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Results for “Caloric Restriction”

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PubMed2004

Ink4a/Arf expression is a biomarker of aging.

The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.

ADP-Ribosylation Factor 1↗

PubMed2004

Decreased final height of children with growth deceleration secondary to poor weight gain during late childhood.

Eighteen healthy, short children with normal growth during most of their childhood were evaluated after a sustained fall in weight and reduced linear growth. Growth was followed after nutritional counseling until final height. This report demonstrates the need for an appropriate-for-age weight gain in growing children as a relatively minor but prolonged caloric restriction, leading to a sustained fall in weight centiles, will affect growth velocities long term and may lead to reduced final heights.

Body Height↗

PubMedDate not supplied

Effects of hypocaloric diet on sleep in young and old rats.

Aging produces a loss in a number of behavioral and cognitive functions, including sleep. Hypocaloric diet is one of the few methods that have been shown to retard the effects due to age. However, the effects of such a diet on sleep have never been investigated. In the present study, 21 months old male F344 rats fed a 60% calorie-reduced diet continued to have a significant reduction in delta power (0.3-4 Hz EEG), less sleep following 12 h total sleep deprivation (TSD) and increased sensitivity to caffeine compared to young rats (3 months) fed a similar diet. These results indicate that caloric restriction is unable to prevent the decline in sleep that occurs with aging.

Age Factors↗

PubMed2006

Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging.

The plasma membrane (PM) contains redox enzymes that provide electrons for energy metabolism and recycling of antioxidants such as coenzyme Q and alpha-tocopherol. Brain aging and neurodegenerative disorders involve impaired energy metabolism and oxidative damage, but the involvement of the PM redox system (PMRS) in these processes is unknown. Caloric restriction (CR), a manipulation that protects the brain against aging and disease, increased activities of PMRS enzymes (NADH-ascorbate free radical reductase, NADH-quinone oxidoreductase 1, NADH-ferrocyanide reductase, NADH-coenzyme Q10 reductase, and NADH-cytochrome c reductase) and antioxidant levels (alpha-tocopherol and coenzyme Q10) in brain PM during aging. Age-related increases in PM lipid peroxidation, protein carbonyls, and nitrotyrosine were attenuated by CR, levels of PMRS enzyme activities were higher, and markers of oxidative stress were lower in cultured neuronal cells treated with CR serum compared with those treated with ad libitum serum. These findings suggest important roles for the PMRS in protecting brain cells against age-related increases in oxidative and metabolic stress.

Aging↗

PubMed2006

Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet.

AIMS/HYPOTHESIS: Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin. METHODS: We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated. RESULTS: In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA. CONCLUSIONS/INTERPRETATION: Intake of diets rich in EPA and DHA leads to elevated systemic concentrations of adiponectin, largely independent of food intake or adiposity and explain, to some extent, their anti-diabetic effects.

AMP-Activated Protein Kinase Kinases↗

PubMed2004

Free radicals and aging.

Aging is characterized by decrements in maximum function and accumulation of mitochondrial DNA mutations, which are best observed in organs such as the brain that contain post-mitotic cells. Oxygen radicals are increasingly considered responsible for part of these aging changes. Comparative studies of animals with different aging rates have shown that the rate of mitochondrial oxygen radical generation is directly related to the steady-state level of oxidative damage to mitochondrial DNA and is inversely correlated with maximum longevity in higher vertebrates. The degree of unsaturation of tissue fatty acids also correlates inversely with maximum longevity. These are the two known traits connecting oxidative stress with aging. Furthermore, caloric restriction, which decreases the rate of aging, proportionately decreases mitochondrial oxygen radical generation, especially at complex I. These findings are reviewed, highlighting the results obtained in the brain.

Aging↗

PubMed2004

Twenty-four-hour rhythms of mitogenic responses, lymphocyte subset populations and amino acid content in submaxillary lymph nodes of growing male rats subjected to calorie restriction.

Peripubertal male Wistar rats were submitted to a calorie restriction diet enriched in proteins and low in fat and carbohydrates for 4 weeks, and starting on day 35 of life. Mitogenic responses, lymphocyte subset populations, interferon (IFN)- gamma release and amino acid content were determined in submaxillary lymph nodes at six time intervals during the 24-h span. The diet employed completely arrested growth in growing rats. After caloric restriction, mean values of Con A response, lymph node T and CD4+ cell number and CD4+/CD8+ ratio augmented, whereas those of B cell number, IFN-gamma release and glutamine and glutamate concentration decreased. Calorie restriction modified 24-h rhythmicity of lymph node mitogenic responses to Con A and LPS, and of T, T-B, CD4+ and CD4+ -CD8+ lymph node cell subsets. It also changed the 24-h pattern of lymph node IFN-gamma release and glutamine, aspartate, glutamate and taurine lymph node content. Availability of nutrients presumably affects the mechanisms that modulate the circadian variation of immune responsiveness in growing rats.

