcal/kg IBW per day on the metabolic response to growth hormone and to determine whether acceleration of body fat loss by growth hormone could be reproduced under conditions predicted to be optimal. PATIENTS AND METHODS: Eleven obese subjects were studied during two 38-day periods of caloric restriction. During one of these periods they received injections of growth hormone, 0.05 mg/kg IBW, for 28 days. Measurements of nitrogen balance, body fat content, insulin like growth factor I (IGF-I), free fatty acids, and glycerol concentrations were performed. RESULTS: Growth hormone injections caused an approximate 2.5-fold increase in IGF-I concentrations so that the mean IGF-I concentration was significantly greater during the injections than during diet alone (growth hormone 69.3 +/- 29.3 nmol/L; diet alone 26.6 +/- 7.6 nmol/L; P < 0.001). Growth hormone also caused nitrogen sparing, and the mean daily nitrogen balance was significantly greater during the injections (growth hormone 36.9 +/- 121.1 mmol/day; diet alone -122.3 +/- 125.9 mmol/day; P < 0.001). This nitrogen-sparing response to growth hormone attenuated over the 4 weeks of the injections. Growth hormone had a persistent lipolytic effect manifested by increases in glycerol concentrations, and body fat loss was greater during injections than during diet alone (fraction of weight lost as fat during injections 0.77 +/- 0.07; diet alone 0.63 +/- 0.06; P < 0.001). CONCLUSION: We conclude that growth hormone exerts anabolic effects that attenuate over time during caloric restriction but maintains its lipolytic effect despite hyperinsulinism and results in accelerated fat loss.

Adipose Tissue↗

PubMed2005

Caloric restriction inhibits steroid-induced gonadotropin surges in ovariectomized rhesus monkeys.

We recently reported that caloric restriction inhibited ovulation in rhesus monkeys. The objective of the current study was to determine if caloric restriction affected the positive feedback response to ovarian steroids in non-human primates. Studies were conducted in four long-term ovariectomized rhesus monkeys. Animals were given an estrogen/progesterone challenge while maintained on a normal diet and on a diet that reduced body weight by approx 20%. In all cases, animals were maintained at the desired weight [based on a calculation of body mass index (BMI)] for a minimum of 4 wk before initiating the steroid challenge. Caloric restriction reduced BMI from 23.3 +/- 0.3 to 18.9 +/- 0.2 kg/m2. The estrogen/progesterone challenge elicited an LH and FSH surge in each animal maintained at a normal BMI. By contrast, gonadotropin surges were significantly compromised when monkeys were challenged at a low BMI. In addition to affecting the reproductive axis, caloric restriction stimulated cortisol release and suppressed T3 secretion. These endocrine effects of caloric restriction are consistent with our findings in ovary-intact monkeys. In summary, our previous reports in ovary-intact animals confirmed an effect of caloric restriction on tonic gonadotropin secretion leading to anovulation. Our current results suggest the effects of caloric restriction on the reproductive axis extend beyond inhibition of tonic gonadotropin secretion to include a disturbance of phasic gonadotropin secretion.

Amenorrhea↗

PubMed1989

Effect of chronic caloric restriction on hepatic enzymes of intermediary metabolism in the male Fischer 344 rat.

It is well established that caloric restriction extends life span and significantly retards the rate of occurrence of most age-associated degenerative disease processes. A paucity of data exists relative to the mechanisms by which caloric restriction accomplishes these events. We have examined the effect of caloric restriction in rats on several hepatic enzymes of intermediary metabolism. The activities of glycolytic and supporting enzymes including lactate dehydrogenase, pyruvate kinase, sorbitol dehydrogenase, and alcohol dehydrogenase were all decreased in response to caloric restriction. Fructose 1-phosphate aldolase and creatine phosphokinase were not altered. Likewise, enzymes associated with lipid metabolism (malic enzyme and glycerokinase) were reduced (fatty acid synthetase was reduced, but not to a statistically significant degree). Activities of enzymes supporting gluconeogenesis (glutamate oxaloacetate transaminase, tyrosine aminotransferase, glutamate pyruvate transaminase, glutamate dehydrogenase, amino acid oxidase, malate dehydrogenase, and glucose 6-phosphatase) were either unchanged or increased significantly by caloric restriction. Glucagon levels were decreased. Comparisons between young ad libitum fed and older calorically restricted rats revealed similar but not identical metabolic activity. These results suggest that caloric restriction produces an effect on intermediary metabolism, favoring the role of glucagon and glucose synthesis; but limiting the role of insulin and glucose catabolism in the liver. The former observation provides for the efficient support of peripheral tissues and the latter a level of energy production necessary only for self maintenance. Limited lipid metabolism suggests decreased potential for fatty acid epoxide formation and free radical damage to cellular macromolecules. Additionally, caloric restriction may delay the progressive age associated changes in the activities of some of the enzymes investigated.

Age Factors↗

PubMed2005

Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity.

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.

