Effects Of Dietary Restriction Research Articles

Food Deprivation Attenuates Seizures through CaMKII and EAG K+ Channels

Accumulated research has demonstrated the beneficial effects of dietary restriction on extending lifespan and increasing cellular stress resistance. However, reducing nutrient intake has also been shown to direct animal behaviors toward food acquisition. Under food-limiting conditions, behavioral changes suggest that neuronal and muscle activities in circuits that are not involved in nutrient acquisition are down-regulated. These dietary-regulated mechanisms, if understood better, might provide an approach to compensate for defects in molecules that regulate cell excitability. We previously reported that a neuromuscular circuit used in Caenorhabditis elegans male mating behavior is attenuated under food-limiting conditions. During periods between matings, sex-specific muscles that control movements of the male's copulatory spicules are kept inactive by UNC-103 ether-a-go-go–related gene (ERG)–like K+ channels. Deletion of unc-103 causes ∼30%–40% of virgin males to display sex-muscle seizures; however, when food is deprived from males, the incidence of spontaneous muscle contractions drops to 9%–11%. In this work, we used genetics and pharmacology to address the mechanisms that act parallel with UNC-103 to suppress muscle seizures in males that lack ERG-like K+ channel function. We identify calcium/calmodulin-dependent protein kinase II as a regulator that uses different mechanisms in food and nonfood conditions to compensate for reduced ERG-like K+ channel activity. We found that in food-deprived conditions, calcium/calmodulin-dependent protein kinase II acts cell-autonomously with ether-a-go-go K+ channels to inhibit spontaneous muscle contractions. Our work suggests that upregulating mechanisms used by food deprivation can suppress muscle seizures.

Dietary restriction in Drosophila is dependent on mitochondrial efficiency and constrained by pre-existing extended longevity

We tested the effects of dietary restriction (DR) on the standard w 1118 strain as well as on our previously described Ra and La strains and their reciprocal isogenic ‘cybrid’ lines containing heterologous nuclear–mitochondrial combinations. The w 1118 and Ra strains, but neither the La strains nor their ‘cybrid’ derivatives, are DR-inducible. The Ra and La animals are more robust than the w 1118 animals, and the Ra strain shows an upward shift in its DR threshold. The non-inducibility of the La strain suggests that it expresses a constituitive version of the inducible DR phenotype of its predecessor Ra strain. The difference in mitochondrial efficiency observed between the Ra and La mitochondria ( Ross, 2000) has real effects on longevity in the adults: the presence of the more efficient La mitochondria enhances the longevity of an otherwise Ra animal; while the maximum longevity inherent in the La nuclear information cannot be fully expressed in the presence of the Ra mitochondria. Despite the absence of any demographic mathematical parameters robustly and uniquely associated with extended longevity, there are some common trends in that longer lived cohorts have a longer period of low and often constant early life mortality rates (comprising the “health span”), leading to a delayed onset of senescence as noted by the late life increase in age-specific mortality rates (comprising the “senescence span”). There is a genetic basis to this phenotype, but the context-dependence of the demographic data suggests that there is not likely to be only one mechanism or pathway involved in the DR response. In addition, the presence of live yeast had systemic strain specific effects such that it increased longevity in the w 1118 animals but decreased it in the Ra and derived lines. Higher density (4–10×) foods yielded a decreased longevity in all strains at the highest level, showing that malnutrition occurs at both low and high caloric levels.

Caenorhabditis elegans integrates food and reproductive signals in lifespan determination

Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity.

