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Results for “Caloric Restriction”

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PubMed2005

Serine utilization in mouse liver: influence of caloric restriction and aging.

The influence of caloric restriction (CR) on the activities of hepatic serine metabolizing enzymes in young (3 months) and old (30 months) mice was studied. Serine dehydratase (SDH) activity increased markedly with age in both diet groups and in old mice was higher in the CR group. No effects of CR were observed in the young. Serine:pyruvate transaminase (SPT) and glycerate kinase activities were unaffected by age and diet. However, glycerate dehydrogenase activity was decreased in old CR mice but not in young CR. The results of this study show that long-term CR influenced serine utilization only in the pathway catalyzed by SDH. This suggests that in mouse liver this pathway is critical for serine utilization in gluconeogenesis, while the SPT pathway plays a minor role. The increase in SDH activity with long-term CR is consistent with sustained increase in gluconeogenesis.

Aging↗

PubMed2004

Role of sirtuin proteins in life extension by caloric restriction.

The deacetylase activity of sirtuin proteins may play a key role in the life extending action of caloric restriction in organisms ranging from yeast to mammals. Recent research has been focused on the possible afferent pathway by which caloric restriction increases the deacetylase activity and on the efferent pathway by which the increased deacetylase activity extends life. Further research is needed to firmly establish the role of sirtuin proteins in life extension by caloric restriction in mammals.

Animals↗

PubMed2004

Circulating adiponectin levels increase in rats on caloric restriction: the potential for insulin sensitization.

Caloric restriction (CR) has a well-known insulin sensitizing effect in vivo. Although this effect has been confirmed in rodents and primates for many years, its precise molecular mechanisms remain unknown. Here we show a significant increase in plasma adiponectin and a decrease in blood glucose, plasma triglyceride and insulin levels in rats maintained on CR diet for 2, 10, 15, and 20 months. Long-term CR rats exhibited significantly higher insulin-stimulated insulin receptor tyrosine phosphorylation and lower PTP-1B activity both in liver and skeletal muscle than those observed in rats fed ad libitum (AL). In addition, the triglyceride levels in these tissues were significantly lower in long-term CR animals. Interestingly, concentrations of plasma adiponectin in long-term CR rats were associated with increased expression of the transcription factor mRNAs for the peroxisome proliferator-activated receptor (PPAR)alpha, gamma and delta, but decreased expression for SREBP-1c, resulting in a concerted modulation in the expression of key transcription target genes involved in fatty acid oxidation and energy combustion in liver. Taken together, our findings suggest an important role for adiponectin in the beneficial effects of long-term CR.

Adiponectin↗

PubMed2006

The age-related paraoxonase 1 response is altered by long-term caloric restriction in male and female rats.

Caloric restriction (CR) has been shown to attenuate age-related oxidative damage and to improve major atherosclerotic risk factors. Paraoxonase 1 (PON1), an enzyme specifically associated with HDL containing apolipoproteins A-I and J, has been reported to prevent the proatherosclerotic effects of oxidized LDL. The aim of this study was to evaluate whether modulation of PON1 activity is part of the underlying CR mechanisms that attenuate the age-associated negative effects. Experimental groups were 1 year old rats of both genders subjected to 40% CR for 1 year and two ad libitum-fed groups, also including rats of both genders, euthanized at 6 months or 2 years. Aging impaired the serum lipid profile and increased lipid peroxidation, PON1 activities, and the content of both PON1 and apolipoprotein J in HDL, which suggests an HDL subfraction redistribution to protect LDL more effectively from oxidation. The CR-associated improved lipid profile and the decreased lipid peroxide levels would lead to the decreased arylesterase activity seen in old CR animals, suggesting that PON1 modulation is not an integral part of the main antioxidant mechanisms of CR but rather that CR would determine a more youthful and less oxidative situation in which the protection of LDL would be less necessary.

Aging↗

PubMed2005

Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.

