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Results for “Caloric Restriction”

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PubMed2007

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid.

Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrand's factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.

Aging↗

PubMed2004

Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression.

The ketogenic diet is a very low-carbohydrate, high-fat diet used to treat refractory epilepsy. We hypothesized that this diet may act by increasing expression of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis. Thus, we evaluated brain GAD levels in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest ( approximately 10%) calorie restriction, we studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). We found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.

Animals↗

PubMed2004

Krebs cycle enzymes from livers of old mice are differentially regulated by caloric restriction.

Krebs cycle enzyme activities and levels of five metabolites were determined from livers of old mice (30 months) maintained either on control or on long-term caloric restriction (CR) diets (28 months). In CR mice, the cycle was divided into two major blocks, the first containing citrate synthase, aconitase and NAD-dependent isocitrate dehydrogenase which showed decreased activities, while the second block, containing the remaining enzymes, displayed increased activity (except for fumarase, which was unchanged). CR also resulted in decreased levels of citrate, glutamate and alpha-ketoglutarate, increased levels of malate, and unchanged levels of aspartate. The alpha-ketoglutarate/glutamate and malate/alpha-ketoglutarate ratios were higher in CR, in parallel with previously reported increases with CR in pyruvate carboxylase activity and glucagon levels, respectively. The results indicate that long-term CR induces a differential regulation of Krebs cycle in old mice and this regulation may be the result of changes in gene expression levels, as well as a complex interplay between enzymes, hormones and other effectors. Truncation of Krebs cycle by CR may be an important adaptation to utilize available substrates for the gluconeogenesis necessary to sustain glycolytic tissues, such as brain.

Aging↗

PubMed2002

Effects of caloric restriction on development of the proximal growth plate and metaphysis of the caput femoris in spontaneously hypertensive rats: microscopic and computer-assisted image analyses.

We previously demonstrated that caloric restriction (CR) reduced the prevalence of osteonecrosis in caput femoris of spontaneously hypertensive rats (SHR), a model of human Perthes' disease. The effects of CR on the development and pathology in the proximal femoral growth plate (GP) and adjacent structures in SHR were investigated by morphometric and computer-assisted image analyses. From 6 weeks of age, the food intake of SHR was restricted to 65% of the mean intake of ad libitum fed control SHR (SHR-AL). Wistar Kyoto rats (WKY), from which the SHR strain was isolated, fed ad libitum were also included as controls. CR reduced prevalence of chondromucinous degeneration and dysarray of cartilage cell columns in the GP, becoming prevalent between 10 and 20 weeks in the SHR-AL group, attaining the same levels of the WKY group. Thicknesses of non-calcifying cell columns in the GP were greater in the SHR-AL than WKY group; CR slightly reduced the thickness, but incompletely. Thicknesses of calcifying cell columns did not significantly differ among the three groups. CR decreased volume density and mean thicknesses of the trabecular bone in areas adjacent to GPs, and was greater in the SHR-AL than the WKY group. The present morphologic analysis suggested that CR ameliorates dysplastic changes of trabecular bones in areas adjacent to the GP, rather than modulating the ossification process in the GP. The CR paradigm might give insight into the pathogenesis of, and a therapeutic strategy for, human Perthes' disease.

Animals↗

PubMed2026

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA↗

PubMed2005

Caloric restriction modulates insulin receptor signaling in liver and skeletal muscle of rat.

OBJECTIVE: We investigated how the insulin/insulin-like growth factor-1 signaling pathway is involved in the robust antiaging effects produced by caloric restriction. METHODS: We subjected male rats to feeding ad libitum or calorie restriction, i.e., 60% of the ad libitum amount, for 2 and 25 mo and then assessed the effects of calorie restriction on insulin receptor (IR) signaling in liver and skeletal muscle. RESULTS: The results indicated that aging was accompanied by a significant decrease in IR tyrosine phosphorylation after insulin stimulation in live and skeletal muscle, which was associated with a significant increase in the activity of protein tyrosine phosphatase-1B. However, these age-related alterations were attenuated by long-term calorie restriction. Expression profile of mRNA showed an increased expression of mRNAs for IR and insulin-like growth factor-1 receptor in both tissues of calorie-restricted rats, but increased expression of IR mRNA was dissociated with the IR gene product in rats maintained on long-term calorie-restricted diet. CONCLUSION: IR signaling may play an important role in aging and its retardation by calorie restriction, and normal function of IR in liver and skeletal muscle is required for healthy aging and extending lifespan in mammals.

