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PubMed2003

Caloric restriction in trans.

Caloric (or dietary) restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in laboratory mammals. Two of the major questions faced by researchers in this field are the applicability to humans and the biochemical mechanism(s) involved in the actions of CR. Studies in nonhuman primates are beginning to address the former; studies in phylogenetically lower organisms such as yeast and Drosophila are beginning to address the latter. de Cabo and colleagues now provide evidence that some aspects of CR can be reproduced in mammalian tissue culture cells exposed to sera from rats and monkeys subjected to CR. This work presents the initial development of a new model with which to approach mechanistic studies of CR and provides a new form of direct evidence that CR exerts at least some of its effects in trans.

Animals↗

PubMedDate not supplied

Caloric restriction and experimental mammary carcinogenesis.

It has been demonstrated repeatedly that caloric restriction, or underfeeding, will inhibit the growth of spontaneous, transplanted, or induced tumors in mice and rats. Caloric restriction will inhibit tumorigenesis even in the face of a high fat diet. The mechanism of action is moot but caloric restriction reduces plasma insulin levels, increases activities of antioxidant enzymes, and enhances DNA repair. It also reduces oncogene expression. The cancer growth-inhibiting action of caloric restriction may be reversed by adrenalectomy.

Animals↗

PubMed1987

Basal and postprandial lipoprotein lipase activity in adipose tissue during caloric restriction and refeeding.

The effect of a ten-day caloric restriction period and of subsequent refeeding on adipose tissue lipoprotein lipase (LPL) activity was studied in 14 moderately obese women. The enzyme assays were made from subcutaneous fat taken from three separate regions (gluteal, femoral, and abdominal) after overnight fasting and from one region also after a standard meal. There was a close correlation between the activities measured from the different subcutaneous sites. The caloric restriction was followed by a decrease of the basal LPL activity to one fifth of the value recorded during the isocaloric diet. However, the relative postprandial increase of LPL activity was greater during the low-calorie diet than during the isocaloric diet. During refeeding the basal LPL activity rose but remained at a lower level than before the caloric restriction. The postprandial LPL response was markedly exaggerated after ten days of refeeding (21% increase before dieting and 250% after refeeding). The changes of LPL during caloric restriction and subsequent refeeding were not correlated to plasma insulin levels. The mechanism of the exaggerated LPL response to meal during refeeding remains obscure.

Adipose Tissue↗

PubMed2002

Aging increases Nepsilon-(carboxymethyl)lysine and caloric restriction decreases Nepsilon-(carboxyethyl)lysine and Nepsilon-(malondialdehyde)lysine in rat heart mitochondrial proteins.

The present investigation studies the effect of aging, short-term and long-term caloric restriction on four different markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins: protein carbonyls (measured by ELISA); Nepsilon-(carboxyethyl)lysine (CEL), Nepsilon-(carboxymethyl)lysine (CML), and Nepsilon-(malondialdehyde)lysine (MDA-lys) measured by gas chromatography/mass spectrometry. Aging increased the steady state level of CML in rat heart mitochondria without changing the levels of the other three markers of protein damage. Short-term caloric restriction (six weeks) did not change any of the parameters measured. However, long-term (one year) caloric restriction decreased CEL and MDA-lys in heart mitochondria and did not change protein carbonyls and CML levels. The decrease in MDA-lys was not due to changes in the sensitivity of mitochondrial lipids to peroxidation since the measurements of the fatty acid composition showed that the total number of fatty acid double bonds was not changed by caloric restriction. The decrease in CEL and MDA-lys in caloric restriction agrees with the previously and consistently described finding that caloric restriction agrees with the previously and consistently described finding that caloric restriction lowers the rate of generation of reactive oxygen species (ROS) in rodent heart mitochondria, although in the case of CEL a caloric restriction-induced lowering of glycaemia can also be involved. The CEL and MDA-lys results support the notion that caloric restriction decreases oxidative stress-derived damage to heart mitochondrial proteins.

Aging↗

PubMed2003

Decreasing serum concentrations of all-trans, 13-cis retinoic acids and retinol during fasting and caloric restriction.

