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Results for “Caloric Restriction”

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PubMed2000

Influences of pre- and postnatal nutritional exposures on vascular/endocrine systems in animals.

Human epidemiological and animal studies have revealed the long-term effects of malnutrition during gestation and early life on the health of the offspring. The aim of the current review is to survey the different means of achieving fetal malnutrition and its consequences, mainly in animals, and to identify key areas in which to direct future research. We address the impact of various models of a maternal protein-restricted diet and global maternal caloric restriction (either through the reduction of nutrient supply or through mechanic devices), the influence of maternal diabetes, and other maternal causes of fetal damage (maternal infections and toxic food components). More specifically, we enumerate data on how the different insults at different prenatal and early postnatal periods affect and program the development and the function of organs involved in diabetes, hypertension, and cardiovascular disease. Particular emphasis is given to the endocrine pancreas, but insulin-sensitive tissues, kidneys, and vasculature are also analyzed. Where available, the protective effects of maternal food supplementation for fetal organ development and function are discussed. Specific attention is paid to the amino acids profile, and the preventive role of taurine is discussed. Tentative indications about critical time windows for fetal development under different deleterious conditions are presented whenever possible. We also discuss future research and intervention.

Animals↗

PubMed2003

Synchronization of the molecular clockwork by light- and food-related cues in mammals.

The molecular clockwork in mammals involves various clock genes with specific temporal expression patterns. Synchronization of the master circadian clock located in the suprachiasmatic nucleus (SCN) is accomplished mainly via daily resetting of the phase of the clock by light stimuli. Phase shifting responses to light are correlated with induction of Per1, Per2 and Dec1 expression and a possible reduction of Cry2 expression within SCN cells. The timing of peripheral oscillators is controlled by the SCN when food is available ad libitum. Time of feeding, as modulated by temporal restricted feeding, is a potent 'Zeitgeber' (synchronizer) for peripheral oscillators with only weak synchronizing influence on the SCN clockwork. When restricted feeding is coupled with caloric restriction, however, timing of clock gene expression is altered within the SCN, indicating that the SCN function is sensitive to metabolic cues. The components of the circadian timing system can be differentially synchronized according to distinct, sometimes conflicting, temporal (time of light exposure and feeding) and homeostatic (metabolic) cues.

ARNTL Transcription Factors↗

PubMed2003

Evolutionary medicine: from dwarf model systems to healthy centenarians?

Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.

Aging↗

PubMed2004

Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.

Little is known regarding the long-term effects of caloric restriction (CR) on the risk for atherosclerosis. We evaluated the effect of CR on risk factors for atherosclerosis in individuals who are restricting food intake to slow aging. We studied 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. We measured serum lipids and lipoproteins, fasting plasma glucose and insulin, blood pressure (BP), high-sensitivity C-reactive protein (CRP), platelet-derived growth factor AB (PDGF-AB), body composition, and carotid artery intima-media thickness (IMT). The CR group were leaner than the comparison group (body mass index, 19.6 +/- 1.9 vs. 25.9 +/- 3.2 kg/m(2); percent body fat, 8.7 +/- 7% vs. 24 +/- 8%). Serum total cholesterol (Tchol), low-density lipoprotein cholesterol, ratio of Tchol to high-density lipoprotein cholesterol (HDL-C), triglycerides, fasting glucose, fasting insulin, CRP, PDFG-AB, and systolic and diastolic BP were all markedly lower, whereas HDL-C was higher, in the CR than in the American diet group. Medical records indicated that the CR group had serum lipid-lipoprotein and BP levels in the usual range for individuals on typical American diets, and similar to those of the comparison group, before they began CR. Carotid artery IMT was approximately 40% less in the CR group than in the comparison group. Based on a range of risk factors, it appears that long-term CR has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery IMT.

Adult↗

PubMed2004

The Sir2 family of protein deacetylases.

The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD+-dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD+, the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.

Aging↗

PubMed1994

Chronic calorie restriction alters glycogen metabolism in rhesus monkeys.

Chronic caloric restriction (CR) prevents the development of obesity and maintains health, slows aging processes, and prevents or substantially delays the development of non-insulin-dependent diabetes. Because changes in energy metabolism could be involved in all of these positive effects of CR, we examined glycogen synthase (GS) and glycogen phosphorylase (GP) activities and glucose 6-phosphate (G6P) and glycogen concentrations in skeletal muscle samples before and during a euglycemic hyperinsulinemic clamp in 6 older aged monkeys in which CR had been continued for 10.4 +/- 2.1 years. Basal GS activity (fractional velocity and independent) was significantly higher in the CR monkeys than has been previously shown in normal, hyperinsulinemic and diabetic monkeys. The normal effect of insulin to activate GS was absent in the CR group due to the paradoxical finding in some of these monkeys of a reduction in GS activity by insulin. Insulin also had the unexpected effect of increasing the independent activity of GP above basal activity (p<0.05). There was an inverse relationship between the change (insulin-stimulated minus basal) in GS fractional velocity and GP activity ratio (r=-0.91, p<0.005). The basal independent activities of GS and GP were also inversely correlated (r=-0.79, p<0.05). The insulin-stimulated concentration of G6P tended to be higher than the basal concentration (p<0.06) and was significantly higher than that previously shown in normal monkeys (p<0.05). We suggest that long-term calorie restriction (1) results in alterations in glycogen metabolism that may be important to the anti-diabetogenic and antiaging effects of CR and (2) unmasks early defects which may indicate the likelihood of ultimately developing obesity and diabetes.