Dietary restriction alters demographic but not behavioral aging in Drosophila

Dietary restriction extends lifespan substantially in numerous species including Drosophila. However, it is unclear whether dietary restriction in flies impacts age-related functional declines in conjunction with its effects on lifespan. Here, we address this issue by assessing the effect of dietary restriction on lifespan and behavioral senescence in two wild-type strains, in our standard white laboratory stock, and in short-lived flies with reduced expression of superoxide dismutase 2. As expected, dietary restriction extended lifespan in all of these strains. The effect of dietary restriction on lifespan varied with genetic background, ranging from 40 to 90% extension of median lifespan in the seven strains tested. Interestingly, despite its robust positive effects on lifespan, dietary restriction had no substantive effects on senescence of behavior in any of the strains in our studies. Our results suggest that dietary restriction does not have a global impact on aging in Drosophila and support the hypothesis that lifespan and behavioral senescence are not driven by identical mechanisms.

Null Effect of Dietary Restriction on Prostate Carcinogenesis in the Wistar-Unilever Rat

: Chronic dietary restriction inhibits carcinogenesis in several sites in laboratory animals. To determine the effects of dietary restriction on prostate carcinogenesis, prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate (50 mg/day; 21 days); testosterone propionate (100 mg/kg/day; 3 days); N-methyl-N-nitrosourea [MNU; 30 mg/kg; single dose]; and testosterone (subcutaneous implants of 2 pellets containing 40 mg each). Dietary restriction (0% [ad libitum control], 15%, or 30%) was initiated 2 wk post-MNU, and continued until study termination at 12 mo. Dietary restriction induced a rapid suppression of body weight gain but conferred no protection against prostate carcinogenesis. 74% of carcinogen-treated ad libitum controls developed accessory sex gland cancers, versus cancer incidences of 64% and 72% in groups restricted by 15% and 30%, respectively. Similarly, 44% of dietary controls developed cancers limited to the dorsolateral/prostate, versus incidences of 45% and 53% in groups restricted by 15% and 30%. The results of the present study do not support the hypothesis that prostate carcinogenesis can be prevented by reducing caloric intake. Reducing mean body weight by up to 25% through chronic dietary restriction has no effect on the induction of prostate cancers in the Wistar-Unilever rat model.

Dietary restriction in two rotifer species: the effect of the length of food deprivation on life span and reproduction

According to resource allocation theory, animals face a trade off between the allocation of resources into reproduction and into individual growth/maintenance. This trade off is reinforced when food conditions decline. It is well established in biological research that many animals increase their life span when food is in suboptimal supply for growth and/or reproduction. Such a situation of reduced food availability is called dietary restriction. An increase in life span under dietary restricted conditions is seen as a strategy to tolerate periods of food shortage so that the animals can start reproduction again when food is in greater supply. In this study, the effect of dietary restriction on life span and reproduction in two rotifer species, Cephalodella sp. and Elosa worallii, was investigated using life table experiments. The food concentration under dietary restricted conditions was below the threshold for population growth. It was (1) tested whether the rotifers start reproduction again after food replenishment, and (2) estimated whether the time scale of dietary restricted conditions is relevant for the persistence of a population in the field. Only E. worallii responded to dietary restriction with an increase in life span at the expense of reproduction. After replenishment of food, E. worallii started to reproduce again within 1 day. With an increase in the duration of dietary restricted conditions of up to 15 days, which is longer than the median life span of E. worallii under food saturation, the life span increased and the life time reproduction decreased. These results suggest that in a temporally (or spatially) variable environment, some rotifer populations can persist even during long periods of severe food deprivation.

Regional Differences in End-Stage Renal Disease and Amount of Protein Intake in Japan