OBJECTIVES: To investigate the effects of caloric restriction on the serum concentrations of retinoids in man. DESIGN: Samples were drawn before and during caloric restriction by fasting or 4-6 weeks after gastric surgery. SUBJECTS: The fasting group included 17 healthy subjects (11 women and six men) and 16 obese patients (10 women and six men) who underwent bariatric surgery (vertical banded gastroplasty). MAIN OUTCOME MEASURES: Serum concentrations of all-trans, 13-cis, 4-oxo-13-cis retinoic acids and retinol. RESULTS: The serum concentrations of retinol, all-trans and 13-cis retinoic acids decreased by about 20% after 5 days of fasting. After gastroplasty, the serum concentration of retinol, all-trans, 13-cis retinoic acids, retinol-binding protein and transthyretin also decreased to a similar extent after 1 month. In both groups we found a correlation between the delta values of 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic acid. In all subjects there were also correlations between the delta values of the retinoids. However, these correlations were comparatively weak (e.g. r2 = 0.36 for retinol--all-trans retinoic acid). The change in retinoid concentrations did not correlate to the change of weight or body mass index. CONCLUSION: Our results support the hypothesis that serum retinol is one of the determinants of serum concentrations of all-trans and 13-cis retinoic acid and that the catabolism of 13-cis retinoic acid is not affected by fasting. However, in the individual case, S-Retinol is a poor predictor of S-All-trans retinoic acid.

Adult↗

PubMed2003

Short-term caloric restriction and regulatory proteins of apoptosis in heart, skeletal muscle and kidney of Fischer 344 rats.

Long-term caloric restriction reduces oxidative stress, increases mean and maximum lifespan in rodents and tends to enhance apoptosis, particularly in the liver. We investigated the effect of short-term (2 months) caloric restriction (40% reduction) in 6-month-old male Fischer 344 rats on various indicators of apoptosis (caspase-3, -7, -12, the inhibitor of apoptosis protein XIAP and cytoplasmic histone-associated DNA fragments) in the post-mitotic heart and gastrocnemius muscle, and the kidney that contains mitotic cells. Short-term caloric restriction significantly reduced body mass (30%), gastrocnemius muscle mass (22%), heart mass (25%) and kidney mass (32%) compared to ad libitum controls. The levels of procaspase-3 in gastrocnemius muscle and caspase-3 in kidney were significantly lower in the caloric restricted than in the ad libitum fed group. While caloric restriction did not alter DNA fragmentation levels (indicative of apoptosis), differences did exist amongst tissues with significantly elevated levels of fragmentation in the kidney compared to the heart and gastrocnemius muscle and significantly higher levels in the heart compared to gastrocnemius muscle. No differences were observed between groups in the levels of procaspase-7 or -12 or in XIAP (an endogenous inhibitor of apoptosis, particularly of caspase-3 and -7) in any tissue. The active forms of caspase-7 and -12 were present only in the kidney. These findings suggest that while the rate of apoptosis was higher in the kidney, which contains mitotic cells, compared to the post-mitotic heart and gastrocnemius muscle, short-term caloric restriction did not enhance the apoptosis rate in any tissue measured.

Aging↗

PubMed2003

The effect of caloric restriction on glycation and glycoxidation in skin collagen of nonhuman primates.

The accumulation of Maillard reaction products increases with age in long-lived proteins and can be retarded by caloric restriction. Here we determined whether caloric restriction inhibits formation of glycation and glycoxidation products in skin collagen of squirrel and rhesus monkeys between 1990-1997. Restricted monkeys (n = 11, n = 30, respectively) were maintained at 70% of caloric intake of controls (n = 25, n = 32, respectively). Glycation was assessed by furosine and glycoxidation by pentosidine and carboxymethyl-lysine. With age, the rate of furosine formation moderately but nonsignificantly (p >.05) increased in both control monkey groups. It significantly (p =.011) decreased in the caloric-restricted rhesus, but not squirrel monkeys. Caloric restriction did not significantly decrease the pentosidine or carboxymethyl-lysine rates in either species of monkeys. These results suggest that caloric restriction, when maintained long-term in nonhuman primates, tends to decrease glycation, but not glycoxidation.

Aging↗

PubMed1985

The effects of triiodothyronine on energy expenditure, nitrogen balance and rates of weight and fat loss in obese patients during prolonged caloric restriction.

