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Results for “Caloric Restriction”

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PubMed1993

Evidence that DNA repair may not be modified by age or chronic caloric restriction.

Pretreatment of animals with mixed-function oxidase inducers has been shown to increase the metabolic activation capacity of isolated hepatocytes resulting in an apparent increase in DNA repair. We recently reported decreases in chemically-induced DNA repair, measured as unscheduled DNA synthesis (UDS), in hepatocyte cultures isolated from aging ad libitum (AL) and caloric restricted (CR) diet-fed animals. In the present study, we evaluated the effects of pretreatment with Aroclor 1254 (ARO) on the genotoxicity of 4 carcinogens, from different chemical classes, in primary hepatocytes isolated from male Fischer 344 rats. ARO-induced old AL- and CR-derived cultures, treated with 2-acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA), and dimethylnitrosamine (DMN), exhibited significant induction-related increases in DNA repair in comparison to uninduced old AL and CR animals. These data indicate that the constitutive levels of specific cytochrome P450 decline with age and chronic caloric restriction, while the ability to respond to exogenous inducers is retained, and suggest that DNA repair may not be modified with age or diet restriction.

2-Acetylaminofluorene↗

PubMed1992

Enhanced unscheduled DNA synthesis by secondary cultures of lung cells established from calorically restricted aged rats.

Unscheduled DNA synthesis (UDS) induced by two exposure levels of ultraviolet light (UV) or two concentrations of methyl methane sulfonate (MMS) was evaluated in secondary cultures of lung fibroblasts established from weanling, 11-month-old and 31-month-old female Fischer 344 rats fed ad libitum (AL) or calorically restricted (CR) diets. [3H]Thymidine incorporation as a function of UDS was highest for weanling-derived cells treated with either UV or MMS, declining consistently with increased age between cells from weanling, 11-month-old and 31-month-old animals. [3H]Thymidine incorporation as a function of UDS in cells from 11-month-old AL vs. CR rats differed only at the highest UV exposure level. In contrast, cells derived from 31-month-old CR rats exhibited UDS levels which were at least twice as high at each UV treatment level as UDS levels of cells derived from the same age AL rats. Cells from both old AL and old CR rats were shown to initiate DNA excision repair at about the same rate. Cells from CR rats, however, repaired DNA damage at an accelerated rate and completed excision repair while repair in cells from AL animals was slower and apparently did not proceed to completion. Data from this study indicate that cells from young and old AL and CR animals initiate excision repair, but demonstrate an age-related loss of UV- or MMS-stimulated [3H]thymidine incorporation in cells derived from AL animals. Cells derived from CR animals did not exhibit that age-related loss of UDS activity; rather, they showed an enhanced UDS response to DNA damage and appeared to complete ligation as the final step in excision repair. The data suggest that caloric restriction of a cell donor animal not only delays the age-associated decrease in in vitro DNA excision repair capacity in cells from that animal, but may actually enhance repair capacity.

Aging↗

PubMed2002

Effect of moderate caloric restriction and/or weight cycling on mammary tumor incidence and latency in MMTV-Neu female mice.

Recently, we reported that intermittent caloric restriction-refeeding reduces mammary tumor (MT) incidence and extends latency in murine mammary tumor virus (MMTV)-transforming growth factor (TGF)-a mice to a greater extent than does chronic caloric restriction. Here, this same weight-cycling protocol was applied to MMTV-Neu female mice, which develop MTs at a much younger age than do TGF-a mice. This study consisted of three experimental groups: mice fed an AIN-93M diet ad libitum, mice intermittently fed an AIN-93 modified diet (2-fold increase in protein, fat, vitamins, and minerals) at 50% of the amount fed to the ad libitum-fed mice for 3-wk intervals and then fed an AIN-93M diet ad libitum for 3-wk intervals, and mice chronically restricted, pair fed to the intermittently restricted mice by feeding 2:1 mixtures of AIN-93M-AIN-93 modified diets for each 6-wk feeding interval. Mice were euthanized when MTs reached a length of 20 mm or at 80 wk of age. Cumulative caloric intake was 10% lower (not significant) for intermittently restricted mice and 16% lower (P < 0.05) for chronically restricted mice than for ad libitum-fed mice. Final body weights were significantly different as follows: ad libitum-fed > intermittently restricted > chronically restricted. Fat pad weights were greater in ad libitum-fed than in intermittently restricted and chronically restricted mice. MT incidence of ad libitum-fed mice was 37% compared with 22% for intermittently restricted mice and 33% for chronically restricted mice (not significant). There were no differences in MT weight or number among the groups. These results indicate that intermittent caloric restriction-refeeding provides a moderate protective effect, whereas chronic caloric restriction provides no significant protection against MT development in transgenic Neu mice.