Animals↗

PubMed2004

Assessment of auditory function in rhesus monkeys (Macaca mulatta): effects of age and calorie restriction.

Age-related alterations in auditory function were evaluated in adult male rhesus monkeys (Macaca mulatta) involved in a long-term study evaluating the effects of caloric restriction (CR) on aging. We assessed 26 monkeys in a control group fed a low fat, high fiber diet at approximately ad libitum levels and 24 monkeys in a CR group that were fed the same diet reduced in amount by 30% compared to age- and weight-matched controls. The following measures of auditory function were obtained while monkeys were maintained under anesthesia: (1) distortion product otoacoustic emissions (DPOAEs); (2) auditory brainstem responses (ABRs); and (3) middle latency responses (MLRs). All DPOAE measures and peak II amplitude significantly decreased with age, while peak IV latency and ABR threshold significantly increased with age. We found no significant effects of CR on any auditory parameters examined.

Aging↗

PubMedDate not supplied

Modulation of cutaneous aging with calorie restriction in Fischer 344 rats: a histological study.

OBJECTIVE: To examine whether histological changes in skin owing to intrinsic aging in a laboratory rodent model are modulated by caloric restriction (CR). METHODS: The abdominal skin from colony-raised ad libitum-fed Fischer 344 rats and age-matched rats subjected to CR was studied in the light microscope using histological morphometric methods. Animals 4, 12, and 24 months or older were used in this study. We studied the skin to obtain (1) quantitative data on the depth of the epidermis, dermis, and fat layer, the epidermal cellular density, the percentage fraction of dermal collagen, elastic fibers, pilosebaceous units, and capillaries, and the fibroblast density; and (2) qualitative assessment of histological staining for dermal glycosaminoglycans. We analyzed data by means of general linear model 2-way analysis of variance to obtain significance for the effects of age, diet, and age-diet interaction. RESULTS: The ad libitum-fed rats showed age-related increase in the depth of the epidermis, dermis, and fat layer. Calorie restriction prevented these changes, but epidermal nuclear density appeared to be stimulated. A trend toward increased values for collagen and elastic fibers, fibroblasts, and capillaries in skin samples from CR rats was observed. Pilosebaceous units were not modified. Moderately reduced staining for the dermal glycosaminoglycans in the skin of CR rats was noticed. CONCLUSIONS: Histomorphological changes resulting from intrinsic aging affected some of the studied variables in the rat skin, and these changes were delayed or prevented by CR. Some stimulatory effects, such as increased densities of fibroblasts and capillary profiles and higher values of connective tissue fibers resulting from CR, were also observed. Cutaneous morphological changes due to natural aging in this rat model seem to be modified by physiological or metabolic alterations imposed by CR.

Analysis of Variance↗

PubMed2004

Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.

A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.

Acetylation↗

PubMed1995

Suspension osteopenia in mice: whole body electromagnetic field effects.

Whole-body fields were tested for their efficacy in preventing the osteopenia caused by tail suspension in mice. The fields had fundamental frequencies corresponding to the upper range of predicted endogenous impact-generated frequencies (0.25-2.0 kHz) in the long bones. Three distinct whole-body EMFs were applied for 2 weeks on growing mice. Structural, geometric, and material properties of the femora, tibiae, and humeri of suspended mice were altered compared to controls. Comparison of suspended mice and mice subjected to caloric restriction indicates that the changes in caloric intake do not explain either the suspension or the field-induced effects. In agreement with past studies, rather, unloading appears to cause the suspension effects and to be addressed by the EMFs. The EMF effects on bone properties were apparently frequency dependent, with the lower two fundamental frequencies (260 and 910 Hz) altering, albeit slightly, the suspension-induced bone effects. The fields are not apparently optimized for frequency, etc., with respect to therapeutic potential; however, suspension provides a model system for further study of the in vivo effects of EMFs.

Animals↗

PubMed2004

Ageing, oxidative stress, and mitochondrial uncoupling.

