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Results for “Caloric Restriction”

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At least 991 records · Page 55Linked to original sources

PubMed2005

Effect of every other day feeding diet on gene expression in normal and in long-lived Ames dwarf mice.

Ames dwarf mutant mice are long-lived, hypoinsulinemic and hypoglycemic and exhibit enhanced sensitivity to injected insulin. Their phenotypic characteristics show many similarities to animals subjected to caloric restriction (CR) but Ames dwarf mice are not CR mimetics. Reducing daily food intake by 30% prolongs longevity in both normal and Ames dwarf mice. In the present study, the animals were subjected to a different type of CR, every other day feeding (EOD). Using real-time PCR, we have examined the expression of genes related to insulin signaling in the liver of normal and dwarf mice after 9 months of EOD. The results indicate that EOD produces some changes in the insulin and IGF1 signaling pathways, and that these changes are consistent with EOD increasing insulin sensitivity.

Adipose Tissue↗

PubMed2004

Life extension in the dwarf mouse.

Ames dwarf mice and Snell dwarf mice lack growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH), live much longer than their normal siblings, and exhibit many symptoms of delayed aging. "Laron dwarf mice," produced by targeted disruption of the GH receptor/GH-binding protein gene (GHR-KO mice), are GH resistant and also live much longer than normal animals from the same line. Isolated GH deficiency in "little" mice is similarly associated with increased life span, provided that obesity is prevented by reducing fat content in the diet. Long-lived dwarf mice share many phenotypic characteristics with genetically normal (wild-type) animals subjected to prolonged caloric restriction (CR) but are not CR mimetics. We propose that mechanisms linking GH deficiency and GH resistance with delayed aging include reduced hepatic synthesis of insulin-like growth factor 1 (IGF-1), reduced secretion of insulin, increased hepatic sensitivity to insulin actions, reduced plasma glucose, reduced generation of reactive oxygen species, improved antioxidant defenses, increased resistance to oxidative stress, and reduced oxidative damage. The possible role of hypothyroidism, reduced body temperature, reduced adult body size, delayed puberty, and reduced fecundity in producing the long-lived phenotype of dwarf mice remains to be evaluated. An important role of IGF-1 and insulin in the control of mammalian longevity is consistent with the well-documented actions of homologous signaling pathways in invertebrates.

Aging↗

PubMed2004

Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus.

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.

Animals↗

PubMed2006

Optimal diet for glycemia and lipids.

Concentrations of glucose and lipids in the blood have important health implications and are influenced by dietary intake. Dietary intake and energy expenditure regulate body weight, which is also an important determinant of health. Thus it would be important to determine the optimal diet for affecting blood glucose and lipids and body weight. Many professional health organizations in different countries have made dietary recommendations that include caloric restriction when needed to prevent or reverse overweight or obesity, limitation of saturated and trans fat, and emphasis on fruits and vegetables. These professional groups have not recommended extremely low carbohydrate or extremely low fat diets, despite much popular interest and recent research in these approaches. In several clinical trials, diet and exercise interventions prevented or delayed the development of type-2 diabetes. These trials showed the value of diet interventions, but did not attempt to determine which dietary approach was optimal. Clinical trials attempting to determine the optimal diet suffer from small sample sizes, short follow-up, and poor follow-up of participants. Therefore, the optimal balance between the total fat and carbohydrate contents and the optimal types of fats and carbohydrates remain unknown.

Blood Glucose↗

PubMed2007

Energy intake and amyotrophic lateral sclerosis.

Roy Walford, a physician and scientist who pioneered research on the anti-aging effects of caloric restriction and subjected himself to a low-energy diet, recently died from amyotrophic lateral sclerosis (ALS). Information from his case, epidemiological findings, and recent controlled studies in mouse models of ALS suggest that low-energy diets might render motor neurons vulnerable to degeneration, whereas high-energy diets are ameliorative. This contrasts with the effects of low-energy diets on various neuronal populations in the brain that respond adaptively, activating pathways that promote plasticity and resistance to disease. One reason that motor neurons might be selectively vulnerable to low-energy diets is that they are unable to engage neuroprotective responses to energetic stress response involving the protein chaperones, such as, heat-shock protein-70.