We recently showed regional differences in the incidence of end-stage renal disease (ESRD) within Japan, which is generally ethnically homogenous, suggesting that factors other than genetic may contribute to the difference. We examined regional differences in the amounts of dietary nutrient intake, especially protein in our search for an explanation. Annually, the Japanese Society for Dialysis Therapy reports the numbers of patients entering maintenance dialysis in each prefecture of Japan. We used these numbers from 1984 to 2002 to calculate the annual ESRD incidence in each of 12 regions of Japan. The regional differences were analyzed in relation to the amounts of nutrient intake reported annually by National Nutrition Survey in corresponding regions for these 19 years. Each year, approximately 15,000 subjects from 5000 households in randomly selected 300 districts were included to obtain a representative sample of the entire population of Japanese in a manner of age, sex, and body mass matched. There were marked regional differences in the annual ESRD incidence and small regional differences in dietary intake of each nutrient. Multiple regression analysis showed that the annual ESRD incidence was negatively correlated with energy intake (r = -0.65, F = 240, n = 228) and positively correlated with animal protein intake (r = 0.25, F = 30). Across 12 regions in the values averaged for 19 years in each region, however, the incidence of ESRD was negatively correlated only with the amounts of energy intake (r = -0.74, F = 12, n = 12), but not with animal protein (r = 0.07, F = 0.04). The present study, relating regional differences between ESRD dynamics and the amounts of nutrient intake in a nationwide population of Japan, revealed that the renal protective effects of dietary restriction of protein, suggested by animal models of progressive nephropathies but yet unproved by large-scale clinical trials, remained unestablished even on a macro level of whole Japan through mapping approaches.

Smelling Their Way to an Early Grave

When animals are reared on a near-starvation diet, they live much longer than those that eat freely. Even the fruit fly Drosophila has this reaction to a low-glucose diet and lives considerable longer on a 5% than on a 15% sugar-yeast diet. This effect of dietary restriction is easily reversed when flies consume more food. Libert et al . report a less expected effect: Just the smell of the flies’ food (yeast) can inhibit some of the effects of dietary restriction and shorten the flies’ life span by 6 to 18%. Flies lacking an essential part of their odor receptors, which have greatly impaired senses of smell, live longer than flies with intact odor sensation. S. Libert, J. Zwiener, X. Chu, W. VanVoorhies, G. Roman, S. D. Pletcher, Regulation of Drosophila life span by olfaction and food-derived odors. Science 315 , 1133-1137 (2007). [Abstract] [Full Text] M. Leslie, Odor of food hastens dieting flies’ deaths. Science 315 , 584 (2007). [Summary] [Full Text]

Regulation of Drosophila Life Span by Olfaction and Food-Derived Odors

Smell is an ancient sensory system present in organisms from bacteria to humans. In the nematode Caenorhabditis elegans, gustatory and olfactory neurons regulate aging and longevity. Using the fruit fly, Drosophila melanogaster, we showed that exposure to nutrient-derived odorants can modulate life span and partially reverse the longevity-extending effects of dietary restriction. Furthermore, mutation of odorant receptor Or83b resulted in severe olfactory defects, altered adult metabolism, enhanced stress resistance, and extended life span. Our findings indicate that olfaction affects adult physiology and aging in Drosophila, possibly through the perceived availability of nutritional resources, and that olfactory regulation of life span is evolutionarily conserved.

Effect of Dietary Restriction on Improvement of Lipid Metabolism and on Mineral Status in Spontaneously Obese Rat (Minko Rat) with Abnormal Lipid Metabolism

Effect of Dietary Restriction on Improvement of Lipid Metabolism and on Mineral Status in Spontaneously Obese Rat (Minko Rat) with Abnormal Lipid Metabolism

Comparative effects of dietary restriction of carbohydrate or fat on circulating adipokines

