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PubMed2002

Effects of chronic caloric restriction on mitochondrial respiration in the ischemic reperfused rat heart.

Dietary restriction increases life span and delays the development of age-related diseases in rodents. We have recently demonstrated that chronic dietary restriction is beneficial on recovery of heart function following ischemia. We studied whether the metabolic basis of this benefit is associated with alterations in mitochondrial respiration. Male Wistar rats were assigned to an ad libitum-fed (AL) group and a food restricted (FR) group, in which food intake was reduced to 55% of the amount consumed by the AL group. Following an 8-month period of restricted caloric intake, isolated working hearts perfused with glucose and high levels of fatty acids were subjected to global ischemia followed by reperfusion. At the end of reperfusion, total heart mitochondria respiration was assessed in the presence of pyruvate, tricarboxylic acid intermediates, and palmitoylcarnitine. Recovery of heart function following ischemia was greater in FR hearts compared to AL hearts. Paralleling these changes in heart function was an increase in state 3 respiration with pyruvate. The respiratory control ratios in the presence of pyruvate and tricarboxylic acid intermediates were higher in FR hearts compared to AL hearts, indicating well-coupled mitochondria. Overall energy production, expressed as the ADP:O ratio and the oxidative phosphorylation rate, was also improved in FR hearts. Our results indicate that the beneficial effect of FR on recovery of heart function following ischemia is associated with changes in mitochondrial respiration.

Adenosine Diphosphate↗
PubMedDate not supplied

Distinct roles of processes modulated by histone deacetylases Rpd3p, Hda1p, and Sir2p in life extension by caloric restriction in yeast.

Caloric restriction has been demonstrated to extend life span and postpone aging in a variety of species. The recent extension of the caloric restriction paradigm to yeast places the emphasis of the search for the longevity effectors at the cellular level. To narrow the range of potential effectors of the caloric restriction response, we have examined the effects of the histone deacetylases Rpd3p, Hda1p, and Sir2p, which have distinguishable but partially overlapping influences on global patterns of gene expression, on the life extension afforded by caloric restriction. Deletion of the RPD3 gene extended life span, and there was no additive effect of caloric restriction. Deletion of HDA1 had no effect of its own on longevity but acted synergistically with caloric restriction to increase life span. SIR2 deletion shortened life span but did not prevent extension of life span by caloric restriction. The results suggest that Rpd3p affects both processes that play an obligate and those that play a synergistic role in life extension by caloric restriction, while Hda1p and Sir2p affect processes that are not the obligate longevity effectors of caloric restriction but instead synergize with them, although in opposite directions. From the known patterns of gene expression elicited by rpd3delta, hda1delta, and sir2delta, we propose that the major longevity effectors of caloric restriction in yeast involve carbohydrate/energy metabolism and mitochondrial function.

Energy Metabolism↗
PubMed1993

Effect of restricted caloric intake on the development of the azoxymethane-induced glutathione S-transferase placental form positive hepatocellular foci in male F344 rats.

The modifying effect of 30% caloric restriction on the occurrence of azoxymethane (AOM)-induced glutathione S-transferase placental form (GST-P) positive hepatocellular foci was investigated in male F344 rats. Starting at 5 weeks of age, groups of animals were fed ad libitum a high-fat (23.5%) semipurified diet. At 7 weeks of age, all animals except the vehicle-treated groups were s.c. injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). Four days after the second injection, groups of animals were continued on high-fat diet and fed ad libitum (ad libitum group) whereas other groups were restricted to 70% of total calories (calorie-restricted group) consumed by the ad libitum group, but received the same amounts of fiber, vitamins and minerals. Thirty-two weeks after AOM injections, all animals were necropsied and livers were sectioned and stained for GST-P by a immunohistochemical technique for quantitative analysis of enzyme altered foci of the liver. Comparing AOM treated groups. The density and the unit area of enzyme altered foci were significantly lower in the calorie-restricted group (3.84 +/- 1.55/cm2, 7.96 +/- 5.43%) than in the ad libitum group (10.14 +/- 3.62/cm2, 28.11 +/- 12.33%). The size of foci was also reduced in the calorie-restricted group (17.15 x 10(-3) mm2 vs. 32.36 x 10(-3) mm2). The incidence and density of hepatocellular foci in rats fed calorie restricted diet were significantly lower than those in rats fed ad libitum, comparing vehicle-treated groups. These results indicate that calorie restriction inhibited the occurrence of both of spontaneous and AOM induced GST-P positive foci in rats.