It is widely held that caloric restriction (CR) extends lifespan by preventing or reducing the age-related accumulation of irreversible molecular damage. In contrast, our results suggest that CR can act rapidly to begin life and health span extension, and that its rapid genomic effects are closely linked to its health effects. We found that CR begins to extend lifespan and reduce cancer as a cause of death within 8 weeks in older mice, apparently by reducing the rate of tumor growth. Further, 8 weeks of CR progressively reproduces nearly three quarters of the genomic effects of long-term CR (LTCR) in liver. Fewer of the genomic effects of LTCR are rapidly reproduced by the initiation of CR in the heart, but the changes produced are keys to cardiovascular health. Thus, the genomic effects of CR may be established more rapidly in mitotic than in postmitotic tissues. Most of the genomic effects of LTCR dissipate 8 weeks after switching to a control diet. Consistent with these results, others have shown that acute CR rapidly and reversibly reduces the short-term risk of death in Drosophila to that of LTCR treated flies. Further, in late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins. CR also rapidly and reversibly mitigates biomarkers of aging in adult rhesus macaques and humans. These data argue that highly conserved mechanisms for the rapid and reversible enhancement of life- and health-span exist for mitotic and postmitotic tissues.

Aging↗

PubMed2005

Lack of effect of caloric restriction on bioenergetics and reactive oxygen species production in intact rat hepatocytes.

To investigate the hypothesis that caloric restriction alters mitochondrial function in situ, intact hepatocytes were isolated from fully fed and calorie-restricted (55% of control food intake, 4 months duration) male Brown-Norway rats at 6 months of age, and various parameters were determined. Overall, the production of reactive oxygen species was not affected by caloric restriction, neither were the mitochondrial membrane potential, oxygen consumption driving proton leak, or oxygen consumption driving ATP turnover. It is concluded that while isolated mitochondria from liver tissue of calorie-restricted animals display a reduction in the generation of reactive oxygen species, it was not possible to confirm this effect in isolated hepatocytes. Further work is required to establish what effect, if any, caloric restriction has on the rate of generation of reactive oxygen species in intact cells and tissues and importantly at the whole-animal level.

Adenosine Triphosphate↗

PubMed2004

Breast cancer risk after caloric restriction during the 1944-1945 Dutch famine.

BACKGROUND: Data from animal models suggest that caloric restriction may reduce the risk of breast cancer, although not all dietary regimens produce similar effects. We examined whether caloric restriction imposed as a consequence of the 1944-1945 Dutch famine reduced the risk of breast cancer in women participating in a Dutch breast cancer screening program. METHODS: Between 1983 and 1986, approximately 15 000 women, aged 2 to 33 years during the 1944-1945 Dutch famine, responded to a questionnaire about their famine experience. A famine exposure score, graded as absent, moderate, or severe exposure, was derived from answers regarding hunger, cold, and weight loss. During follow-up until January 2000, 585 women with incident breast cancer were identified by the regional cancer registry. The relationship between famine exposure and breast cancer risk was assessed by weighted Cox regression models, in which person-years lived for the entire cohort was extrapolated from data from a random sample of 15% of the cohort. RESULTS: Women who were severely exposed to the famine had a statistically significantly higher risk of breast cancer (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.09 to 2.01) than women who were not exposed. Women who were moderately exposed to the famine had a 13% increased risk of breast cancer (HR = 1.13, 95% CI = 0.92 to 1.38; P(trend) = 0.016). The association between famine exposure and breast cancer risk was stronger for women who were exposed between the ages of 2 and 9 years (severely exposed versus unexposed: HR = 2.01, 95% CI = 0.92 to 4.41) than for women who were exposed at older ages. CONCLUSIONS: The risk of breast cancer was increased in women who were severely exposed to a short but severe famine decades earlier. This result is compatible with data from the few animal studies investigating effects of short-term, transient caloric restriction.

Adolescent↗

PubMed1994

Combined chronic low dose radiation-caloric restriction: a model for regression of spontaneous mammary tumor.