We have shown in previous studies that a very low carbohydrate ketogenic diet (VLCKD) can ameliorate the metabolic disturbances of the insulin resistance syndrome (IRS) including adiposity, dyslipidemia, glucose and insulin control, inflammation, and vascular function. The favorable effects of a VLCKD on IRS may be modulated in part by altered adipokine secretion. We measured serum adipokines in 40 overweight men and women who consumed an ad libitum VLCKD (1504 kcal:%CHO:fat:protein=12:59:28) or a low fat diet (LFD) (1478 kcal: %CHO:fat:protein=56:24:20) for 12 wk. Compared to subjects in the LFD group, subjects consuming the VLCKD reduced body weight and adiposity. Serum leptin levels were reduced in subjects following the VLCKD compared to the LFD (−42 vs −18%). The significantly greater decrease in leptin in subjects following the VLCKD persisted after normalizing values to body mass and fat mass, indicating an increase in leptin sensitivity. Serum RBP4 levels are directly associated with insulin resistance, and were reduced more in subjects consuming the VLCKD compared to the LFD (−20 vs 5%). Plasminogen-activatorinhibitor-1 (PAI-1) has antifibrinolytic functions, and was also reduced more in subjects consuming the VLCKD compared to LFD (−34 vs −8%). Restriction of dietary carbohydrate is more effective than a low fat diet for reducing the adipokines leptin, RBP4, and PAI-1 and improving markers of IRS.

Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: Effects of diet restriction and phenobarbital

Thioacetamide (TA) undergoes saturation toxicokinetics in ad libitum (AL) fed rats. Diet restriction (DR) protects rats from lethal dose of TA despite increased bioactivation-mediated liver injury via CYP2E1 induction. While a low dose (50 mg TA/kg) produces 6-fold higher initial injury, a 12-fold higher dose produces delayed and mere 2.5-fold higher injury. The primary objective was to determine if this less-than-expected increase in injury is due to saturation toxicokinetics. Rats on AL and DR for 21 days received either 50 or 600 mg TA/kg i.p. T(1/2) and AUCs for TA and TA-S-oxide were consistent with saturable kinetics. Covalent binding of (14)C-TA-derived-radiolabel to liver macromolecules after low dose was 2-fold higher in DR than AL rats. However, following lethal dose, no differences were found between AL and DR. This lack of dose-dependent response appears to be due to saturation of bioactivation at the higher dose. The second objective was to investigate the effect of phenobarbital pretreatment (PB) on TA-initiated injury following a sub-lethal dose (500 mg/kg). PB induced CYP2B1/2 approximately 350-fold, but did not increase covalent binding of (14)C-TA, TA-induced liver injury and mortality, suggesting that CYP2B1/2 has no major role in TA bioactivation. The third objective was to investigate the role of CYP2E1 using cyp2e1 knockout mice (KO). Injury was assessed over time (0-48 h) in wild type (WT) and KO mice after LD(100) dose (500 mg/kg) in WT. While WT mice exhibited robust injury which progressed to death, KO mice exhibited neither initiation nor progression of injury. These findings confirm that CYP2E1 is responsible for TA bioactivation.

Dietary restriction, glycolysis, hormesis and ageing

The possibility is discussed that dietary restriction modulates ageing and onset of related pathologies by, in addition to upregulation of proteolysis, suppression of glycolysis which in turn decreases generation of methylglyoxal (MG), a highly toxic glycating agent which can provoke cellular senescence and many age-related pathologies. This proposal is supported by the observation that intermittent feeding can mimic dietary restriction's effects on mouse lifespan without any overall reduction in calorie intake. That MG-induced modification of the chaperone and anti-apoptotic protein (Hsp27) increases its protective functions suggests a possible hormetic response to transient MG production during transient periods of glycolysis in dietary restricted animals. It is suggested that in the ad libitum-fed state permanent glycolysis would suppress proteolysis and continuously generate MG which overwhelms the anti-MG defence systems. It is proposed that periods of fasting might be a more acceptable approach than permanent undernutrition in our attempts to slow human ageing, although timing of meals may prove important.