We studied ten obese patients on prolonged caloric restriction by metabolic balance techniques two weeks before and two weeks after the start of treatment with triiodothyronine (T3) (0.36-1.01 micrograms/kg/d). The rate of weight, nitrogen and fat loss calculated from metabolic balance increased during T3 therapy and these effects were maximal in the second week of treatment. In seven patients studied continuously for four weeks on T3 therapy, the rates of weight and fat loss during the fourth week of treatment were not significantly different from pretreatment values while nitrogen loss was still significantly greater. The increase in nitrogen loss, studied after the period of adaptation to caloric restriction, implies that prolonged treatment with T3 can result in significant losses of lean tissue in addition to that resulting from caloric restriction alone. Mean weight loss increased by 92 g/d during T3 therapy. T3 significantly increased the metabolic rate as measured by two other independent measures: the resting energy expenditure (REE), measured by indirect calorimetry (fourteen patients), and the sleeping heart rate (six patients).

Adolescent↗

PubMed1993

Effects of caloric restriction and dietary fat on epithelial cell proliferation in rat colon.

Epidemiological studies indicate that caloric intake and dietary fat content influence colonic carcinogenesis. In rodents, caloric restriction reduces, and some fats increase, carcinogen-induced colon cancer incidence. The present study was designed to investigate the effects of caloric restriction on colonic cell proliferation (CCP) in carcinogen-treated or control rats fed low- or high-fat diets. F344 rats were treated with azoxymethane (15 mg/kg x2) and then fed an isocaloric AIN 76A diet containing either 5 or 23% corn oil, ad libitum or calorie-restricted to 70 or 80% of the kilocalories consumed by ad libitum rats. Biopsies of the distal colon were taken at 10 and 20 weeks, and rats were sacrificed at 21 or 34 weeks on the experimental diets. Distal CCP was determined by microautoradiography after [3H]thymidine labeling in vitro or presacrifice administration in vivo. The labeling index and number of labeled cells per crypt column were significantly reduced by caloric restriction at all time points (10, 20, 21, 34 weeks). Caloric restriction reduced CCP in high fat- and low fat-fed rats and in azoxymethane-treated and control rats. High fat resulted in decreased CCP in the distal colon compared to low fat at 34 weeks but not earlier. The findings indicate that: (a) caloric restriction is effective in favorably modulating CCP, an intermediate biomarker of colon cancer risk; (b) a high fat ad libitum diet, which increased tumor yield, does not increase distal colon proliferation; (c) dietary fat intake alters proliferation in a manner differing from that induced by changing dietary caloric intake.

Animals↗

PubMed2001

Caloric restriction mimetics: metabolic interventions.

Caloric restriction (CR) retards diseases and aging in laboratory rodents and is now being tested in nonhuman primates. One way to apply these findings to human health is to identify and test agents that may mimic critical actions of CR. Panel 2 focused on two outcomes of CR, reduction of oxidative stress and improved glucoregulation, for which candidate metabolic mimics exist. It was recommended that studies on oxidative stress should emphasize mitochondrial function and to test the efficacy of nitrone and other antioxidants in mimicking CR's effects. Studies should also focus on the long-term effects of compounds known to lower circulating glucose and insulin concentrations or to increase insulin sensitivity. Also, four other developing areas were identified: intermediary metabolism, response to infection, stress responses, and source of dietary fat. These areas are important because either they hold promise for the discovery of new mimetics or they need to be explored prior to initiation of CR trials in humans. Other recommendations were that transgenic approaches and adult-onset CR should be emphasized in future studies.

Animals↗

PubMed1999

Caloric restriction and genomic stability.

Caloric restriction (CR) without malnutrition is the only experimental manipulation that has consistently been shown to increase the mean and maximum lifespan of laboratory rodents. It has been suggested that CR extends the longevity of rodents and reduces the incidence of age-related pathological lesions by reducing the levels of DNA damage and mutations that accumulate with age within a cells genome. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by the observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage. However, all the evidence supporting the premise that the accumulation of DNA damage/mutations plays a role in aging and CR is correlative, i.e., the anti-aging action of CR-fed rodents is correlated with decreased DNA damage and mutation and increased DNA repair capacity. Therefore, additional experiments are required which employ more accurate assays of the DNA repair pathways as well as genetically engineered animal models to establish the role of specific DNA repair pathways and/or enzymes in the anti-aging action of CR. In this paper, we review the proposed mechanisms of DNA damage/repair while providing insight into current research that may assist in "unlocking" the mechanisms behind the life-prolonging effect of CR.

Aging↗

PubMed2006

Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans.