Adenocarcinoma↗

PubMed1998

Response of lens epithelial cells to hydrogen peroxide stress and the protective effect of caloric restriction.

Hydrogen peroxide (H2O2) has been reported to be present at significant levels in the lens and aqueous humor in some cataract patients and suggested as a possible source of chronically inflicted damage to lens epithelial (LE) cells. We measured H2O2 effects on bovine and mouse LE cells and determined whether LE cells from old calorically restricted mice were more resistant to H2O2-induced cellular damage than those of same age ad libitum fed (AL) mice. Bovine lens epithelial cells were exposed to H2O2 at 40 or 400 microM for 2 h and then allowed to recover from the stress. The cells were assayed for DNA damage, DNA synthesis, cell viability, cell morphology, response to growth stimuli, and proliferation potential. Hydrogen peroxide-treated cells showed an increased DNA unwinding 50% greater than that for untreated controls. These DNA strand breaks appeared to be almost completely rejoined by 30 min following removal of the cells from a 2-h exposure. The 40 microM exposure did not produce a significantly lower DNA synthesis rate than the control, it responded to growth factor stimuli, and it replicated as did the control cells after removal of H2O2. The 400 microM H2O2 severely affected DNA synthesis and replication, as shown by increased cell size and by markedly reduced clonal cell growth. The cells did not respond to growth stimulation by serum or growth factors and lost irreversibly the capacity to proliferate. The responses of LE cells from old adlib diet (AL) and calorically restricted (CR) mice to H2O2 were significantly different. Exposure of LE cells to 20, 40, or 100 microM H2O2 for 1 h induces a significant loss of cellular proliferation in cells from old AL mice. LE cells from long-term CR mice of the same strain and age were more resistant to oxidative damage at all three concentrations of H2O2 than those of both old and young AL mice and showed a significantly higher proliferation potential following treatment. It is concluded that CR results in superior resistance to reactive oxygen radicals in the lens epithelium.

Age Factors↗

PubMed1992

Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo.

To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34-week, double-blind clinical trial of 60 mg extended-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% +/- 1.2%, mean +/- SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 +/- 0.9 kg, or 15.9% +/- 0.9% of initial weight (n = 58), versus a loss of 4.6 +/- 0.8 kg or 4.9% +/- 0.9% of initial weight by subjects taking placebo (n = 54; p less than 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 +/- 0.5 versus 20.3 +/- 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 +/- 0.3 versus 13.5 +/- 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.

Adult↗

PubMed2000

Caloric restriction and immunosenescence: a current perspective.

The age-related decrease in immunologic function is believed to be the major predisposing factor contributing to increased morbidity and mortality with age. Hence, the restoration of immunologic function is expected to have a beneficial effect in reducing pathology and maintaining a healthy condition in advanced age. Among various intervention strategies, caloric restriction (CR) has been shown to be the most powerful modulator of aging process. It is the most efficacious means of increasing longevity and reducing pathology. Several mechanisms have been proposed to explain its beneficial and robust action on various physiological systems, including the immune system. Experimental evidence suggests that CR increases longevity and reduces pathology through its action on the immune system. The observation that CR attenuates immunosenescence has provided a rationale for studying whether CR exerts its action through modulation of gene expression. The available data indicate that the effect of CR on signal transduction and gene expression can vary considerably from gene to gene and from one signaling molecule to another. This review summarizes the studies on the influence of CR on aging immune system and discusses the current state of knowledge on the molecular mechanisms responsible for the immunomodulatory action of caloric restriction.