Aging↗

PubMed2003

T cell chemokine receptor expression in aging.

Changes in chemokine receptor expression are important in determining T cell migration and the subsequent immune response. To better understand the contribution of the chemokine system in immune senescence we determined the effect of aging on CD4(+) T cell chemokine receptor function using microarray, RNase protection assays, Western blot, and in vitro chemokine transmigration assays. Freshly isolated CD4(+) cells from aged (20-22 mo) mice were found to express a higher level of CCR1, 2, 4, 5, 6, and 8 and CXCR2-5, and a lower level of CCR7 and 9 than those from young (3-4 mo) animals. Caloric restriction partially or completely restored the aging effects on CCR1, 7, and 8 and CXCR2, 4, and 5. The aging-associated differences in chemokine receptor expression cannot be adequately explained by the age-associated shift in the naive/memory or Th1/Th2 profile. CD4(+) cells from aged animals have increased chemotactic response to stromal cell-derived factor-1 and macrophage-inflammatory protein-1alpha, suggesting that the observed chemokine receptor changes have important functional consequences. We propose that the aging-associated changes in T cell chemokine receptor expression may contribute to the different clinical outcome in T cell chemokine receptor-dependent diseases in the elderly.

Aging↗

PubMedDate not supplied

Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior.

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.

Aged↗

PubMed1986

Effects of severe dietary restriction on male reproductive hormones.

The reproductive hormone response to severe caloric restriction (600 Cal day-1) was studied in six men 33-67% over ideal body weight who completed a 32-day protocol consisting of three periods in the following order: control (4 days), maintenance protein and energy; diet A (14 days), 50 g lean beef protein plus 50 g casein; and diet B (14 days), 50 g lean beef protein plus 50 g carbohydrate. Weight loss (8.7-12.5 kg) was associated with a decrease in mean blood glucose [4.52 +/- 0.60 (+/- SEM), 3.49 +/- 0.29, and 3.80 +/- 0.30 mM] and an increase in beta-hydroxybutyrate (less than 0.10, 2.09 +/- 0.44, and 1.06 +/- 0.34 mM), as determined on the final morning of each period. On the same days, mean serum FSH and LH responses to LHRH infusion of 0.2 micrograms min-1 for 4 h (expressed as milliinternational units per ml area under the concentration-time curve) were: FSH, 1558 +/- 359, 1336 +/- 545, and 1337 +/- 321 (P = NS); and LH, 1730 +/- 545, 1612 +/- 481, and 1782 +/- 556 (P = NS), respectively. Basal serum FSH, LH, free testosterone (T), and total T changed, while 24-h urinary LH and FSH excretion increased on diet A only. Unlike 10 days of total fasting, during which the same amount of weight was lost, basal serum FSH and LHRH-stimulated serum FSH responses were both significantly diminished by 25%, and serum T was diminished by 19% (1), these same parameters were little changed by either low energy diet. The increased urinary excretion of FSH and LH during diet A suggests that greater ketosis increases renal gonadotropin clearance.

Adult↗

PubMed2004

Long term consequences of the 1944-1945 Dutch famine on the insulin-like growth factor axis.

The insulin-like growth factor axis is highly responsive to nutritional status and may be involved as one of the underlying mechanisms through which caloric restriction could affect cancer risk. High levels of circulating insulin-like growth factor (IGF)-I, or IGF-I relative to IGF binding protein (IGFBP)-3 have been related to various human cancer types. In a group of 87 postmenopausal women, we found that childhood exposure to the 1944-1945 Dutch famine was associated with increased plasma levels of IGF-I and IGFBP-3, whereas IGFBP-1 and -2 levels were weakly decreased. These results are opposite to immediate responses seen under starvation and we hypothesize that this could indicate a permanent overshoot upon improvement of nutritional status after the famine.

Adolescent↗

PubMed2005

Mrg19 depletion increases S. cerevisiae lifespan by augmenting ROS defence.