Animals↗

PubMed1994

Adaptation of muscle glucose transport with caloric restriction in adult, middle-aged, and old rats.

The effects of prolonged caloric restriction (60% of ad libitum intake initiated at 14 wk of age) on glucose transport activity in isolated epitrochlearis muscles were studied in female Fischer 344 rats aged 8, 18, and 23 mo. Basal 3-O-methylglucose transport (3-MG) rate (without insulin) was not significantly altered by caloric restriction. With a submaximally effective insulin concentration (75 microU/ml), 3-MG transport was enhanced in the caloric-restricted groups by 59, 59, and 105% at 8, 18, and 23 mo of age, respectively. With a maximally effective insulin concentration (20,000 microU/ml), 3-MG transport was increased after caloric restriction, despite no change in muscle GLUT4 glucose transporter protein content. These results indicate that chronic caloric restriction enhances insulin stimulation of the glucose transport system independent of changes in basal glucose transport or muscle GLUT4 levels, and insulin-stimulated glucose transport is enhanced in rats with chronic caloric restriction at least until 23 mo of age.

3-O-Methylglucose↗

PubMed1993

Relationship between lipid peroxidation, fatty acid composition, and ascorbic acid in the liver during carbohydrate and caloric restriction in mice.

Growing OF1 mice were treated on a short-term basis with ad libitum, caloric-restricted, or carbohydrate-restricted diets, maintaining the same intake of vitamins and minerals in the three groups. Caloric intake was 60% of controls both in the caloric-restricted and in the carbohydrate-restricted groups. Neither global nor carbohydrate restriction changed liver superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, cytochrome oxidase, GSH, uric acid, or malondialdehyde (HPLC). Ascorbate was decreased in both restricted groups. Carbohydrate restriction, but not caloric restriction, increased unsaturation indexes of fatty acids in all lipid classes analyzed and increased sensitivity to peroxidation by one order of magnitude. It is concluded that short-term caloric restriction does not seem to increase antioxidants and decrease peroxidation in the mouse liver whereas long-term restriction can avoid decreases of antioxidants and increases of peroxidation during aging. Our experiments support the prevailing view that the caloric restriction phenomenon is due to a reduction in calories themselves instead of to a reduction in carbohydrates. This last manipulation strongly increases sensitivity to peroxidative damage in the liver. The results show that in vivo fatty acid unsaturation is a main factor in determining the sensitivity to lipid peroxidation.

Animals↗

PubMed1997

Caloric restriction attenuates dityrosine cross-linking of cardiac and skeletal muscle proteins in aging mice.

Oxidative damage, particularly to proteins, has been widely postulated to be a major causative factor in the loss of functional capacity during senescence. The nature of the various mechanisms that may contribute to protein oxidation is only partially understood. In this study, concentrations of two markers for oxidative damage, o,o'-dityrosine and o-tyrosine, were determined using stable isotope dilution gas chromatography-mass spectrometry in four tissues of the mouse, namely heart, skeletal muscle, brain, and liver, during youth (4 months old), adulthood (14 months old), and old (30 months old) age. A comparison was made between mice that had access to unlimited calories with those that were restricted to 60% of the caloric intake of the ad libitum regimen. Caloric restriction of this magnitude extends the average and maximum life span of mice by approximately 40%. In vitro studies demonstrated that o,o'-dityrosine was generated selectively in proteins exposed to tyrosyl radical. o-Tyrosine increased in proteins oxidized with hydroxyl radical, which also resulted in a variable increase in o,o'-dityrosine. In mice fed ad libitum, levels of o,o'-dityrosine increased with age in cardiac and skeletal muscle but not in liver or brain. In contrast, o-tyrosine levels did not rise with age in any of the tissues examined. These results suggest that tyrosyl radical-induced protein oxidation increases selectively with age in skeletal muscle and heart. Caloric restriction prevented the increase in o,o'-dityrosine levels in cardiac and skeletal muscle but did not influence o-tyrosine levels in any of the four tissues. This selective increase in o,o'-dityrosine levels and its prevention by a life-prolonging caloric restriction regimen raise the possibility that oxidation of muscle proteins by tyrosyl radical contributes to the deterioration of cardiac and skeletal muscle function with advancing age.

Aging↗

PubMed2006

Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats.

Dietary restriction (DR) has been shown to increase life span, delay or prevent age-associated diseases, and improve functional and metabolic cardiovascular risk factors in rodents and other species. To investigate the effects of DR on beat-to-beat heart rate and diastolic blood pressure variability (HRV and DPV) in male Sprague-Dawley rats, we implanted telemetric transmitters and animals were maintained on either intermittent fasting (every other day feeding) or calorie-restricted (40% caloric reduction) diets. Using power spectral analysis, we evaluated the temporal profiles of the low- and high-frequency oscillatory components in heart rate and diastolic blood pressure signals to assess cardiac autonomic activity. Body weight, heart rate, and systolic and diastolic blood pressure were all found to decrease in response to DR. Both methods of DR produced decreases in the low-frequency component of DPV spectra, a marker for sympathetic tone, and the high-frequency component of HRV spectra, a marker for parasympathetic activity, was increased. These parameters required at least 1 month to become maximal, but returned toward baseline values rapidly once rats resumed ad libitum diets. These results suggest an additional cardiovascular benefit of DR that merits further studies of this potential effect in humans.