Aging↗

PubMed1997

The accumulation of non-replicative, non-functional, senescent T cells with age is avoided in calorically restricted mice by an enhancement of T cell apoptosis.

Peripheral blood lymphocytes of elderly humans show an increased percentage of T cells with characteristics of replicative senescence. Similarly, the overall decrease in T cell proliferation in aged mice reflects a progressively increasing proportion of non-functional cells rather than a uniform decline in function by all cells. The improved immune function of calorically restricted (CR) animals is, paradoxically, accompanied by a relative lymphopenia. To test whether the reduction in lymphocyte number in the CR mice might reflect more efficient elimination of T cells, we measured apoptosis in young, old and CR old mice. T cell apoptosis induced by irradiation, Staurosporine, anti-CD3, and heat shock was reduced by 62, 42, 32, and 30%, respectively, in old compared with young mice. Caloric restriction normalized apoptosis in T cells from aged mice. Enhanced elimination of non-functional T cells in CR mice may be, at least in part, responsible for their improved immune functional status relative to non-CR mice of the same age.

Aging↗

PubMedDate not supplied

Autonomic nervous activity in obese subjects before and after caloric restriction.

The heart rate response to deep breathing (DB test) and standing (30:15 r test) and the blood pressure response to standing (LS test) and sustained handgrip (HG test) were assessed in 19 obese subjects and 15 age matched lean controls. The results of DB, 30:15 r and LS tests were not significantly different in both groups. The diastolic blood pressure increase during handgrip was significantly higher in obese than in control subjects. After a period of caloric restriction the tests were repeated in 9 patients who had obtained a weight loss of at least 5 kg: a significant decrease in heart rate, diastolic blood pressure and 30:15 r results was observed, whereas the caloric restriction did not cause significant variations in the results of DB, LS and HG tests. Our results suggest that in obese patients some autonomic nervous changes can occur before and after weight loss.

Adult↗

PubMed2005

Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse.

Caloric restriction (CR) prolongs lifespan in insects, rodents, and nonhuman primates, a process attributed to a reduction in oxidative stress. Transgenic mice that overexpress the mutant human Cu/Zn-superoxide dismutase (SOD1) gene (G93A mice) are an animal model of amyotrophic lateral sclerosis showing progressively lower motor neuron weakness and increased oxidative stress. We investigated the effect of CR on motor performance, clinical onset, disease progression, and lifespan in G93A mice. Starting at 40 days of age, 14 separately caged G93A mice were randomly divided into two groups: ad libitum (AL; n = 6) and calorie-restricted (CR; n = 8) with a diet equal to 60% of AL. The CR mice (mean +/- SEM: 14.0 +/- 0.7 g) weighed 31% less than the AL mice (20.3 +/- 1.0 g) (P = 0.0002). From 74 to 93 days of age, the CR mice performed better on the rotarod than the AL mice: fall time, P = 0.039; fall speed, P = 0.009. The CR mice had a faster rate of reaching clinical onset than the AL mice (hazard ratio = 4.3, P = 0.0006). The CR and AL mice reached clinical onset of disease at age 99 +/- 1 and 110 +/- 2 days, respectively (P = 0.0003), with no significant difference in disease progression. The CR mice tended to reach endpoint sooner than the AL mice (age-specific death: 125 +/- 3 vs. 133 +/- 3 days, respectively, P = 0.09). We conclude that CR diet transiently improves motor performance but hastens clinical onset of disease in G93A mice. These results suggest that CR diet is not a protective strategy for patients with amyotrophic lateral sclerosis (ALS) and hence is contraindicated.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Central thyrotropin-releasing hormone infusion opposes cardiovascular and metabolic suppression during caloric restriction.