Animals↗
PubMed1993

Evidence for success of caloric restriction in weight loss and control. Summary of data from industry.

Data voluntarily supplied by industry were examined to evaluate the success of commercial weight loss programs and products. Information about the safe loss of weight, the maintenance of this lowered weight, and resultant health benefits were reviewed. Information was received from companies that produce over-the-counter preparations designed for persons with a small weight loss goal and from physician-supervised programs for morbidity obese persons placed on very-low-calorie diets. Regardless of the products used, successful weight loss and control was limited and required individualized programs consisting of restricted caloric intake, behavior modification, and exercise. Although some manufacturers of physician-supervised weight loss products for obese persons hav defined the effectiveness of their programs with controlled clinical studies, other industry programs have only begun to accurately assess their effectiveness or safety. Given the importance to public health of reducing obesity, rigorous studies on current weight control practices should be pursued aggressively.

Behavior Therapy↗
PubMed1987

Effect of restricted caloric intake on azoxymethane-induced colon tumor incidence in male F344 rats.

The effect of 30% caloric restriction on azoxymethane (AOM)-induced colon carcinogenesis was investigated in male F344 rats. Starting at 5 weeks of age, groups of animals were fed ad libitum a high-fat (23.5%) semipurified diet. At 7 weeks of age, all animals except the vehicle-treated groups were s.c. injected with AOM (15 mg/kg body wt, once weekly for 2 weeks). Four days after the second AOM injection, groups of animals were continued on high-fat diet and fed ad libitum (ad libitum group) whereas other groups were restricted to 70% of total calories (calorie-restricted group) consumed by the ad libitum group, but received same amounts of fiber, vitamins, and minerals. Thirty-two weeks after AOM injections, all animals were necropsied. The animals in the calorie-restricted group developed significantly fewer colon tumors and had a lower colon tumor incidence than did the rats in the ad libitum group. The size of colon tumors was also reduced in the calorie-restricted group.

Animals↗
PubMed1999

Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals.

Moderate caloric restriction (60% of ad libitum intake) is an important model to investigate potential mechanisms of biological aging. This regimen has been reported to decrease the number of pathologies and increase life span in all species tested to date. Although moderate caloric restriction induces a wide range of physiological changes within the organism, adaptive changes within the endocrine system are evident and serve to maintain blood levels of glucose. These alterations include an increase in growth hormone secretory dynamics and a decline in plasma levels of IGF-1. These endocrine compensatory mechanisms can be induced at any age, and we have proposed that these alterations mediate some of the beneficial aspects of moderate caloric restriction. Numerous studies indicate that growth hormone and IGF-1 decrease with age and that administration of these hormones ameliorates the deterioration of tissue function evident in aged ad libitum-fed animals, suggesting that the absence of these hormones contributes to the phenotype of aging. Nevertheless, IGF-1 is an important risk factor in age-related pathologies including lung, breast, and prostate cancer. From these studies, we propose that endocrine compensatory mechanisms induced by moderate caloric restriction (including increased growth hormone and decreased IGF-1) decrease the stimulus for cellular replication, resulting in a decline in pathologies and increased life span observed in these animals. These findings have important implications for potential mechanisms of moderate caloric restriction and suggest that neuroendocrine compensatory mechanisms exert a key role on the actions of moderate caloric restriction on life span.

Aging↗
PubMed1998

Caloric restriction prevents age-related decline in skeletal muscle dihydropyridine receptor and ryanodine receptor expression.