Age Factors↗

PubMed2005

Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "Mitohormesis" for health and vitality.

The precise mechanistic sequence producing the beneficial effects on health and lifespan seen with interventions as diverse as caloric restriction, intermittent fasting, exercise, and consumption of dietary phytonutrients is still under active characterization, with large swaths of the research community kept in relative isolation from one another. Among the explanatory models capable of assisting in the identification of precipitating elements responsible for beneficial influences on physiology seen in these states, the hormesis perspective on biological systems under stress has yielded considerable insight into likely evolutionarily consistent organizing principles functioning in all four conditions. Recent experimental findings provide the tantalizing initial lodestones for an entirely new research front examining molecular substrates of stress resistance. In this novel body of research, a surprising new twist has emerged: Reactive oxygen species, derived from the mitochondrial electron transport system, may be necessary triggering elements for a sequence of events that result in benefits ranging from the transiently cytoprotective to organismal-level longevity. With the recent appreciation that reactive oxygen species and reactive nitrogen species function as signaling elements in a interconnected matrix of signal transduction, the entire basis of many widely accepted theories of aging that predominated in the past may need to be reconsidered to facilitate the formulation of an new perspective more correctly informed by the most contemporaneous experimental findings. This perspective, the mitohormesis theory, can be used in many disparate domains of inquiry to potentially explain previous findings, as well as point to new targets of research. The utility of this perspective for research on aging is significant, but beyond that this perspective emphasizes the pressing need to rigorously characterize the specific contribution of the stoichiometry of reactive oxygen species and reactive nitrogen species in the various compartments of the cell to cytoprotection and vitality. Previous findings regarding the influences of free radical chemistry on cellular physiology may have represented assessments examining the consequences of isolated elevation of signaling elements within a larger signal transductive apparatus, rather than definitive characterizations of the only modality of reactive oxygen species (and reactive nitrogen species) influence. In applying this perspective, it may be necessary for the research community, as well as the practicing clinician, to engender a more sanguine perspective on organelle level physiology, as it is now plausible that such entities have an evolutionarily orchestrated capacity to self-regulate that may be pathologically disturbed by overzealous use of antioxidants, particularly in the healthy.

Animals↗

PubMed2004

Protein profile of aging and its retardation by caloric restriction in neural retina.

Aging is a slow, gradual deterioration process of an organism. The only experimental intervention, which can reliably retard aging and age-related degenerative diseases, is dietary caloric restriction (CR). To gain insight into the mechanism of CR intervention, we have investigated the protein profile of aging and its retardation by CR in the neural retina of Brown Norway (BN) rats using the comprehensive proteomic approach. We found that the intensities of 18 proteins decreased significantly with age. CR intervention can completely prevent seven of them, and partially protect eight of them, from such age-related declines. The major protein targets protected by CR intervention appear to be glycolytic enzymes and molecular chaperones. These data are the first to suggest that CR may retard the age-related degeneration of retina by maintaining sufficient glucose metabolism, by ensuring proper protein folding, and/or by preventing protein denaturation in the neural retina.

Aging↗

PubMed2004

Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors.

The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fasting-responsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1alpha (PGC-1alpha). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor alpha (PPARalpha), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPARalpha. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPARalpha, including Cyp4a10 and Cyp4a14, involved in fatty acid omega-oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1alpha. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPARalpha-null mice due to inadequate tissue repair. These results demonstrate that PPARalpha mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.

Animals↗

PubMed2004

Effect of age and caloric restriction on coenzyme Q and alpha-tocopherol levels in the rat.

Alterations in the amount of coenzyme Q and alpha-tocopherol during aging and in response to 40% reduction in caloric intake were determined in homogenates and mitochondria of liver, heart and kidney of the rat. A comparison among 4-, 19- and 28-month-old ad libitum fed (AL) rats indicated an age-related loss in the amount of CoQ9 and alpha-tocopherol in mitochondria of all the three tissues. Depletion of alpha-tocopherol, but not of CoQ, was also detectable in tissue homogenates, apparently due to the preferential sequestration of CoQ in the mitochondrial fraction. Comparison of 19-month-old AL and calorically restricted (CR) rats indicated that CR elevates the level of mitochondrial CoQ, but greatly diminishes the alpha-tocopherol content. Activity of DT-diaphorase, a quinone reductase, increased with age as well as in response to CR. Altogether, results are interpreted to suggest that the widely observed age-related increase in mitochondrial oxidative damage may be associated with depletion of CoQ and alpha-tocopherol, which are known to act in tandem to prevent oxidative damage to membranes.