BACKGROUND: Caloric restriction (CR) has long been recognized as a dietary therapy that improves health and increases longevity. Little is known about the persistent effects of CR on plasma biomarkers (glucose, ketone bodies, and lipids) following re-feeding in mice. It is also unclear how these biomarker changes in calorically restricted mice relate to those observed previously in calorically restricted humans. RESULTS: Three groups of individually housed adult female C57BL/6J (B6) mice (n = 4/group) were fed a standard rodent chow diet either: (1) unrestricted (UR); (2) restricted for three weeks to reduce body weight by approximately 15-20% (R); or (3) restricted for three weeks and then re-fed unrestricted (ad libitum) for an additional three weeks (R-RF). Body weight and food intake were measured throughout the study, while plasma lipids and levels of glucose and ketone bodies (beta-hydroxybutyrate) were measured at the termination of the study. Plasma glucose, phosphatidylcholine, cholesterol, and triglycerides were significantly lower in the R mice than in the UR mice. In contrast, plasma fatty acids and beta-hydroxybutyrate were significantly higher in the R mice than in the UR mice. CR had no effect on plasma phosphatidylinositol levels. While body weight and plasma lipids of the R-RF mice returned to unrestricted levels upon re-feeding, food intake and glucose levels remained significantly lower than those prior to the initiation of CR. CONCLUSION: CR establishes a new homeostatic state in B6 mice that persists for at least three weeks following ad libitum re-feeding. Moreover, the plasma biomarker changes observed in B6 mice during CR mimic those reported in humans on very low calorie diets or during therapeutic fasting.

3-Hydroxybutyric Acid↗

PubMed1990

Influence of caloric restriction and exercise on tumorigenesis in rats.

Underfeeding or caloric restriction have been shown to inhibit the growth of spontaneous, transplanted, or chemically induced tumors in rats and mice. At 40% caloric restriction, growth of 7,12-dimethylbenz(a)anthracene-induced mammary and 1,2-dimethylhydrazine-induced colonic tumors is inhibited significantly even when the restricted diet contains twice as much fat as the control diet. Some inhibitory effects become evident even at 10% caloric restriction. In studies involving high fat diets, we find that rats receiving 20% fat ad libitum exhibit significantly higher 7,12-dimethylbenz(a)anthracene-induced mammary tumor incidence, multiplicity, and weight than rats ingesting the same amount of fat daily, but in a diet containing 25% fewer calories. In a study of intermittent ad libitum and restrictive feedings, chemically induced tumorigenicity varies inversely with feed efficiency. Exercise has also been shown to inhibit tumor growth. Sedentary rats fed ad libitum have a 108% higher incidence of 1,2-dimethylhydrazine-induced colon tumors than rats fed ad libitum but subjected to vigorous treadmill exercise. Caloric flux (either reduced intake or increased outflow) appears to reduce tumorigenicity in rodents.

1,2-Dimethylhydrazine↗

PubMed1997

A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research.

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.

Aging↗

PubMedDate not supplied

Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats.

The present study was designed to assess the impact of moderate caloric restriction (60% of ad libitum fed animals) on cerebral vascular density and local cerebral blood flow. Vascular density was assessed in male Brown-Norway rats from 7-35 months of age using a cranial window technique. Arteriolar density, arteriole-arteriole anastomoses, and venular density decreased with age and these effects were attenuated by moderate caloric restriction. Analysis of local cerebral blood using [14C]iodoantipyrine indicated that basal blood flow decreased with age in CA1, CA3 and dentate gyrus of hippocampus; similar trends were evident in cingulate, retrosplenal, and motor cortex. Basal blood flow was increased in all brain regions of moderate caloric restricted old animals (compared to old ad libitum fed animals) and no differences were observed between ad libitum fed young and caloric restricted older animals. In response to a CO2 challenge to maximally dilate vessels, blood flow increased in young and old ad libitum fed animals, but a similar increase was not observed in caloric restricted old animals. We conclude that a decrease in cerebral vasculature is an important contributing factor in the reduction in blood flow with age. Nevertheless, vessels from young and old animals have the capacity to dilate in response to a CO2 challenge and, after CO2, no differences are observed between the two age-groups. These results are consistent with the hypothesis that aged animals fail to adequately regulate local cerebral blood flow in response to physiological stimuli. Moderate caloric restriction increases microvascular density and cerebral blood flow in aged animals but tissues exhibit little or no increase in blood flow in response to CO2 challenge. The cause of this deficient response may indicate that vessels are maximally dilated in aged calorically restricted animals or that they fail to exhibit normal regulatory control.

Aging↗

PubMed1989

Inhibition of DMBA-induced mammary tumorigenesis by caloric restriction in rats fed high-fat diets.