Aging↗

PubMed2003

Evaluation of thyroid function in obese dogs and in dogs undergoing a weight loss protocol.

Obesity and weight loss have been shown to alter thyroid hormone homeostasis in humans. In dogs, obesity is the most common nutritional problem encountered and weight loss is the cornerstone of its treatment. Therefore, it is important to clarify how obesity and weight loss can affect thyroid function test results in that species. The objectives of this study were to compare thyroid function in obese dogs and in lean dogs and to explore the effects of caloric restriction and weight loss on thyroid hormone serum concentrations in obese dogs. In the first experiment, 12 healthy lean beagles and 12 obese beagles were compared. Thyroid function was evaluated by measuring serum concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), thyrotropin (TSH), and reverse triiodothyronine (rT3) as well as a TSH stimulation test using 75 microg i.v. of recombinant human TSH. In the second experiment, eight obese beagles were fed an energy-restricted diet [average 63% maintenance energy requirement (MER)] until optimal weight was obtained. Blood samples for determination of TT4, FT4, TT3, TSH and rT3, were taken at the start and then weekly during weight loss. Only TT3 and TT4 serum concentrations were significantly higher in obese dogs as compared to lean dogs. In the second experiment, weight loss resulted in a significant decrease in TT3 and TSH serum concentrations. Thus obesity and energy restriction significantly alter thyroid homeostasis in dogs, but the observed changes are unlikely to affect interpretation of thyroid function test results in clinics.

Animals↗

PubMed2006

Measurement of dietary restraint: validity tests of four questionnaires.

This study tested the validity of four measures of dietary restraint: Dutch Eating Behavior Questionnaire, Eating Inventory (EI), Revised Restraint Scale (RS), and the Current Dieting Questionnaire. Dietary restraint has been implicated as a determinant of overeating and binge eating. Conflicting findings have been attributed to different methods for measuring dietary restraint. The validity of four self-report measures of dietary restraint and dieting behavior was tested using: (1) factor analysis, (2) changes in dietary restraint in a randomized controlled trial of different methods to achieve calorie restriction, and (3) correlation of changes in dietary restraint with an objective measure of energy balance, calculated from the changes in fat mass and fat-free mass over a six-month dietary intervention. Scores from all four questionnaires, measured at baseline, formed a dietary restraint factor, but the RS also loaded on a binge eating factor. Based on change scores, the EI Restraint Scale was the only measure that correlated significantly with energy balance expressed as a percentage of energy required for weight maintenance. These findings suggest that, of the four questionnaires tested, the EI Restraint Scale was the most valid measure of the intent to diet and actual caloric restriction.

Adult↗

PubMed2004

Dynamics of keratinocytes in vivo using HO labeling: a sensitive marker of epidermal proliferation state.

A heavy water ((2)H(2)O) labeling method recently developed to measure cell proliferation in vivo is applied here to the measurement of murine epidermal cell turnover and to investigate conditions in which keratinocyte proliferation is either inhibited or stimulated. The technique is based on incorporation of (2)H(2)O into the deoxyribose moiety of deoxyribonucleotides in dividing cells. Label incorporation and die-away studies in cells isolated from C57BL/6J mouse epidermis revealed the replacement rate to be 34%-44% per wk (half-life of 1.6-2 wk). The kinetics provided evidence of a non-proliferative subpopulation of cells (10%-15% of the total) within the epidermis. Topical administration of 7,12-dimethylbenz(a)anthracene and 12-O-tetradecanoylphorbol-13-acetate for 3 wk increased epidermal cell proliferation by 55% in SENCAR mice. Topical addition of lunasin, an anti-mitotic agent from soy, decreased epidermal cell proliferation modestly though significantly (16% given alone, 9% given with carcinogens). Caloric restriction (by 33% of energy intake) for 4 wk decreased the epidermal cell proliferation rate by 45% in C57BL/6J mice. In summary, epidermal cell proliferation can be measured in vivo using (2)H(2)O labeling in normal, hyper- and hypo-proliferative conditions. Potential applications of this inherently safe method in humans might include studies of psoriasis, wound healing, chemopreventive agents, and caloric intake.

Animals↗

PubMed2004

Anti-aging effects of anti-lipolytic drugs.