PURPOSE: This study was carried out to determine whether chronic low dose radiation can act alone or in synergy with restricted diet in down-regulating spontaneously occurring mammary tumor in tumor-susceptible female C3H/He mice and whether immune cells are involved. METHODS AND MATERIALS: At 7 months of age, one-half of the experimental mice were maintained on an ad lib diet, and the other half was adapted over a period of 1 month to a diet of 70% of the daily amount of food consumed by the ad lib-fed mice. The food of the restricted diet was enriched such that the vitamin and mineral intake was the same for both groups. Half of the mice in each group was then subjected to chronic low dose radiation (0.04 Gy per exposure from a 60Co source, 3 x-per-week for 4 weeks) and the other half was sham irradiated. The 70% calorically restricted diet was maintained throughout the study. RESULTS: Chronic low dose radiation alone was ineffective in down-regulating spontaneous mammary tumor, unlike caloric restriction. However, chronic low dose radiation when combined with caloric restriction promoted regression of mammary tumors, which were infiltrated with massive numbers of CD8+ T cells. These phenomena were not seen in mice subjected to caloric restriction alone. CONCLUSION: Combined chronic low dose radiation-caloric restriction appears to be a useful model for promoting spontaneous mammary tumor regression.

Animals↗

PubMed1995

Source of dietary carbohydrate affects life span of Fischer 344 rats independent of caloric restriction.

Previous investigations suggest that increased life span of calorie-restricted rodents is a function of caloric intake rather than the macro- or micronutrient composition of the diet. However, the dietary source of carbohydrate has not been widely investigated. We hypothesized that the dietary carbohydrate source may affect the life span of rats independent of caloric restriction. This hypothesis was tested in male Fischer 344 rats fed ad libitum or restricted to 60% of ad libitum, an isocaloric diet containing 14% protein, 10% fat, and 66% sucrose or cornstarch. Body weights of the ad libitum- and restricted-fed sucrose rats were consistently greater throughout the experimental period compared to diet-matched animals. Food intake did not differ significantly. The survival curves of ad libitum starch- vs sucrose-fed rats were significantly different. That is, the mean, median and upper 10th percentile survival were significantly greater in the ad libitum starch- vs sucrose-fed rats (mean life span: cornstarch-fed, 720 +/- 23 days; sucrose-fed, 659 +/- 19 days). Calorie-restricted starch-fed rats had poorer early life survival, and no significant increase in mean life span compared to ad libitum cornstarch-fed animals (726 vs 720 days). These animals did, however, have the greatest upper 10th percentile survival of all four experimental groups. Mean life span of calorie-restricted sucrose-fed rats was significantly greater than that of all other groups (890 +/- 18 days). The differences in survival rates between sucrose- and cornstarch-fed animals could not be attributed to the effects of carbohydrate source on body weight, energy absorption, or on the timing and severity of the pathological lesions normally associated with aging and/or caloric restriction in this species. These data support the hypothesis that the dietary source of carbohydrate, i.e., sucrose vs cornstarch, can significantly affect life span independently of caloric intake.

Animals↗

PubMed1994

Mechanisms of caloric restriction affecting aging and disease.

Caloric restriction (CR) appears to affect aging by the inhibition of the specific chronic diseases which occur at increasing frequency with age. A common disease in F-344 rats, granulocytic leukemia, appears to have a window where it is sensitive to the effects of CR. Other diseases, such as pituitary adenomas, appear to have a different relationship to growth in the animal. Additionally, a model for the major disease for a number of long-lived strains of mice, lymphoma, which CR effects by inhibiting the expression of the causative agent, is being developed. Evaluation of the effects of CR on neoplasia, degenerative disease and physiological parameters suggests that the major factors in expression of these diseases is the alteration of growth factors, hormonal status, etc., and that these alterations also affect strain-specific pathologies depending on when they are changed in the life span. Effecting different diseases at different times in the life span, long-term CR, by limiting exposure to endogenous growth factors, altering physiological characteristics, and limiting exposure to food toxicants, inhibits the onset of disease, and its sequela, aging.

Aging↗

PubMed1991

Influence of age and caloric restriction on expression of hepatic genes for xenobiotic and oxygen metabolizing enzymes in the mouse.