Inhibition of hypothalamic thyrotropin-releasing hormone (TRH) neuronal activity is a well-established adaptation to caloric restriction (CR) that suppresses pituitary secretion of thyroid-stimulating hormone, but may also participate in modulation of autonomic function. Thus, we hypothesized that decreased hypothalamic TRH activity contributes to CR-induced bradycardia and decreased metabolic rate. To test this hypothesis, male Sprague-Dawley rats were instrumented with telemetry devices for measurement of heart rate (HR) and blood pressure (BP) and a lateral intracerebroventricular (i.c.v.) guide cannula for central infusions. After recovery, rats were housed in metabolic chambers and given either ad libitum(ad-lib) or CR treatments for 7 days; half of each diet group was then given continuous i.c.v. infusions of TRH (25 nmol/h) or saline (0.25 microl/h) for 7 days via osmotic pump. This dose of TRH did not significantly alter peripheral free T(4) levels. In ad-lib rats, TRH infusion produced small reductions in food intake and small increases in HR and BP over saline-infused controls. In CR rats, TRH infusion resulted in an increase in HR and also energy expenditure over saline-infused controls. These results support the hypothesis that suppression of central TRH activity contributes to the homeostatic suppression of energy expenditure and HR observed during CR.

Analysis of Variance↗

PubMed1999

Effect of age and caloric restriction on bleomycin-chelatable and nonheme iron in different tissues of C57BL/6 mice.

The objective of this study was to test the hypothesis that the widely observed age-associated increase in the amounts of macromolecular oxidative damage is due to an elevation in the availability of redox-active iron, that is believed to catalyze the scission of H2O2 to generate the highly reactive hydroxyl radical. Concentrations of bleomycin-chelatable iron and nonheme iron were measured in various tissues and different regions of the brain of mice fed on ad libitum (AL) or a calorically restricted (to 60% of AL) diet at different ages. The concentrations of these two pools of iron varied markedly as a function of tissue, age, and caloric intake. There was no consistent ratio between the amounts of nonheme and the bleomycin-chelatable iron pools across these conditions. Nonheme iron concentration increased with age in the liver, kidney, heart, striatum, hippocampus, midbrain and cerebellum of AL animals, whereas bleomycin-chelatable iron increased significantly with age only in the liver. Amounts of both nonheme and bleomycin-chelatable iron remained unaltered during aging in the cerebral cortex and hindbrain of AL mice. Caloric restriction had no effect on iron concentration in the brain or heart, but caused a marked increase in the concentration of both bleomycin-chelatable and nonheme iron in the liver and the kidney. The results do not support the hypothesis that accumulation of oxidative damage with age, or its attenuation by CR, are associated with corresponding variations in redox-active iron.

Aging↗

PubMed1995

Genetics of age-related hearing loss in mice. II. Strain differences and effects of caloric restriction on cochlear pathology and evoked response thresholds.

The effects of genotype and diet on age-related hearing loss were evaluated using auditory brainstem response (ABR) thresholds and post-mortem cochlear histopathology in 5 inbred mouse strains, CBA/H-T6J (CH), DBA/2J (D2), C57BL/6J (B6), BALB/cByJ (BY) and WB/ReJ (WB), and their 10 F1 hybrid strains. The mice had been maintained since weaning on either a high-energy (HE) control diet or low-energy (LE) calorically restricted diet. ABR thresholds were obtained when the mice were 23 months old; the mice were allowed to age until they died from natural causes prior to obtaining the histological material. The severity of post-mortem cochlear pathology in mice maintained with the HE diet supports our earlier genetic model which postulated that B6, BY, and WB strains each possessed a different recessive allele causing age-related hearing loss, D2 mice possessed all 3 genes, and CH mice possessed none. The histopathology indicates that the genes act at the cochlear level. Dietary restriction resulted in increased longevity in a number of strains, but age-related changes in cochlear pathology were not ameliorated in any of these; indeed, in some strains long-lived LE mice exhibited severe cochlear degeneration. In strains for which longevity was not extended by caloric restriction, only B6 mice exhibited an ameliorative effect of the LE diet on cochlear pathology. ABRs in 23-month-olds indicated a slowing of age-related hearing loss in LE mice of 3 F1 hybrid strains.