The dihydropyridine receptor (DHPR), a voltage-gated L-type Ca2+ channel, and the Ca2+ release channel/ryanodine receptor isoform-1 (RyR1) are key molecules involved in skeletal muscle excitation-contraction coupling. We have reported age-related decreases in the level of DHPR expression in fast- and slow-twitch muscles from Fisher 344 cross Brown Norway (F344BNX) rats (Renganathan, Messi and Delbono, J. Membr. Biol. 157 (1997) 247-253). Based on these studies we postulate that excitation-contraction uncoupling is a basic mechanism for the decline in muscle force with aging (Delbono, Renganathan and Messi, Muscle Nerve Suppl. 5 (1997) S88-92). In the present study, we extended our studies to older ages and we intended to prevent or retard excitation-contraction uncoupling by restricting the caloric intake of the F344BNX rats from 16 weeks of age. Three age groups, 8-, 18-, and 33-month old caloric restricted rats, were compared with ad libitum fed animals. The number of DHPR and RyR1 and DHPR/RyR1 ratio (an index of the level of receptors uncoupling) in skeletal muscles of 8-month and 18-month rats was not significantly different in either ad libitum fed or caloric restricted rats. However, the age-related decrease in the number of DHPR, RyR1 and DHPR/RyR1 ratio observed in 33-month old ad libitum fed rats was absent in 33-month old caloric restricted rats. These results suggest that caloric restriction prevents age-related decreases in the number of DHPR, RyR1 and DHPR/RyR1 ratio observed in fast- and slow-twitch rat skeletal muscles.

Aging↗
PubMed1996

Adaptations of intestinal nutrient transport to chronic caloric restriction in mice.

Lifelong caloric restriction increases median and maximum life span and retards the aging process in many organ systems of rodents. Because the small intestine absorbs a reduced amount of nutrients each day, does lifelong caloric restriction induce adaptations in intestinal nutrient transport? We initially compared intestinal transport of sugars and amino acids between 24-mo-old mice allowed free access to food [ad libitum (AL)] and those provided a calorically restricted [40% less than ad libitum (CR)] diet since 3 mo of age. We found that CR mice had significantly greater transport rates for D-glucose, D-fructose, and several amino acids and had significantly lower villus heights. Total intestinal absorptive capacities for D-glucose, D-fructose, and L-proline were each 40-50% greater in CR mice; absorptive capacity normalized to metabolic mass (body weight 0.75) was approximately 80% greater in CR mice. Comparison of uptakes in aged AL and CR mice with previously published results in young AL mice suggests that caloric restriction delays age-related decreases in nutrient transport. In contrast to published studies in hibernation and starvation, chronic caloric restriction enhances not only uptake per milligram but also uptake per centimeter. We then switched 24-mo-old AL mice to a calorie-restricted diet for 1 mo and found that short-term caloric restriction has no effect on intestinal nutrient transport, intestinal mass, and total absorptive capacity. Thus chronic but not short-term caloric restriction increases intestinal nutrient transport rates in aged mice, and the main mechanism underlying these increases is enhanced transport rates per unit intestinal tissue weight.

Adaptation, Physiological↗
PubMed1999

Caloric restriction and aging.

Caloric restriction in species with a short life span has shown it can increase median and maximum life expectancy and reduce or delay the onset of most age-related diseases. The remarkable reproducibility of the phenomenon irrefutably proves its validity and makes caloric restriction one of the most frequently studied paradigms in experimental research on aging.

Aging↗
PubMed2005

Minireview: the role of oxidative stress in relation to caloric restriction and longevity.

Reduction of caloric intake without malnutrition is one of the most consistent experimental interventions that increases mean and maximum life spans in different species. For over 70 yr, caloric restriction has been studied, and during the last years the number of investigations on such nutritional intervention and aging has dramatically increased. Because caloric restriction decreases the aging rate, it constitutes an excellent approach to better understand the mechanisms underlying the aging process. Various investigations have reported reductions in steady-state oxidative damage to proteins, lipids, and DNA in animals subjected to restricted caloric intake. Most interestingly, several investigations have reported that these decreases in oxidative damage are related to a lowering of mitochondrial free radical generation rate in various tissues of the restricted animals. Thus, similar to what has been described for long-lived animals in comparative studies, a decrease in mitochondrial free radical generation has been suggested to be one of the main determinants of the extended life span observed in restricted animals. In this study we review recent reports of caloric restriction and longevity, focusing on mitochondrial oxidative stress and the proposed mechanisms leading to an extended longevity in calorie-restricted animals.

Animals↗
PubMed1996

Short-term caloric restriction augments age-related decreases in gastrin content and release.