The influence of age and life-span-prolonging caloric restriction on the expression of hepatic genes for xenobiotic and activated oxygen metabolism was investigated in female C3B10RF1 mice, a long-lived hybrid strain. Animals were fed either ad libitum, or diets reduced 20% or 52% in total calories but approximately unchanged in total protein, vitamins, and minerals. Cytochrome P1- and P3-450 (cyp1A1 and cyp1A2, respectively) mRNA levels decreased approximately 40% between age 4-5 months (young) and 30-31 months (old) in ad libitum fed animals (p less than or equal to .05). Caloric restriction eliminated this decrease. Manganese-superoxide dismutase mRNA decreased significantly in old ad libitum fed mice, and caloric restriction eliminated this decrease. No change in manganese-superoxide dismutase activity was detected, probably due to its low level and the large variability inherent in the assay. Catalase mRNA increased with age, but was not affected by diet. Catalase activity increased significantly with caloric restriction in young and old mice, in the absence of an increase in catalase mRNA, suggesting translational or posttranslational effects. CuZn-superoxide dismutase, glutathione peroxidase and epoxide hydrolase mRNA, and the ratio of ribosomal to total mRNA did not change with age or diet.

Aging↗

PubMed2002

Immunomodulation of experimental colitis via caloric restriction: role of Nk1.1+ T cells.

Inflammatory bowel diseases are immune-mediated disorders. Dietary restriction and NK1.1+ liver-associated lymphocytes (LAL) are considered to be involved in immunomodulation of autoimmune diseases. Our aim was to evaluate the effect of caloric restriction on experimental colitis and to determine NK1.1+ LAL function in immunoregulation. Experimental colitis was induced in C57 black mice by intracolonic instillation of trinitrobenzene sulfonic acid. Caloric restriction to 60% of the daily requirement was started 2 weeks prior to, or simultaneously with, colitis induction and continued throughout the study. Control mice were fed ad libitum. Colitis was assessed by standard clinical and macroscopic scores. To determine the mechanism involved in immunomodulation, liver lymphocytes were isolated and analyzed for NK1.1+ T-cell markers by FACS. T-cell function was evaluated by T-cell proliferation. Serum cytokines were measured by ELISA. Dietary restriction to 60% markedly ameliorated experimental colitis in both groups. These mice gained weight and showed improved macroscopic parameters of colitis. NK1.1+ LAL numbers increased fourfold and NKT cytotoxicity twofold in caloric-restricted mice. The antigen-specific T-cell proliferation index decreased (from 4.45 in controls to 1.15), and IFN-gamma and IL-12 serum levels decreased (from 290 to 200 pg and from 122 to 53 pg, respectively) in caloric-restricted mice. Our conclusion was that dietary restriction induced immunomodulation of experimental colitis and ameliorated the disease. This effect was mediated via an increase in NK1.1+ T lymphocytes, which may play a critical role in keeping the T-cell balance in immunoregulation.

Animals↗

PubMedDate not supplied

Caloric restriction reduces age at menopause: the effect of the 1944-1945 Dutch famine.

OBJECTIVE: To assess the effect of caloric restriction, as endured during the 1944-1945 Dutch famine, on the age at which natural menopause occurs and to identify specific vulnerable age periods in which caloric restriction has the largest effect. DESIGN: This was a population-based cohort study conducted in Utrecht, the Netherlands. Between 1983 and 1986, 9,471 women aged 40 to 73 years at the time of interview were classified regarding their exposure to the famine. Age at natural menopause was obtained from all available data, retrospectively as well as prospectively. We estimated differences in mean age at natural menopause between famine exposure categories (not, moderately, and severely exposed), with adjustment for smoking, parity, socioeconomic status, body mass index, age at menarche, and year of birth. RESULTS: Women experienced natural menopause on average 0.36 years earlier (95% CI: -0.60, -0.11) when severely exposed to the famine and 0.06 years earlier (95% CI: -0.22, 0.09) when moderately exposed compared with the unexposed women. This effect was particularly pronounced in those severely exposed from 2 to 6 years of age: -1.83 years (95% CI: -3.03, -0.63). CONCLUSIONS: Our findings suggest that caloric restriction decreases age at natural menopause. Early childhood seems to be a particularly sensitive age period for this effect.

Adult↗

PubMed2002

Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart.