Aging↗

PubMed1997

Caloric restriction diminishes the age-associated loss of immunoreactive catalase in rat prostate.

BACKGROUND: Caloric restriction (CR) retards aging and diseases in mice, rats, and other animals by unknown mechanisms. A popular hypothesis is that CR acts by opposing age-associated increases in oxidative stress. METHODS: Because influences of CR on antioxidant enzymes in the prostate have not been previously investigated, immunohistologic methods (light and electron microscopy) were used to determine the prostatic localization of catalase (CAT) in rats of diverse ages (3-32 months) fed either normally or subjected to CR from age 16 months. RESULTS: In 20-month-old rats fed either diet, CAT appeared as dense deposits at the apical poles of the epithelium in the lateral lobes, and within the ductular lumens, suggesting that CAT is secreted. Confirmation of both liver peroxisomal and prostatic apical cytoplasmic localization of CAT was provided by electron microscopic immunogold staining. The amount of CAT was reduced at 30 months in normally fed rats but not in those on CR. CONCLUSIONS: CAT appears to be a secretory product of the epithelial cells in the lateral lobes of the rat prostate. Further, CR from late-middle age opposed the age-associated loss of this intracellular enzyme activity.

Aging↗

PubMed1993

Caloric restriction, aging, and antioxidant enzymes.

The basic mechanisms of aging and its retardation by caloric restriction (CR) remain unclear. One suggested means by which CR could retard aging is based on production of mitochondrial free radicals, and efficiency of their subsequent metabolism. Currently, there is little information concerning the influences of age and CR on the rates of in vivo mitochondrial free radical production. However, evidence for CR-induced modulation of free radical detoxification capacities is mounting. The direction of the influence of CR on free radical detoxification is tissue-specific. These effects are broad and appear to provide positive advantage.

Aging↗

PubMed2005

Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems.

Intermittent fasting (IF; reduced meal frequency) and caloric restriction (CR) extend lifespan and increase resistance to age-related diseases in rodents and monkeys and improve the health of overweight humans. Both IF and CR enhance cardiovascular and brain functions and improve several risk factors for coronary artery disease and stroke including a reduction in blood pressure and increased insulin sensitivity. Cardiovascular stress adaptation is improved and heart rate variability is increased in rodents maintained on an IF or a CR diet. Moreover, rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke. The beneficial effects of IF and CR result from at least two mechanisms--reduced oxidative damage and increased cellular stress resistance. Recent findings suggest that some of the beneficial effects of IF on both the cardiovascular system and the brain are mediated by brain-derived neurotrophic factor signaling in the brain. Interestingly, cellular and molecular effects of IF and CR on the cardiovascular system and the brain are similar to those of regular physical exercise, suggesting shared mechanisms. A better understanding of the cellular and molecular mechanisms by which IF and CR affect the blood vessels and heart and brain cells will likely lead to novel preventative and therapeutic strategies for extending health span.

Animals↗

PubMed2001

Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys.

In laboratory rodents, caloric restriction (CR) retards several age-dependent physiological and biochemical changes in skeletal muscle, including increased steady-state levels of oxidative damage to lipids, DNA, and proteins. We have previously used high-density oligonucleotide arrays to show that CR can prevent or delay most of the major age-related transcriptional alterations in the gastrocnemius muscle of C57BL/6 mice. Here we report the effects of aging and adult-onset CR on the gene expression profile of 7,070 genes in the vastus lateralis muscle from rhesus monkeys. Gene expression analysis of aged rhesus monkeys (mean age of 26 years) was compared with that of young animals (mean age of 8 years). Aging resulted in a selective up-regulation of transcripts involved in inflammation and oxidative stress, and a down-regulation of genes involved in mitochondrial electron transport and oxidative phosphorylation. Middle-aged monkeys (mean age of 20 years) subjected to CR since early adulthood (mean age of 11 years) were studied to determine the gene expression profile induced by CR. CR resulted in an up-regulation of cytoskeletal protein-encoding genes, and also a decrease in the expression of genes involved in mitochondrial bioenergetics. Surprisingly, we did not observe any evidence for an inhibitory effect of adult-onset CR on age-related changes in gene expression. These results indicate that the induction of an oxidative stress-induced transcriptional response may be a common feature of aging in skeletal muscle of rodents and primates, but the extent to which CR modifies these responses may be species-specific.