Analysis of Variance↗

PubMed1998

Caloric restriction prevents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria.

The purpose of this study was to understand the nature of the causes underlying the senescence-related decline in skeletal muscle mass and performance. Protein and lipid oxidative damage to upper hindlimb skeletal muscle mitochondria was compared between mice fed ad libitum and those restricted to 40% fewer calories--a regimen that increases life span by approximately 30-40% and attenuates the senescence-associated decrement in skeletal muscle mass and function. Oxidative damage to mitochondrial proteins, measured as amounts of protein carbonyls and loss of protein sulfhydryl content, and to mitochondrial lipids, determined as concentration of thiobarbituric acid reactive substances, significantly increased with age in the ad libitum-fed (AL) C57BL/6 mice. The rate of superoxide anion radical generation by submitochondrial particles increased whereas the activities of antioxidative enzymes superoxide dismutase, catalase, and glutathione peroxidase in muscle homogenates remained unaltered with age in the AL group. In calorically-restricted (CR) mice there was no age-associated increase in mitochondrial protein or lipid oxidative damage, or in superoxide anion radical generation. Crossover studies, involving the transfer of 18- to 22-month-old mice fed on the AL regimen to the CR regimen, and vice versa, indicated that the mitochondrial oxidative damage could not be reversed by CR or induced by AL feeding within a time frame of 6 weeks. Results of this study indicate that mitochondria in skeletal muscles accumulate significant amounts of oxidative damage during aging. Although such damage is largely irreversible, it can be prevented by restriction of caloric intake.

Age Factors↗

PubMedDate not supplied

Modulation of aberrant crypt foci by dietary fat and caloric restriction: the effects of delayed intervention.

Recent investigations have established that caloric restriction (CR) reduces end tumor incidence in the rat colon. The present study was conducted to determine whether CR at the level of 20% of the ad libitum (AL) intake and dietary fat would alter the growth of intermediate preneoplastic colonic aberrant crypt foci (ACF). F344 rats were given injections of 15mg/kg azoxymethane, fed AL for 11 weeks, and then allocated to 1 of 4 dietary groups (n-20/group): high fat (23% w/w) or low fat (5% w/w) AL (HFAL, LFAL), or high fat or low fat CR (HFCR, LFCR). After 4 weeks only the HFAL and HFCR groups had identifiable adenomas with incidences of 50 and 30%, respectively. There was a significant positive correlation between total fat consumed/day (grams) and the number of ACF with 4-6 crypts focus. After 12 weeks of feeding, the total number of ACF was lower (P < or = 0.05) in the CR groups relative to the AL groups in both the high and low fat diets. The number of ACF with 4-6 crypts/focus and > 6 crypts/focus were lower in the LFCR group compared to the LFAL group, whereas the number of ACF with 1-3 crypts/focus was lower in the HFCR group compared to the HFAL group. CR was the main variable affecting the number and growth of ACF at week 12. Positive correlations were demonstrated between increased mean daily intake of energy and the number of total ACF/colon, ACF with 4-6 crypts/focus, and ACF with > 7 crypts/focus at week 12. Cell proliferation indices did not correlate with ACF or tumor incidence data. These findings demonstrated that (a) dietary fat affects tissue growth characteristics more rapidly than CR, (b) CR alters the development of ACF depending on the level of fat and experimental duration, and (c) ACF with varying growth features respond differently to CR and dietary fat. These findings also suggest that subtle dietary manipulations in fat and caloric content used at the later stages of colon carcinogenesis can modulate tumor development.

Adenocarcinoma↗

PubMed2004

Behavioral and physiologic responses to caloric restriction in mice.