Mitochondria are a cell's single greatest source of reactive oxygen species. Reactive oxygen species are important for many life sustaining processes of cells and tissues, but they can also induce cell damage and death. If their production and levels within cells is not effectively controlled, then the detrimental effects of oxidative stress can accumulate. Oxidative stress is widely thought to underpin many ageing processes, and the oxidative stress theory of ageing is one of the most widely acknowledged theories of ageing. As well as being the major source of reactive oxygen species, mitochondria are also a major site of oxidative damage. The purpose of this review is a concise and current review of the effects of oxidative stress and ageing on mitochondrial function. Emphasis is placed upon the roles of mitochondrial proton leak, the uncoupling proteins, and the anti-ageing effects of caloric restriction.

Aging↗

PubMed2004

Calorie restriction attenuates age-related alterations in the plasma membrane antioxidant system in rat liver.

Aging is associated with increased production of reactive oxygen species and oxidation-induced damage to intracellular structures and membranes. Caloric restriction (CR) is the only non-genetic method proven to extend lifespan in mammals. Although the mechanisms of CR remain to be clearly elucidated, reductions in oxidative stress have been shown to increase lifespan in several model systems. Oxidative stress can be attenuated by CR. Mitochondria and plasma membrane (PM) are normal sources of free radicals. The PM has a trans-membrane redox system that provides electrons to recycle lipophilic antioxidants, such as alpha-tocopherol and coenzyme Q (CoQ). The idea developed in this study is that the PM is intimately involved in cellular physiology controlling the relationship of the cell to its environment. PM is the key for protecting cellular integrity during aging. Specifically, we have investigated age-related alterations and the effects of CR in the trans-PM redox (antioxidant) system in rat liver. We found that age-related declines in the ratio of CoQ(10)/CoQ(9) and alpha-tocopherol in liver PM were attenuated by CR compared to those fed ad libitum (AL). CoQ-dependent NAD(P)H dehydrogenases were increased in CR old rat liver PMs. As a consequence, the liver PM of CR old rats was more resistant to oxidative stress-induced lipid peroxidation than AL rats. Thus, our results suggest that CR induces a higher capacity to oxidize NAD(P)H in the PM of old rat livers and as a result, a higher resistance to oxidative stress-induced damage.

Aging↗

PubMed2004

Experimental allergic encephalomyelitis in male Lewis rats subjected to calorie restriction.

This work analyzes the effect of calorie restriction on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. Plasma levels of ACTH, corticosterone, prolactin and growth hormone (GH) and mitogenic responses in submaxillary lymph nodes were measured. Male Lewis rats (6 weeks-old) were submitted to a calorie restriction equivalent to 66% of food restriction or to a normal diet. Fifteen days later, rats were injected with complete Freund's adjuvant plus spinal chord homogenate (SCH) or with complete Freund's adjuvant alone. Rats were monitored daily for clinical signs of EAE and were killed on day 15 after immunization. Only rats subjected to normal diet exhibited clinical signs of the disease. The increase in plasma ACTH and corticosterone found after SCH immunization in controls was not detectable in calorie restricted rats. Likewise, the correlation between circulating ACTH and corticosterone was no longer found after calorie restriction. Generally, calorie restriction by itself augmented plasma ACTH or corticosterone and this increase was not further amplified by SCH immunization. Only calorie restricted rats exhibited augmented plasma prolactin levels after SCH immunization, and decreased plasma GH levels regardless of immunization. Calorie restriction depressed the mitogenic response of lymphoid cells to concanavalin A but not to lipopolysaccharide. Calorie restricted rats did not exhibit augmented mitogenic response to concanavalin A following SCH immunization as those found in controls. The results are compatible with the view that the course of EAE can be significantly modified by caloric restriction.

Adrenocorticotropic Hormone↗

PubMed2004

Optimizing endothelial nitric oxide activity may slow endothelial aging.

The capacity of vascular endothelium to generate bioactive nitric oxide (NO) decreases with advancing age, even in healthy subjects with a relatively benign risk factor profile; this phenomenon may reflect decreased expression of NO synthase, as well as increased production of superoxide, and evidently contributes importantly to the increased vascular risk associated with aging. Studies with cultured endothelial cells suggest that the rate of endothelial aging is determined primarily by the rate of cell turnover and the associated progressive shortening of telomeres; endothelial cells transfected with the catalytic subunit of telomerase--which preserves a youthful telomere length--do not show a reduction in NO synthase expression after numerous doublings, in contrast to the marked reduction observed in control cells. Also consistent with this view is the fact that, following balloon denudation of arteries, the regenerated endothelium makes less NO. In the vasculature of adults, the rate of endothelial cell mitosis is evidently a reflection of the rate of endothelial cell apoptosis. Numerous cell culture studies demonstrate that physiological levels of NO protect endothelial cells from apoptosis induced by a wide range of noxious stimuli--including vascular risk factors such as oxidized LDL, angiotensin II, and hyperglycemia. In the human vasculature, endothelial cells with disproportionately short telomeres are found capping atheromatous lesions and in atheroma-prone areas where blood flow is turbulent; these findings evidently reflect increased endothelial cell turnover in regions where NO bioactivity is relatively weak. It can be deduced that lifelong adherence to an "endotheliophilic lifestyle" that optimizes vascular NO production, while minimizing that of superoxide, will literally slow the rate of aging of vascular endothelium, such that, at any given advanced age, the optimal functional capacity of the vascular endothelium will be superior to that of age-matched controls. These considerations underline the desirability of actively promoting vascular health in younger and middle-aged individuals in whom risk for vascular events may still be quite low. The impact of lifelong caloric restriction on endothelial aging requires further study, preferably in primates.