Nutrition and allergic disease

SummaryThe prevalence of asthma and allergic diseases has increased dramatically over the past few decades with the highest incidence occurring in children. Most asthma and related atopic disorders have their origins in early life. Thus, it is imperative to understand the early life origins of the disease in order to identify targets for prevention and early intervention. Although atopic diseases have genetic determinants, the increased incidence of these diseases has occurred far too rapidly for genetic changes to explain the increase. This, most likely, results from changes in environmental influences acting on a pre‐existent genetic susceptibility. One of the environmental changes over the last 20–40 years that could have contributed to the recent increase in atopic diseases is diet. Food allergy is often one of the earliest manifestations of atopy, and sensitization to food is a risk factor for the subsequent appearance of respiratory allergy and asthma. However, studies investigating the effects of dietary restrictions on the prevention of allergy have been disappointing. On the other hand, current data suggests that exclusive breastfeeding should be encouraged for at least 4–6 months in infants at both high and low risk of atopy. Increased risk of asthma has also been observed in low birth weight infants, suggesting that under‐nutrition can detrimentally alter foetal development. Epidemiological and immunological studies also suggest that dietary modification or supplementation in the foetal and early life could reduce the development of atopic diseases. The current dietary hypotheses relate to antioxidants, lipids, electrolytes and probiotics. The aims of this report are: (i) to assess the best methods to analyse nutrient intake and nutrient status; (ii) to review the existing epidemiological evidence for an association between dietary intake (nutrients and food) and allergic diseases; and (iii) to define the windows of opportunity for nutritional supplementation to be used as a preventative strategy for asthma and allergy.

Cardiovascular disease could be contained based on currently available data!

Largely due to better control of infectious diseases and significant advances in biomedical research, life expectancy worldwide has increased dramatically in the last three decades. However, as the average age of the population has risen, the incidence of chronic age-related diseases such as arthritis, Alzheimer's, Parkinson's, cardiovascular disease, cancer, osteoporosis, benign prostatic hyperplasia, and late-onset diabetes have increased and have become serious public health problem, as well. The etiology of these disorders is still incompletely understood, therefore, neither preventive strategies nor long-term effective treatment modalities are available for these disorders. In keeping with the aforementioned, the ultimate goal in cardiovascular research is to prevent the onset of cardiovascular episodes and thereby allow successful ageing without morbidity and cognitive decline. Herein, I argue that cardiovascular episodes could be contained with relatively simple approaches. Cardiovascular disorder is characterized by cellular and molecular changes that are commonplace in age-related diseases in other organ system, such alterations include increased level of oxidative stress, perturbed energy metabolism, and "horror autotoxicus" largely brought about by the perturbation of ubiquitin -proteasome system, and excessive oxidative stress damage to the cardiac muscle cells and tissues, and cross-reactions of specific antibodies against human heat shock protein 60 with that of mycobacterial heat shock protein 65. "Horror autotoxicus", a Latin expression, is a term coined by Paul Ehrlich at the turn of the last century to describe autoimmunity to self, or the attack of "self" by immune system, which ultimately results to autoimmune condition. Based on the currently available data, the risk of cardiovascular episodes and several other age-related disorders, including cancer, Alzheimer's disease and diabetes, is known to be influenced by the nature and level of food intake. Now, a wealth of scientific data from studies of rodents and monkeys has documented the significant beneficial effects of calorie restriction (CR) or dietary restriction (DR), and multiple antioxidant agents in extending life span and reducing the incidence of progeroid-related diseases. Reduced levels of cellular oxidative stress, protection of genome from deleterious damage, detoxification of toxic molecules, and enhancement of energy homeostasis, contribute to the beneficial effects of dietary restriction and multiple antioxidant agents. Recent findings suggest that employment of DR and multiple antioxidant agents (including, catalase, glutathione peroxidase, CuZn superoxide dismutase, and Mn superoxide dismutase = enzymes forming the primary defense against oxygen toxicity), and ozone therapy may mount an effective resistance to pathogenic factors relevant to the pathogenesis of cardiovascular episodes. Hence, while further studies will be needed to establish the extent to which CR and multiple antioxidant agents will reduce incidence of cardiovascular episodes in humans, it would seem prudent to recommend CR and multiple antioxidant agents as widely applicable preventive approach for cardiovascular disorders and other progeroid-related disorders.