Aging↗

PubMed1994

Caloric restriction profoundly inhibits liver tumor formation after initiation by 6-nitrochrysene in male mice.

Caloric restriction (CR) inhibited strongly the incidence of chemically-induced tumors in the neonatal B6C3F1 mouse tumorigenicity bioassay, when begun 3 months after treatment with the potent carcinogen 6-nitrochrysene. These data indicate that CR can have a profound inhibitory effect on tumor development even long after metabolic activation and DNA repair have occurred.

Adenoma↗

PubMed1999

Revisiting the role of fat mass in the life extension induced by caloric restriction.

One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in a severalfold decrease in fat mass (FM), the role of fat on life extension was considered to be minimal. Two main reasons accounted for this belief. First, although increased FM is associated with changes in substrate oxidation and in glucose homeostasis, in part through the effects of free fatty acids (FFA) and glycerol, several studies have suggested that longevity is determined independent of FM. Second, CR has systemic effects on a range of functions including neurological, endocrine, reproductive, immunological and antineoplastic, none of which have been historically linked to fat. In the last few years, an explosion of evidence has demonstrated that fat tissue is a very active endocrine gland which secretes a variety of peptides (such as leptin and plasminogen activating inhibitor-1), cytokines (such as tumor necrosis factor), and complement factors (such as D, C3, and B). This is in addition to the presence of substrates, such as glycerol and FFA, which are stored and released by fat cells and are known to have a major role in hepatic and peripheral glucose metabolism. We propose that many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors, and substrates. In fact, all of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to decrease in adipose cells and their products. Other evidence from epidemiological data in human obesity supports the role of fat mass and its body distribution as a risk factor for morbidity and mortality in humans due to impaired glucose metabolism (similar to rodents), for cancer (similar to rodents), and for the development of atherosclerotic vascular disease (in humans). If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate proteins may be explored and manipulated in the search for the most powerful adipose-dependent signals that modulate life expectancy.

Adipose Tissue↗

PubMed2001

The role of fat depletion in the biological benefits of caloric restriction.

One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in substantial decrease in fat mass, the role of fat in life extension was considered minimal. Indeed, in the fields of obesity and diabetes, the amount of fat has been directly implicated in the metabolic consequences. Since it became apparent that fat is a massive endocrine tissue, some of its roles have been recently revised. Many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors and substrates that are produced in fat. Most of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to a decrease in adipose cells and their products. If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate substrates and proteins may be explored and manipulated in searching for the most powerful adipose-dependent signals that modulate life expectancy.

Adipose Tissue↗

PubMed1997

Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle.

The influence of caloric restriction (CR) initiated at 17 months of age was investigated on selected age-associated measures in skeletal muscle. Tissue from young (3-4 months) ad libitum-fed, old (30-32 months) restricted (35% and 50% CR, designated CR35 and CR50, respectively), and old ad libitum-fed rats (29 months) was studied. CR preserved fiber number and fiber type composition in the vastus lateralis muscle of the CR50 rats. In the old rats from all groups, individual fibers were found with either no detectable cytochrome c oxidase activity (COX-), hyperreactivity for succinate dehydrogenase activity (SDH++; also known as ragged red fibers [RRF]), or both COX- and SDH++. Muscle from the CR50 rats contained significantly fewer COX- and SDH++ fibers than did the muscle from CR35 rats. CR50 rats also had significantly lower numbers of mtDNA deletion products in two (adductor longus and soleus) of the four muscles examined compared to CR35 rats. These data indicate that CR begun in late middle age can retard age-associated fiber loss and fiber type changes, as well as increases in the number of skeletal muscle fibers showing mitochondrial enzyme abnormalities. CR also decreased the accumulation of mtDNA deletions.

Aging↗