Animals↗

PubMed1992

Effect of caloric restriction on hepatic nuclear DNA damage in male Fischer 344 rats treated with aflatoxin B1.

Caloric restriction is known to reduce chemically-induced tumor incidence in laboratory animals. The effect is believed to be mediated in part by modification of hepatic drug metabolism, including both phase I and phase II enzymes. Using aflatoxin B1 (AFB1) as a model carcinogen, we studied the effect of caloric restriction on the modification of rat liver nuclear DNA by AFB1 and DNA damage due to the formation of apurinic sites from the AFB1-DNA adduct removal process. Caloric restriction reduced the metabolic activation of AFB1 which resulted in a decrease of AFB1-DNA binding by more than 50%. The results of the study of the effect of caloric restriction on the AFB1-induced DNA strand breakage assayed by the alkaline unwinding technique showed that caloric restriction protected the formation of apurinic sites from the AFB1-DNA adducts and reduced the double strand DNA breakages by 1.3-2.5-fold. Thus, the lower initial AFB1-DNA binding and less DNA damage, presumably by the less apurinic sites formed during the depurination process of AFB1-DNA adducts, contributed to the protective effect of caloric restriction.

Aflatoxin B1↗

PubMed2002

Influence of aging and long-term caloric restriction on oxygen radical generation and oxidative DNA damage in rat liver mitochondria.

The effect of long-term caloric restriction and aging on the rates of mitochondrial H2O2 production and oxygen consumption as well as on oxidative damage to nuclear (nDNA) and mitochondrial DNA (mtDNA) was studied in rat liver tissue. Long-term caloric restriction significantly decreased H2O2 production of rat liver mitochondria (47% reduction) and significantly reduced oxidative damage to mtDNA (46% reduction) with no changes in nDNA. The decrease in ROS production was located at complex I because it only took place with complex I-linked substrates (pyruvate/malate) but not with complex II-linked substrates (succinate). The mechanism responsible for that decrease in ROS production was not a decrease in mitochondrial oxygen consumption because it did not change after long-term restriction. Instead, the caloric restricted mitochondria released less ROS per unit electron flow, due to a decrease in the reduction degree of the complex I generator. On the other hand, increased ROS production with aging in state 3 was observed in succinate-supplemented mitochondria because old control animals were unable to suppress H2O2 production during the energy transition from state 4 to state 3. The levels of 8-oxodG in mtDNA increased with age in old animals and this increase was abolished by caloric restriction. These results support the idea that caloric restriction reduces the aging rate at least in part by decreasing the rate of mitochondrial ROS production and so, the rate of oxidative attack to biological macromolecules like mtDNA.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1994

Effect of caloric restriction on colonic proliferation in obese persons: implications for colon cancer prevention.

Dietary intervention to prevent colon cancer is a major health issue. At present it is not clear which dietary factors modify colon cancer risk. Caloric restriction reduces the incidence of many spontaneous and carcinogen-induced tumors in rodents, but its role in human carcinogenesis is unknown. The relationships of body mass index (BMI), body composition, and resting metabolic rate (RMR) to colon cancer risk are also undefined. In this study involving obese persons, we measured the effect of reducing caloric intake on rectal cell proliferation, a biomarker in colon carcinogenesis, and studied the relation of BMI, body composition, and RMR to rectal cell proliferation. Colonic cell proliferation was measured in rectal biopsies from persons weighing more than 130% of ideal body weight. Follow-up biopsies were performed in patients who enrolled in and completed a 16-week behavior modification weight-reduction program in which caloric intake was reduced. Baseline measurements included body composition by total body electrical conductance, RMR, and BMI. Rectal biopsies were processed for autoradiography following incubation with [3H]thymidine. Epithelial proliferation measurements were evaluable in 35 persons at baseline and in 8 persons before and after caloric restriction. Before caloric restriction, mean (+/- SD) BMI was 38 +/- 4 kg/m2 and percentage of body fat 41 +/- 2%. Subjects reduced their caloric intake by a mean of 34 +/- 4% and their weight by 8.6 +/- 1%. Caloric restriction resulted in a 39% reduction in whole-crypt labeling index (P < 0.001) and a 57% reduction in upper crypt labeling index (P < 0.05) without reduction in crypt depth. Labeling index was unrelated to BMI, RMR, or body composition. We conclude that caloric restriction reduced rectal cell proliferation measurements--intermediate biomarkers related to colon carcinogenesis. BMI, RMR, and body composition were unrelated to colonic proliferation. Caloric restriction may have a role in colon cancer prevention.

Adult↗