Caloric restriction (CR) is the most compelling example of lifespan extension by external manipulation. Although the molecular mechanisms remain unknown, the theory of hormesis has been invoked to explain the life promoting effects of CR. Hormesis is defined as the beneficial effects of low intensity stressor on a cell or organism. Mrg19 is a putative transcription factor that regulates carbon and nitrogen metabolism in yeast. In this study, we have found that deletion of MRG19 gene causes metabolic shift in yeast cells, leading to higher intracellular reactive oxygen species, augmentation of scavenging enzymes and longer lifespan compared to wild-type cells. All these results together suggest that similar to CR, depletion of Mrg19 leads to a condition of mild stress which in turn enhances vitality.

Caloric Restriction↗

PubMed2005

Combined dieting and stress evoke exaggerated responses to opioids in binge-eating rats.

The authors developed an animal model of binge eating where history of caloric restriction with footshock stress (R + S) causes rats to consume twice the normal amount of palatable food. The authors tested the hypothesis that binge eating is mediated by changes in opioid control of feeding by comparing rats' anorectic and orexigenic responses to naloxone and butorphanol, respectively, and by testing the ability of butorphanol to elicit binge eating of chow when palatable food was absent. Mu/kappa opioid-receptor blockade and activation had exaggerated responses in the R + S rats with naloxone suppressing binge eating to control levels, and although butorphanol did not trigger chow binge eating, it enhanced binge eating of palatable food. These responses in sated normal-weight rats strengthen evidence that reward, over metabolic need, drives binge eating.

Analgesics, Opioid↗

PubMed2004

Loss of N-cadherin and alpha-catenin in the proximal tubules of aging male Fischer 344 rats.

Aging is associated with a loss of renal reserve, and increased sensitivity to either xenobiotic or physiologic insult. Given the critical role of the cadherin/catenin complex in establishing and maintaining the integrity and polarity of tubular epithelial cells, it was hypothesized that aging was associated with alterations in renal cadherin/catenin complexes. Histological assessment of aged (24 months) kidneys harvested from male Fischer 344 rats demonstrates mild degeneration of proximal tubules, multifocal chronic lymphocytic infiltration, moderate development of protein casts inside tubules, and tubular dilatation or degeneration. Western blot analysis revealed that N-cadherin protein expression is not constant over 24 months. N-cadherin expression increased from 4 to 9 months, with peak levels at 9 and 13 months. A decrease in expression was seen at 19 months and an almost complete loss of expression was seen at 24 months. In contrast, the expression of E- and Ksp-cadherin was constant over 24 months. A loss of alpha-catenin at was seen at 19 and 24 months in the absence of changes in beta-, gamma-, and p120-catenin. This pattern of N-cadherin expression (increase followed by decrease) was confirmed by real-time PCR analysis, which demonstrated a similar pattern as the Western blot, suggesting that the loss of N-cadherin protein was due to decreased gene expression. The loss of N-cadherin was specific for the kidney, as no changes in N-cadherin expression in the liver, brain, or testes were seen during aging. The conclusion that loss of N-cadherin expression is a critical component of the renal dysfunction associated with aging is supported by the finding that caloric restriction attenuates the loss of N-cadherin, as well as the finding that a significant loss of N-cadherin is seen in the kidneys of ZDF x SHHF rats, a genetic model of end-stage renal disease. Cadherin and catenin expression was further analyzed by immunofluorescence. A significant loss of staining of both N-cadherin and alpha-catenin was seen in the proximal tubules of rats at 24 months. Interestingly, this corresponded with delocalization of the alpha-1 subunit of the Na+K+-ATPase, i.e. aberrant staining on cell-cell borders and some indication of apical staining in proximal tubules. Taken together, these data suggest that aging is associated with decreased expression of N-cadherin and alpha-catenin and is associated with a loss of cell polarity.

Aging↗

PubMed2007

Circadian clocks: setting time by food.