Genetic disruption of insulin and insulin-like signaling pathways may extend lifespan. Hyperinsulinemia and insulin resistance may accelerate aging. The hypothesis was tested that a once-a-week life-long inhibition of insulin secretion by the administration of anti-lipolytic drugs might have anti-aging effects. Groups of 3-month-old male Sprague-Dawley rats were (a) given standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted 1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by the gastric tube. The AL, FW and EOD groups received saline intragastrically. Treatment with ACIPIMOX transiently decreased plasma free fatty acids, glucose and insulin and increased valine plasma levels, and had no long-term effect on food consumption and body weight. By age 6, 12 and 24 months subgroups were taken and the age-related changes in liver dolichol and autophagic proteolysis--which are correlated with life-expectancy--were measured. Liver dolichol levels increased and autophagic proteolysis decreased in mature and older AL rats; EOD and FWA fully counteracted these changes; FW rats had significant but smaller beneficial effects. It is concluded that life-long weekly-repeated transient inhibition of insulin secretion by antilipolytic drugs may have an anti-aging effect, additive to the anti-aging effect of a milder caloric restriction. Speculation is that transiently lower plasma insulin levels might stimulate the anti-aging cell-repair mechanism autophagy, which has longer lasting effects on cell housekeeping.

Aging↗

PubMed2006

Computational model of in vivo human energy metabolism during semistarvation and refeeding.

Changes in body weight and composition are the result of complex interactions among metabolic fluxes contributing to macronutrient balances. To better understand these interactions, a mathematical model was constructed that used the measured dietary macronutrient intake during semistarvation and refeeding as model inputs and computed whole body energy expenditure, de novo lipogenesis, and gluconeogenesis as well as turnover and oxidation of carbohydrate, fat, and protein. Published in vivo human data provided the basis for the model components that were integrated by fitting a few unknown parameters to the classic Minnesota human starvation experiment. The model simulated the measured body weight and fat mass changes during semistarvation and refeeding and predicted the unmeasured metabolic fluxes underlying the body composition changes. The resting metabolic rate matched the experimental measurements and required a model of adaptive thermogenesis. Refeeding caused an elevation of de novo lipogenesis that, along with increased fat intake, resulted in a rapid repletion and overshoot of body fat. By continuing the computer simulation with the prestarvation diet and physical activity, the original body weight and composition were eventually restored, but body fat mass was predicted to take more than one additional year to return to within 5% of its original value. The model was validated by simulating a recently published short-term caloric restriction experiment without changing the model parameters. The predicted changes in body weight, fat mass, resting metabolic rate, and nitrogen balance matched the experimental measurements, thereby providing support for the validity of the model.

Adipose Tissue↗

PubMed2005

Alzheimer's disease: channeling APP to non-amyloidogenic processing.

A good number of pharmacologic agents have over the years been touted as potentially beneficial in either preventing the onset or delay the progression of Alzheimer's disease. These include compounds such as non-steroidal anti-inflammatory drugs (NSAIDs) (HMG-CoA reductase inhibitors (statins)) and flavonoids. The underlying mechanisms for the beneficial effect of these agents are by and large attributed to their ability to reduce beta-amyloid (Abeta) production and amyloid load in the brain, via inhibition of amyloidogenic gamma-secretase activity. Recent reports have now provided mechanistic insights as to how non-amyloidogenic processing might also be enhanced by these seemingly unrelated treatments. Intriguingly, this appears to involve the inhibition of the activity of small GTPase Rho and its effector, the Rho-associated kinase, ROCK. Dietary caloric restriction (CR) also enhances non-amyloidogenic processing of APP, and this may be part of a more general anti-aging effect of CR mediated by gene expression changes downstream of the activity of the histone deacetylase SIRT1.

Alzheimer Disease↗

PubMedDate not supplied

The inherent, age-dependent loss of retinal ganglion cells is related to the lifespan of the species.

Retinal ganglion cells are neurons that transmit visual information from the retina to the brain. With age, there is an inherent loss of retinal ganglion cells that we have quantitated by retrograde labeling of these neurons. In adult mice, the loss of retinal ganglion cells is approximately 2.3% per month; in adult rats, the loss of retinal ganglion cells is approximately 1.5% per month. The total losses of these neurons over the average lifespans of mice and rats are similar to those which have been reported in monkeys and humans. Furthermore, caloric restriction, which extends the lifespans of mice and rats, slows the temporal age-related loss of retinal ganglion cells. Thus, the total age-dependent losses of these neurons appear to be approximately the same over the lifespans of these mammalian species.

Aging↗

PubMedDate not supplied

Effects of phentermine and phenformin on biomarkers of aging in rats.