Mitochondria are chronically exposed to reactive oxygen intermediates. As a result, various tissues, including skeletal muscle and heart, are characterized by an age-associated increase in reactive oxidant-induced mitochondrial DNA (mtDNA) damage. It has been postulated that these alterations may result in a decline in the content and rate of production of ATP, which may affect tissue function, contribute to the aging process, and lead to several disease states. We show that with age, ATP content and production decreased by approximately 50% in isolated rat mitochondria from the gastrocnemius muscle; however, no decline was observed in heart mitochondria. The decline observed in skeletal muscle may be a factor in the process of sarcopenia, which increases in incidence with advancing age. Lifelong caloric restriction, which prolongs maximum life span in animals, did not attenuate the age-related decline in ATP content or rate of production in skeletal muscle and had no effect on the heart. 8-Oxo-7,8-dihydro-2'-deoxyguanosine in skeletal muscle mtDNA was unaffected by aging but decreased 30% with caloric restriction, suggesting that the mechanisms that decrease oxidative stress in these tissues with caloric restriction are independent from ATP availability. The generation of reactive oxygen species, as indicated by H2O2 production in isolated mitochondria, did not change significantly with age in skeletal muscle or in the heart. Caloric restriction tended to reduce the levels of H2O2 production in the muscle but not in the heart. These data are the first to show that an age-associated decline in ATP content and rate of ATP production is tissue specific, in that it occurs in skeletal muscle but not heart, and that mitochondrial ATP production was unaltered by caloric restriction in both tissues.

Adenosine Triphosphate↗

PubMed2003

Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats.

BACKGROUND & AIMS: Ghrelin is an orexigenic hormone secreted by the stomach. Increased plasma ghrelin concentration was reported during diet-induced weight loss in obese humans, suggesting that ghrelin contributes to adaptive increment in appetite associated with caloric restriction. Leptin reduces spontaneous food intake and body weight in rodents. The current study tested the hypothesis that increased plasma leptin prevents the potential increase in plasma ghrelin concentration during moderate caloric restriction in lean rats. METHODS: Six-month-old male rats (body weight, 367 +/- 9 grams) were randomly assigned to one of the following treatments (8 rats each) for 1 week: (1) leptin subcutaneous infusion to induce moderate hyperleptinemia and moderate caloric restriction (-26% of ad libitum), (2) vehicle infusion and pair feeding, and (3) vehicle infusion and ad libitum feeding. RESULTS: Leptin-treated (-19 +/- 5 grams) and pair-fed (-19 +/- 2) rats lost weight compared with ad libitum-fed rats (-3 +/- 1, P < 0.05). Compared with control (6.8 +/- 0.7 ng/mL), plasma leptin was higher in leptin-treated (18.6 +/- 0.9 ng/mL, P < 0.01) rats and lower in pair-fed rats (4.3 +/- 0.4 ng/mL, P < 0.05). Plasma ghrelin was substantially higher in calorie-restricted than control rats (2505 +/- 132 pg/mL vs. 1790 +/- 134 pg/mL, P < 0.01), and leptin treatment (1625 +/- 117 pg/mL) completely prevented this change. Plasma ghrelin concentration was negatively correlated with body weight changes in calorie-restricted and control (r = -0.75, P < 0.01) but not in leptin-treated rats (P > 0.8). CONCLUSIONS: Moderate hyperleptinemia prevents an increase of plasma ghrelin during moderate short-term caloric restriction. Satiety-inducing effects of leptin include suppression of gastric orexigenic signals and disruption of a potential feedback mechanism between body weight changes and plasma ghrelin in lean adult rats.

Animals↗

PubMed2002

Oxidative, glycoxidative and lipoxidative damage to rat heart mitochondrial proteins is lower after 4 months of caloric restriction than in age-matched controls.