Administration, Oral↗

PubMed2006

The adversities of aging.

The aging process is evolutionarily conserved and subject to quantitative modification by both genetic and environmental factors. Fundamental mechanisms of aging result in progressive deficits in the function of cells and organs, often leading to diseases that ultimately kill the organism such as cancers, cardiovascular disease and neurodegenerative disorders. Oxidative stress and damage to all of the major classes of molecules in cells are involved in aging and age-related diseases. The widely pursued approach of targeting disease-specific processes to develop therapeutic interventions has not had a major impact on healthspan. A more productive approach would be to target the fundamental mechanisms of aging throughout adult life so as to extend healthspan. Caloric restriction and regular exercise are two such approaches.

Aged↗

PubMed2002

Life history, ecology and longevity in bats.

The evolutionary theory of aging predicts that life span should decrease in response to the amount of mortality caused by extrinsic sources. Using this prediction, we selected six life history and ecological factors to use in a comparative analysis of longevity among 64 bat species. On average, the maximum recorded life span of a bat is 3.5 times greater than a non-flying placental mammal of similar size. Records of individuals surviving more than 30 years in the wild now exist for five species. Univariate and multivariate analyses of species data, as well as of phylogenetically independent contrasts obtained using a supertree of Chiroptera, reveal that bat life span significantly increases with hibernation, body mass and occasional cave use, but decreases with reproductive rate and is not influenced by diet, colony size or the source of the record. These results are largely consistent with extrinsic mortality risk acting as a determinant of bat longevity. Nevertheless, the strong association between life span and both reproductive rate and hibernation also suggests that bat longevity is strongly influenced by seasonal allocation of non-renewable resources to reproduction. We speculate that hibernation may provide a natural example of caloric restriction, which is known to increase longevity in other mammals.

Animals↗

PubMed2001

The impact energy metabolism and genome maintenance have on longevity and senescence: lessons from yeast to mammals.

The phenomenon that caloric restriction increases life span in a variety of species from yeast to mice has been the focus of much interest. Recent observations suggest that a protein important for heterochromatin formation, Sir2, is central for caloric restriction-induced longevity in lower organisms. Interestingly, Sir2 is also capable of repairing DNA double-strand breaks by nonhomologous end joining which may be important, along with proteins that repair breaks by recombinational repair, for minimizing the age-related deleterious effects of DNA damage induced by oxygen by-products of metabolism. I propose that competition between these two distinct functions could influence longevity and the onset of senescence. In addition, sequence and functional similarities between Sir2 and other chromatin metabolism proteins present the possibility that genetic components for longevity and senescence are conserved from yeast to mammals.

Aging↗

PubMed2006

Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons.

We have studied the mechanisms underlying nonpathological age-related neuronal cell death. Fifty per cent of neurons in the rat enteric nervous system are lost between 12 and 18 months of age in ad libitum (AL) fed rats. Caloric restriction (CR) protects almost entirely against this neuron loss. Using the ROS-sensitive dyes, dihydrorhodamine (DHR) and 2-[6-(4'-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid (HPF) in vitro, we show that the onset of cell death is linked with elevated intraneuronal levels of reactive oxygen species (ROS). Treatment with the neurotrophic factors NT3 and GDNF enhances neuronal antioxidant defence in CR rats at 12-15 months and 24 months but not in adult or aged AL-fed animals. To examine the link between elevated ROS and neuronal cell death, we assessed apoptotic cell death following in vitro treatment with the redox-cycling drug, menadione. Menadione fails to increase apoptosis in 6-month neurons. However, in 12-15mAL fed rats, when age-related cell death begins, menadione induces a 7- to 15-fold increase in the proportion of apoptotic neurons. CR protects age-matched neurons against ROS-induced apoptosis. Treatment with neurotrophic factors, in particular GDNF, rescues neurons from menadione-induced cell death, but only in 12-15mCR animals. We hypothesize that CR enhances antioxidant defence through neurotrophic factor signalling, thereby reducing age-related increases in neuronal ROS levels and in ROS-induced cell death.

Aging↗