In mammals, daily rhythms in behaviour and physiology are driven by a circadian timing system comprised, in a hierarchical way, of a master pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus and of peripheral oscillators in most body cells. At the molecular level, in both the SCN and peripheral oscillators, the circadian clock mechanism is built from interconnected feedback loops in gene expression that operate in a cell-autonomous and self-sustained fashion. The SCN clock is mainly entrained by light/dark cycles. By contrast, peripheral oscillators can be strongly affected by daily feeding cycles, which have little effect on the phase of the SCN. However, when feeding schedules are coupled with a caloric restriction, behavioural and physiological circadian rhythms and gene expression in the SCN are shifted and/or entrained to meal-time. Moreover, the reward and motivational value of food can also be a potent synchroniser for the SCN clock. This suggests that energy metabolism and motivational properties of food can influence the clock mechanism of the SCN. Food-related cues may entrain clock genes of the SCN with a direct effect, or be mediated indirectly by another neural or peripheral site. In addition, there may be one or more oscillator sites that would play an integral role as a food-entrained oscillator (FEO), responsible for anticipation of meal-time. The site housing, or the network underlying, this putative FEO is still unknown. The aim of this review is to summarise our current knowledge of the central and peripheral circadian clocks and how they can be entrained by feeding at the physiological and molecular levels.

Animals↗

PubMed2005

The 1944-1945 Dutch famine and subsequent overall cancer incidence.

Caloric restriction seems to be the most potent dietary intervention to protect against a variety of cancers in animals. We investigated whether overall cancer risk is affected in humans after exposure to a brief famine, followed by a period of abundance. We used data of approximately 15,000 women who were exposed at various degrees to the 1944-1945 Dutch famine at ages between 2 and 33 years. Between 1983 and 1986, these women were asked about their individual experiences of famine exposure ("absent," "moderate," or "severe exposure"). During follow-up until January 2000, 1,602 new cancer cases were identified by the regional cancer registry. We assessed the relation between famine and total cancer risk by weighted Cox regression models, in which a 15% random sample was used to represent person-years lived in the entire cohort. In these models, we adjusted for potential confounders. Overall cancer risk was increased in women having been severely famine exposed compared with women having been unexposed (hazard ratio, 1.25; 95% confidence interval, 1.01-1.55). Exclusion of breast cancer cases from our analyses showed that this increase in risk was largely driven by the previously reported increase in breast cancer risk: women who were severely exposed to the famine were at a 1.12 (95% confidence interval, 0.87-1.43) times increased risk of non-breast cancer compared with the unexposed. In conclusion, we found no indications that this brief famine has affected overall cancer risk, exclusive of breast cancer. Counteracting increased caloric intake following the famine, however, may have obscured any relation.

Adolescent↗

PubMed2004

Endocrine and metabolic effects of physiologic r-metHuLeptin administration during acute caloric deprivation in normal-weight women.

Leptin is a nutritionally regulated hormone that may modulate neuroendocrine function during caloric deficit. We hypothesized that administration of low-dose leptin would prevent changes in neuroendocrine function resulting from short-term caloric restriction. We administered physiologic doses of r-metHuLeptin [(0.05 mg/kg sc daily or identical placebo in divided doses (0800, 1400, 2000, and 0200 h)] to 17 healthy, normal-weight, reproductive-aged women during a 4-d fast. Leptin levels were lower in the placebo-treated group during fasting (3.3 +/- 0.2 vs. 9.6 +/- 1.0 ng/ml, P < 0.001, placebo vs. leptin-treated at end of study). Fat mass decreased more in the leptin than the placebo-treated group (-0.6 +/- 0.1 vs. -0.2 +/- 0.1 kg, P = 0.03). Both overnight LH area (38.9 +/- 21.5 vs. 1.2 +/- 11.1 microIU/ml.min, P = 0.05) and LH peak width increased (15.8 +/- 7.1 vs. -2.3 +/- 6.7 min, P = 0.06) and LH pulsatility decreased (-2.0 +/- 0.9 vs. 1.0 +/- 0.8 peaks/12 h, P = 0.03) more in the leptin vs. placebo group. LH pulse regularity was higher in the leptin-treated group (P = 0.02). Twenty-four-hour mean TSH decreased more in the placebo than the leptin-treated group, respectively (-1.06 +/- 0.27 vs. -0.32 +/- 0.18 microIU/ml, P = 0.03). No differences in 24-h mean GH, cortisol, IGF binding protein-1, and IGF-I were observed between the groups. Hunger was inversely related to leptin levels in the subjects randomized to leptin (r = -0.76, P = 0.03) but not placebo (r = -0.18, P = 0.70) at the end of the study. Diminished hunger was seen among subjects achieving the highest leptin levels. Our data provide new evidence of the important role of physiologic leptin regulation in the neuroendocrine response to acute caloric deprivation.