Aging is associated with significant structural and functional changes in the gastrointestinal tract. Gastrin, a hormone produced by G cells in the antrum of the stomach, stimulates proliferation of gastric mucosa; its synthesis appears to decrease with age. Life-long restriction of caloric intake is the only experimental manipulation that has been shown to retard aging processes in rats. The purpose of this study was to examine the effect of short-term caloric restriction (CR) on the production and release of the hormone gastrin with aging. Aging causes a fall in both fasting plasma levels of gastrin and antral content of gastrin in Fischer 344 rats; short-term CR appears to augment this age-related decrease. Steady state levels of antral gastrin mRNA were decreased with aging, and short-term CR resulted in an augmented decrease in aged, but not in young rats. Our findings indicate that gastrin release, synthesis and gene expression decrease with age. Restriction of the caloric intake for a short period (i.e. 8 weeks) augments this age-related decrease in antral gastrin and fasting plasma levels. Short-term CR appears to decrease the production of gastrin at the level of gene expression.

Aging↗
PubMed1998

Does caloric restriction alter IL-2 transcription?

Caloric restriction has been the subject of intensive research and is known to be the most efficacious means of increasing longevity and reducing pathology. Caloric restriction has been found to influence a wide variety of age-sensitive immunological parameters such as interleukin-2 (IL-2) gene expression, and overall, the immunological status of rodents fed a caloric restriction diet is superior to the immunological status of the non-restricted animals. IL-2 is a growth promoting cytokine that plays a critical role in immune function. The expression of IL-2 has been shown to decrease with age, and the decrease in IL-2 expression parallels the age-related decrease in immune function. The focus of this review article is to discuss the studies on the influence of caloric restriction on IL-2 expression and the recent findings on the mechanisms by which caloric restriction enhances IL-2 gene expression. A number of studies have demonstrated that caloric restriction alters the expression of the IL-2 gene at the level of transcription. The increase in IL-2 expression correlates with an increase in binding activity of the transcription factor NFAT which plays a predominant role in IL-2 transcription. In addition, preliminary results suggest that activation of the upstream signaling molecules, the mitogen-activated protein kinase (MAPK) signaling cascade, may play a role in the enhancement of IL-2 transcription.

Animals↗
PubMed2004

Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction.

Aging is strongly correlated with the accumulation of oxidative damage in DNA, particularly in mitochondria. Oxidative damage to both mitochondrial and nuclear DNA is repaired by the base excision repair (BER) pathway. The "mitochondrial theory of aging" suggests that aging results from declining mitochondrial function, due to high loads of damage and mutation in mitochondrial DNA (mtDNA). Restriction of caloric intake is the only intervention so far proven to slow the aging rate. However, the molecular mechanisms underlying such effects are still unclear. We used caloric-restricted (CR) mice to investigate whether lifespan extension is associated with changes in mitochondrial BER activities. Mice were divided into two groups, receiving 100% (PF) or 60% (CR) of normal caloric intake, a regime that extends mean lifespan by approximately 40% in CR mice. Mitochondria isolated from CR mice had slightly higher uracil (UDG) and oxoguanine DNA glycosylase (OGG1) activities but marginally lower abasic endonuclease and polymerase gamma gap-filling activities, although these differences were tissue-specific. Uracil-initiated BER synthesis incorporation activities were significantly lower in brain and kidney from CR mice but marginally enhanced in liver. However, nuclear repair synthesis activities were increased by CR, indicating differential regulation of BER in the two compartments. The results indicate that a general up-regulation of mitochondrial BER does not occur in CR.

Aging↗
PubMed2003

Effects of age and caloric restriction on glutathione redox state in mice.

The main purpose of this study was to determine whether the aging process in the mouse is associated with a pro-oxidizing shift in the redox state of glutathione and whether restriction of caloric intake, which results in the extension of life span, retards such a shift. Amounts of reduced and oxidized forms of glutathione (GSH and GSSG, respectively) and protein-glutathione mixed disulfides (protein-SSG) were measured in homogenates and mitochondria of liver, kidney, heart, brain, eye, and testis of 4, 10, 22, and 26 month old ad libitum-fed (AL) mice and 22 month old mice fed a diet containing 40% fewer calories than the AL group from the age of 4 months. The concentrations of GSH, GSSG, and protein-SSG vary greatly (approximately 10-, 30-, and 9-fold, respectively) from one tissue to another. During aging, the ratios of GSH:GSSG in mitochondria and tissue homogenates decreased, primarily due to elevations in GSSG content, while the protein-SSG content increased significantly. Glutathione redox potential in mitochondria became less negative, i.e., more pro-oxidizing, as the animal aged. Caloric restriction (CR) lowered the GSSG and protein-SSG content. Results suggest that the aging process in the mouse is associated with a gradual pro-oxidizing shift in the glutathione redox state and that CR attenuates this shift.