Most previous studies on the inhibiting effect of caloric restriction during promotion of DMBA-induced mammary carcinogenesis have used low to moderate levels of dietary fat, i.e., about 4 to 14% by weight. The current study was designed to test whether a moderate degree of caloric restriction, 25%, would inhibit tumor growth in rats fed the equivalent of 20% dietary fat which approximates human consumption in affluent countries. Rats were fed diets ad libitum that contained 5, 15 or 20% corn oil. Groups of rats were pair-fed to the last 2 groups, but subjected to a 25% caloric restriction. These groups were fed 20 or 26.7% corn oil so that absolute fat intake in the paired groups was identical. Significant inhibition of tumor incidence, tumor weight, tumor burden, body fat deposition, and fasting serum insulin were observed in the 2 calorically restricted groups. We conclude that moderate caloric restriction is significantly more effective in inhibiting tumor growth than is the promoting effect of diets high in fat. Total body weight, body fat and serum insulin concentrations may be better correlates of risk of developing mammary tumors than is dietary fat.

3-Hydroxybutyric Acid↗

PubMed2002

Caloric restricted male rats demonstrate fewer synapses in layer 2 of sensorimotor cortex.

Previous studies have demonstrated an age-related decline in the density of presumptive inhibitory synapses in layer 2 of rat sensorimotor cortex [J. Comp. Neurol. 439(1) (2001) 65]. Caloric restriction has been shown to ameliorate age-related deterioration in a variety of systems and to extend life span. The present study tested the hypothesis that caloric restriction would prevent the previously reported age-related synaptic decline. Accordingly, synaptic density in layer 2 of sensorimotor cortex was compared between 29-month-old male rats fed ad libitum and 29-month-old male rats that were caloric restricted (60% of ad libitum calories) from 4 months of age. In serial electron micrographs, the physical disector was used to determine the numerical density of presumptive excitatory and inhibitory synapses (those containing round or nonround vesicles, respectively) as well as that of neurons. Not only was the previously reported age-related decline in numerical density of presumptive inhibitory synapses not ameliorated by caloric restriction, the numerical density was significantly lower in caloric restricted than in ad libitum fed rats for total as well as for presumptive excitatory and inhibitory synapses. Analysis further revealed no difference in the numerical density of neurons in this region. Relating synapse density to neuron density as the ratio of synapses to neuron also demonstrated significantly fewer synapses per neuron in caloric restricted than in ad libitum fed old rats. Finally, synapse length was significantly less in caloric restricted rats. These results suggest that not only does caloric restriction fail to prevent the age-related decline in presumptive inhibitory synapses, it results in fewer presumptive excitatory synapses as well.

Aging↗

PubMed1999

Caloric restriction abolishes enhanced metabolic efficiency induced by ectopic agouti protein in yellow mice.

Caloric restriction (CR), from approximately 3 months of age, at 70% of the ad libitum (AL) caloric intake prevented development of overt obesity in female "viable yellow" Avy/A (BALB/cStCrlfC3Hf/Nctr x VY/WffC3Hf/Nctr-Avy) F1 hybrid mice. In adult yellow Avy/A mice, caloric restriction eliminated the increased metabolic efficiency associated with the presence of agouti protein in ectopic sites. At 4 weeks of age, the yellow Avy/A mice were approximately 14% heavier and by 12 weeks of age, when caloric restriction began, they were approximately 24% heavier than the congenic agouti A/a mice. Between 4 and 12 weeks, the yellow mice gained approximately 63% in body weight, whereas the agouti mice gained only approximately 44%. While the comparable AL Avy/A mice gained approximately 128% and the AL A/a mice gained approximately 41% between 12 and 51 weeks of age, the CR Avy/A and A/a mice gained only 16% and 15%, respectively. Mean brain weights of CR mice of both genotypes were lower than those of the comparable ad libitum-fed (AL) groups; however, CR Avy/A mice had slightly, but significantly (P < 0.0001), higher brain weights than CR A/a mice. The larger mean brain weight and retention, during caloric restriction, of the somewhat greater prerestriction Avy/A mean body weight compared with prerestriction A/a mice were consonant with the hypothesis that ectopic agouti protein affects somatic growth directly or indirectly. This may be related to altered developmental/metabolic programming in yellow mice, indicated by greater metabolic efficiency and by an early transient increase in circulating IGF-1 levels. The specific cellular processes modulated by the agouti protein in ectopic sites remain to be identified.

Age Factors↗