Adult↗

PubMed2003

Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice.

Infant macrosomia is a classic feature of a gestational diabetes mellitus (GDM) pregnancy and is associated with increased risk of adult obesity and type II diabetes mellitus, however mechanisms linking GDM and later disease remain poorly understood. The heterozygous leptin receptor-deficient (Lepr(db/+)) mouse develops spontaneous GDM and the fetuses display characteristics similar to infants of GDM mothers. We examined the effects of GDM on maternal insulin resistance, fetal growth, and postnatal development of hepatic insulin resistance. Fetal body weight on d 18 of gestation was 6.5% greater (p < 0.05) in pups from ad libitum-fed db/+ mothers compared with wild-type (WT) controls. Pair-feeding db/+ mothers to the intake of WT mothers normalized fetal weight despite less than normal maternal insulin sensitivity. More stringent caloric restriction reduced insulin and glucose levels below WT controls and resulted in fetal intrauterine growth restriction. The level of hepatic insulin receptor protein was decreased by 28% to 31% in both intrauterine growth restriction and fetuses from ad libitum-fed GDM mothers compared with offspring from WT mothers. In 24-wk-old adult offspring from GDM mothers, body weight was similar to WT offspring, however, the females from GDM mothers were fatter and hyperinsulinemic compared with offspring from WT mothers. Insulin-stimulated phosphorylation of Akt, a key intermediate in insulin signaling, was severely decreased in the livers of adult GDM offspring. Hepatic glucose-6-phosphatase activity was also inappropriately increased in the adult offspring from GDM mothers. These results suggest that spontaneous GDM in the pregnant Lepr(db/+) mouse is triggered by overfeeding, and this effect results in obesity and insulin resistance in the livers of the adult offspring. The specific decrease in Akt phosphorylation in livers of adult offspring suggests that this may be a mechanism for reduced insulin-dependent physiologic events, such as suppression of hepatic glucose production, a defect associated with susceptibility to type II diabetes mellitus.

Adipose Tissue↗

PubMed2005

Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.

Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1--which modulates ageing in several species--controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1alpha. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

Acetylation↗

PubMed2006

High-cholesterol feeding aggravates cerebral infarction via decreasing the CB1 receptor.

We examined how feeding conditions affect the CB1 receptor and cerebral infarction caused by cerebral ischemia. Mice were divided into the following three groups: normal diet (ND), caloric restriction (CR) and high-cholesterol-enriched diet (HCD), and were kept for 6 weeks. After 6 weeks, we measured both serum and brain cholesterol and the expression level of cannabinoid CB1 receptor within the brain in intact mice. In addition, middle cerebral artery (MCA) was occluded for 2 h following reperfusion. Serum cholesterol significantly increased in the HCD group in comparison with both the ND and CR groups. However, brain cholesterol decreased in the HCD group. Then, the expression level of CB1 receptor significantly decreased in the HCD group, while that of the CR group clearly increased in comparison with the ND group in intact mice. In MCA-occluded mice, The HCD group produced the most severe cerebral infarction, while cerebral infarction was significantly decreased in the CR group. These results suggest that CR prevents infarction by increasing CB1 receptor expression, while high-cholesterol feeding aggravates cerebral infarction both by hypercholesterolemia in serum and by decreasing CB1 receptor expression modulated by hypocholesterolemia within the brain.

Animals↗