Aging↗
PubMed2001

Biological effects of long-term caloric restriction: adaptation with simultaneous administration of caloric stress plus repeated immobilization stress in rats.

In the present study, we have established the biological effects during 8 weeks of (i) caloric restriction (Cal) and (ii) simultaneous administration of Cal plus 2 hr daily immobilization stress using male Sprague-Dawley rats. Animals were divided into three equal groups: (i) ad libitum fed, (ii) 30% restriction of food intake of the ad libitum diet, and (iii) 30% restriction of food intake plus 2 hr daily immobilization stress. Caloric-restricted animals gained only 30% of the total body weight of the unrestricted animals but received 70% of the food of those rats. Cal animals showed a significant loss in their relative liver and-thymus weight and a significant gain in their relative adrenal and testis weight as compared to the control animals. Cal animals had almost 2-fold higher levels of plasma corticosterone levels with a dramatic decrease in the total glucocorticoid receptor (GR) levels in the liver, thymus, heart, and testis as compared to ad libitum fed control animals. Interestingly, Cal animals showed higher levels of lipid peroxidation in both the liver and heart, indicating increased oxidative activities in these tissues when compared with the control animals. In addition, Cal animals had increased heat shock protein 70 (HSP 70) content in the testis. Surprisingly, hardly any significant differences were observed in either total body weight gain, organ weights, plasma corticosterone levels, or lipid peroxidation between Cal animals and Cal plus immobilization-stressed animals. The results obtained suggest that (i) several stress-related responses such as inhibition of total body weight gain, increased adrenal weight, decreased thymus weight, increased plasma corticosterone, and lipid peroxidation levels in the liver and heart are associated with Cal, but (ii) no additional effects were observed on the parameters that were measured when two stress regimens were given simultaneously, suggesting that animals subjected to two stress regimens can protect themselves by controlling their stress-related thresholds of response through adaptation.

Adaptation, Biological↗
PubMed1989

Exercise reverses depressed metabolic rate produced by severe caloric restriction.

The effects of caloric restriction and exercise on resting metabolic rate (RMR) were studied in five obese humans. Subjects consumed a 500 kcal.d-1 diet for 4 wk, with the subjects remaining sedentary during the first 2 wk and then exercising 30 min daily at 60% VO2max during the last 2 wk of caloric restriction. After 2 wk of dieting, RMR decreased to approximately 87% of the pre-dieting control value. Over the last 2 wk of dieting with the addition of daily exercise, the fall in RMR was reversed as it returned to the pre-dieting level. In summary, daily exercise reversed the drop in RMR associated with severe caloric restriction.

Adult↗
PubMed2006

Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice.

Caloric restriction (CR) increases healthy life span in a range of organisms. The underlying mechanisms are not understood but appear to include changes in gene expression, protein function, and metabolism. Recent studies demonstrate that acute CR alters mortality rates within days in flies. Multitissue transcriptional changes and concomitant metabolic responses to acute CR have not been described. We generated whole genome RNA transcript profiles in liver, skeletal muscle, colon, and hypothalamus and simultaneously measured plasma metabolites using proton nuclear magnetic resonance in mice subjected to acute CR. Liver and muscle showed increased gene expressions associated with fatty acid metabolism and a reduction in those involved in hepatic lipid biosynthesis. Glucogenic amino acids increased in plasma, and gene expression for hepatic gluconeogenesis was enhanced. Increased expression of genes for hormone-mediated signaling and decreased expression of genes involved in protein binding and development occurred in hypothalamus. Cell proliferation genes were decreased and cellular transport genes increased in colon. Acute CR captured many, but not all, hepatic transcriptional changes of long-term CR. Our findings demonstrate a clear transcriptional response across multiple tissues during acute CR, with congruent plasma metabolite changes. Liver and muscle switched gene expression away from energetically expensive biosynthetic processes toward energy conservation and utilization processes, including fatty acid metabolism and gluconeogenesis. Both muscle and colon switched gene expression away from cellular proliferation. Mice undergoing acute CR rapidly adopt many transcriptional and metabolic changes of long-term CR, suggesting that the beneficial effects of CR may require only a short-term reduction in caloric intake.

Animals↗