In this investigation the effect of 4 months of 40% restriction of calories on defined markers of oxidative, glycoxidative or lipoxidative damage to heart mitochondrial proteins was studied. The protein markers assessed were N(epsilon)-(carboxyethyl)lysine (CEL), N(epsilon)-(carboxymethyl)lysine (CML), N(epsilon)-(malondialdehyde)lysine (MDA-lys), and the recently described (PNAS 98:69-74, 2001) main constituents of protein carbonyls glutamic and aminoadipic semialdehydes. All these markers were measured by gas chromatography/mass spectrometry. The results showed that glutamic semialdehyde was present in rat heart mitochondria at levels 20-fold higher than aminoadipic semialdehyde. After 4 months of caloric restriction, the levels of CEL, CML, MDA-lys and glutamic semialdehyde were significantly lower in the mitochondria from caloric restricted animals than in the controls. These decreases were not due to a lower degree of oxidative attack to mitochondrial proteins, since the rate of mitochondrial oxygen radical generation was not modified by 4 months of caloric restriction. The decreases in MDA-lys and CML were not due either to changes in the sensitivity of mitochondrial lipids to peroxidation since measurements of the fatty acid composition showed that the total number of fatty acid double bonds and the peroxidizability index were not changed by caloric restriction. The results globally indicate that caloric restriction during 4 months decreases oxidative stress-derived damage to heart mitochondrial proteins. They also suggest that these decreases are due to an increase in the capacity of the restricted mitochondria to decompose oxidatively modified proteins.

Aldehydes↗

PubMed1996

Moderate caloric restriction prevents the age-related decline in growth hormone receptor signal transduction.

A decline in plasma concentration of insulin-like growth factor-1 (IGF-1) has been hypothesized to contribute to a decrease in tissue protein synthesis and function in aging animals and man. In this study, the effects of aging and long-term caloric restriction on growth hormone receptor signal transduction were assessed in hepatic tissue to determine whether alterations in tissue responsiveness to growth hormone contribute to the decline in IGF-1 gene expression. Liver slices from female C57/BL mice (10, 17, and 31 months) were prepared in media and stimulated with growth hormone (2 nM). An increase in growth hormone receptor binding was observed in 31-month ad libitum-fed animals (p < .01) compared to 10- or 17-month-old animals), and this effect was partially attenuated by moderate caloric restriction. However, growth hormone (2 nM)-induced IGF-1 gene expression was significantly lower in old ad libitum-fed animals (p < .05 compared to 10-month-old ad libitum and 31-month-old caloric-restricted animals). Further analysis revealed that growth hormone receptor and JAK2 kinase phosphorylation as well as mitogen-activated protein (MAP) kinase activity were significantly lower in old animals compared to the adult or middle-age groups (p < .05). Old caloric-restricted animals demonstrated a significant increase in growth hormone receptor and JAK2 kinase phosphorylation and MAP kinase activity in response to growth hormone. The results demonstrate that growth hormone increases growth hormone receptor and JAK2 kinase phosphorylation as well as MAP kinase activity in liver. These responses decrease with age and are attenuated by moderate, long-term caloric restriction.

Aging↗

PubMed1993

The effect of caloric restriction on the lateral diffusion constant of hepatocyte membrane proteins in C57BL/6 male mice of different ages: FRAP studies on liver smears.

The lateral mobility of proteins in hepatocyte plasma membranes was compared in calorically restricted and ad libitum (AL)-fed C57BL/6 male mice in age groups from 7 to 28 months. Caloric restriction was achieved by means of the every-other-day (EOD) feeding regimen, maintained for various periods from 1 to 15 months. Protein lateral diffusion constant (D) in hepatocyte membranes was measured by means of fluorescence recovery after photobleaching (FRAP) in liver smears. The peroxide-induced autofluorescence (PIAF) was utilized as a fluorescent label. A mild (1 mM for 10 min) H2O2 treatment of liver smears produces oxidation of riboflavin that is bound to all proteins of the cell membrane. Using this technique, the average lateral diffusion constant (D) and the fractional recovery (FR) of these proteins can be measured. EOD feeding resulted in a significant decrease in body weights and also a significant increase in the values of D in all age groups after 1 month of EOD feeding. After 3.5 months of EOD feeding a further increase of D was observed (up to about 15%). Nevertheless no further change in D occurred if the EOD feeding was maintained for 6.5 or even 15 months. The negative linear age correlation of D observed in the AL-fed animals was present also under the EOD feeding; however, the whole regression equation shifted towards higher values. These experiments indicate that caloric restriction influences the lateral diffusion constant of membrane proteins in hepatocytes. The results are interpreted as a result of an increased protein turnover caused by the caloric restriction.

Aging↗