The longevity effect of dietary restriction in Caenorhabditis elegans

The nematode Caenorhabditis elegans has been subjected to DR by food ( Escherichia coli) dilution, growth in axenic medium and using animals having defects in feeding behavior or in specific nutrient transporter proteins. There is evidence that DR causes increased resistance against environmental stressors but no decrease of metabolic rate. The insulin/IGF-1 signaling pathway does not mediate the longevity effect of DR in this species, but TOR signaling may be involved. The metabolic stability–longevity theory offers a plausible explanation of the longevity effect of DR but needs experimental validation.

Dietary restriction-induced life extension: a broadly based biological phenomenon

It is concluded that dietary restriction will extend the life of all species in the Animalia Kingdom, including the human species. This conclusion is based on the fact that hormesis is a component of the life-extending action and the other anti-aging effects of dietary restriction. It is also concluded that given the currently available database, it is not possible to predict the quantitative effect of dietary restriction on the human life span.

Can dietary restriction increase longevity in all species, particularly in human beings? Introduction to a debate among experts

This article introduces a special issue of Biogerontology, for which a number of international experts who are still active or have been active in research on the effects of dietary restriction (DR) were asked to answer the following question. Do you think that DR can increase longevity in all species, particularly in human beings? Twelve scientists responded with their opinion articles of which roughly half of them taking the position that yes, DR can be applicable to human beings, while the other half arguing for the inapplicability of DR to humans. The conclusions of these learned opinions are summarized here.

The dietary restriction effect in C. elegans and humans: is the worm a one-millimeter human?

Dietary restriction (DR) lengthens life span in wide range of vertebrate and invertebrate species. The molecular mechanism by which DR increases life span and the universality of its effects (and hence its applicability to humans) are currently debated in gerontology. This article addresses these two problems from both an experimental perspective, using the nematode C. elegans as a model system, and a theoretical viewpoint, by appealing to recent mechanistic and evolutionary models of aging. Molecular mechanisms of aging are analysed by contrasting the rate of living/oxidative stress hypothesis with the metabolic stability/longevity hypothesis, a new model of aging which postulates that the robustness of metabolic networks, rather than metabolic rate per se, is the major determinant of aging. Studies of food-restricted worms are shown to be consistent with the metabolic stability/longevity hypothesis. The universality of the effects of DR is addressed in terms of directionality theory, an evolutionary model, which is based on the analytical fact that the robustness or the stability of demographic networks determines Darwinian fitness. Directionality theory, in conjunction with the metabolic stability hypothesis, predicts that DR will have negligible effects on equilibrium species (late age of sexual maturity, small size of progeny sets and broad reproductive span) and large effects on opportunistic species (early age of maturity, large size of progeny sets, narrow reproductive span). Empirical studies using C. elegans (an opportunistic species) and computational studies on human populations (an equilibrium species) are shown to be consistent with these predictions.

Effect of Dietary Restriction on Learning and Memory Impairment and Histologic Alterations of Brain Stem in Senescence‐Accelerated Mouse (SAM) P8 Strain

The age-associated spontaneous spongy degeneration in the brain stem of senescence-accelerated mouse (SAM) P8 strain has been suggested to be closely associated with the ability to learn and memorize. In this study, we investigated the effects of dietary restriction (DR) initiated from weaning on learning and memory and histologic changes of the brain stem in P8 and control R1 mice. Although no effect of DR was observed in the retention of the passive-avoidance response in both the P8 and R1 mice, the acquisition of the task was significantly improved by DR in P8 mice. On the other hand, the total area and number of vacuoles in the brain stem was significantly higher in ad libitum-fed (AD)-P8 mice than in AD-R1 mice. However, no significant effect was observed on the vacuole formation in the brain stem of P8 mice by DR. These observations suggest that the improvement of the acquisition of the task by DR in P8 mice is possibly due to changes in neuronal function rather than histologic alteration in brain stem.