BACKGROUND: Caloric restriction (CR) is the only treatment known to substantially prolong both average and maximal life span in experimental animals. Interventions that mimic certain effects of CR could be potential anti-aging treatments in humans. Drugs which reduce appetite (anorexiants) represent one class of candidate treatments. Agents that reduce the glucose utilization by the organism could also represent another class of candidate CR mimetics. OBJECTIVE: In our study, we addressed the following questions: (1) Does treatment with an anorexiant reduce caloric intake and body weight of experimental animals comparable to that caused by CR? (2) Does treatment with an antidiabetic agent influence caloric intake and body weight? (3) Does treatment with any of these drugs affect metabolic parameters of an organism in the way similar to that observed with CR? METHODS: One hundred and twenty 6-month-old female Wistar-derived LIO rats were randomly subdivided into four groups and exposed to: (1) ad libitum feeding with placebo (controls); (2) the antidiabetic drug phenformin (2 mg/kg); (3) the anorectic drug phentermine (1 mg/kg), and (4) the same amount of food as the group with the least food intake during the previous week (pair-fed controls). Food and water intake, body weight, and rectal temperature were measured weekly during 16 weeks. At the end of the 16th week of the experiment, serum levels of glucose, total beta-lipoprotein and pre-beta-lipoprotein fractions, cholesterol, triglycerides, insulin, total triiodothyronine, and free thyroxine were estimated. The contents of diene conjugates and Schiff's bases, total antioxidant activity, the activities of Cu/Zn superoxide dismutase, glutathione S-transferase, and glutathione peroxidase, and the generation of reactive oxygen species (ROS) were studied in brain and liver homogenates and in the serum. RESULTS: The controls exposed to pair feeding had a significantly reduced food consumption (about 20%) as compared with the ad libitum fed controls and thus exhibited a moderate CR. Treatment with phentermine reduced the caloric intake by about 12% as compared with the ad libitum fed controls. Body weight and water intake in this group were only slightly decreased (by about 2 and 5%, respectively) as compared with the controls. The mean rectal temperature in the phentermine group (38 degrees C) was significantly higher than in the ad libitum fed (37.8 degrees C) and pair-fed (37.6 degrees C) controls. Treatment with phentermine also resulted in significantly reduced ROS levels in all tissues studied, while the highest ROS production was found in ad libitum (blood serum) and pair-fed (brain) controls. Treatment with phenformin did not significantly influence food and water consumption, body weight, and temperature when compared with the ad libitum fed controls. Rats treated with this antidiabetic drug showed intermediate values of ROS generation. Differences among the groups in total antioxidant activity were not obvious. CONCLUSIONS: Treatment with phentermine reduces caloric intake slightly less than is commonly observed in CR studies. CR due to forcibly reduced feeding and CR due to substance-suppressed appetite appear to act through different metabolic mechanisms and thus may affect aging and longevity in different ways.

Aging↗

PubMed2003

Does dietary sugar and fat influence longevity?

Simultaneous consideration of the influence of the different types of carbohydrates and fats in human diets on mortality rates (especially the diseases of aging), and the probable retardation of such diseases by caloric restriction (CR) leads to the hypothesis that restriction of foods with a high glycemic index and saturated or hydrogenated fats would avoid or delay many diseases of aging and might result in life extension. Many of the health benefits of CR might thereby be available to humans without the side effects or unacceptability of semi-starvation diets.

Aging↗

PubMedDate not supplied

Qualitative versus quantitative caloric intake: are they equivalent paths to successful aging?

With the increasing demands placed on our society to perform better for longer, in addition to the large increase in the old segment of our population, a race has begun to forestall or reverse the ubiquitous declines that emerge from growing old. Currently, little is known about the mechanisms responsible for the neuronal degeneration seen during both normal aging and neurodegenerative disease; however, among the prime candidates responsible for producing these effects are free radicals. It has been hypothesized that brain aging results from a progressive inability to cope with such insults as oxidative stress and inflammation. As a result, this inability provides a fertile environment for the subsequent development of neurodegenerative disease. Therefore, if the preservation of neuronal function and associated cognitive and motor performance during aging will enhance the probability of aging successfully, then it is of crucial importance to find ways to preserve or decrease the responsiveness of the brain to these insults. The purpose of this review is to discuss two strategies, caloric restriction and antioxidant supplementation (through foods and supplements), both proven to be successful at protecting the brain from age-related oxidative insults. The two interventions will be compared and contrasted in terms of their effectiveness, safety, and generalization capacity for human treatment.

Aged↗

PubMed2006

The involvement of macroautophagy in aging and anti-aging interventions.

Macroautophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair, and as a source of nutrients for metabolic use in early starvation. Extensive evidence has been reported that macroautophagy process declines with increasing age. This impairment, probably due to ad libitum feeding, may cause accumulation of altered structures leading to the age-related decline in cell functions. It has been suggested that caloric restriction (CR) and disruption of insulin-like signals contrast the process of aging by prolonged stimulation of macroautophagy. According to this hypothesis, it is shown that life-long weekly administration of an anti-lipolytic drug decreases glucose and insulin levels, stimulates autophagy and intensifies anti-aging effects of submaximal CR.

Aging↗