The purpose of the review is to highlight the influences of ambient temperature (T(a)) and caloric restriction (CR) on metabolism, cardiovascular function and behavior in mice. Standard vivarium ambient temperatures (T(a)?23 degrees C) are a mild cold stress for mice requiring elevated metabolic rate and food intake. Increasing T(a) into the zone of thermoneutrality (TMN?29-33 degrees C) markedly reduces food intake, metabolic rate, heart rate (HR) and blood pressure in mice. Mice are members of a diverse, yet unique group of homeothermic animals that respond to thermal and energetic challenges by allowing body temperature (T(b)) to fall to less than 31 degrees C, a condition known as torpor. In mice housed at standard T(a), torpor is induced by a single night of fasting or a few days of CR. The mechanisms responsible for initiating torpor are related to reduced caloric availability, but do not require leptin. Mice housed at TMN and subjected to CR exhibit physiologic reductions in metabolic rate and HR, but do not appear to enter torpor. Finally, mice exhibit differential locomotor activity responses during CR that depends on T(a). At standard T(a), mice display increased light-phase home-cage activity with CR. This response is virtually eliminated when CR is performed at TMN. We suggest that researchers using mice to investigate energy homeostasis and cardiovascular physiology carefully consider the influence of T(a) on physiology and behavior.

Animals↗

PubMed1985

Moderate caloric restriction in obese women with gestational diabetes.

The effect of moderate caloric restriction on weight gain during pregnancy and fetal outcome in 22 obese women with gestational diabetes mellitus was assessed. A new tool was used to assess dietary compliance in an outpatient setting. The authors observed that obese gestational diabetics gained less weight during pregnancy than ten normal pregnant women or 31 lean women with gestational diabetes. Paradoxically, the placentas of obese gestational diabetics were larger (P not significant), and infants of these mothers were significantly heavier than those of normal women or lean women with gestational diabetes (P less than .03). The authors suggest that the currently recommended daily caloric allowances for normal women may be excessive for obese gestational diabetics who are not prone to ketosis but have a complex metabolic problem characterized by hyperinsulinemia and insulin resistance.

Birth Weight↗

PubMed1979

The influence of caloric restriction on serum prolactin.

Nine obese female patients were placed on a liquid formula diet containing 320 kcal (1.34 MJ), 31 g protein, 44 g carbohydrate, 1.5 g fat, vitamins and essential minerals for a period of four weeks under metabolic-ward conditions. The diet was tolerated well in all patients and mean weight loss was 2.49 kg per week during the four-week period. Basal serum prolactin levels were normal (2.9 +/- 0.6 ng/ml) and did not show any change during this period. In six patients a TRH test was performed before and during caloric restriction. The maximal increment of PRL after TRH was significantly lowered during dietary treatment: 53.2 +/- 16.2 vs. 32.3 +/- 11.6 ng/ml; mean +/- s.e.m.; P less than 0.025). No change was observed in the serum TSH responset to TRH before and during caloric restriction. Dietary restriction suppresses prolactin synthesis and secretion as measured in response to TRH in obese female patients.

Adolescent↗

PubMed1999

Life-long caloric restriction suppresses age-associated Fas expression in the Fischer 344 rat kidney.

It has been shown that the expression of Fas is substantially increased in the aging process in various organs, but its role in the aging kidney is not yet clear. In this study, the expression of Fas in the kidneys of 6- and 24-month-old male Fischer 344 rats fed ad libitum was studied by using quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. In addition, possible effects of life-long caloric restriction (30% as those of ad libitum fed group) in the expression of Fas were also studied in 6- and 24-month-old rat kidneys. Kidneys obtained from 24-month-old ad libitum fed rats showed glomerulosclerosis with marked tubulointerstitial damage including interstitial fibrosis, while in the kidneys of 24-month-old calorie-restricted rats, renal damage was remarkedly less than that noted in 24-month-old ad libitum fed rats kidneys. RT-PCR and immunohistochemical analysis showed an increased expression of Fas in both mRNA and protein level in 24-month-old rat kidneys; life-long caloric restriction significantly reduces renal expression of Fas. Our results suggest that increased expression of Fas is associated with age-related renal damage and that life-long diet-restricted alteration of its expression is associated with the modulation of age-associated renal structural damage.

Aging↗