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PubMed2003

Restriction of multiple divergent retroviruses by Lv1 and Ref1.

The mouse gene Fv1 encodes a saturable restriction factor that selectively blocks infection by N-tropic or B-tropic murine leukemia virus (MLV) strains. Despite the absence of an Fv1 gene, a similar activity is present in humans that blocks N-MLV infection (Ref1). Moreover, some non-human primate cell lines express a potentially related inhibitor of HIV-1 and/or SIVmac infection (Lv1). Here, we examine the spectrum of retrovirus-restricting activities expressed by human and African green monkey cell lines. Human cells restrict N-MLV and equine infectious anemia virus (EIAV), but not HIV-1, HIV-2, SIVmac or SIVagm, whilst AGM cells restrict N-MLV, EIAV, HIV-1, HIV-2 and SIVmac. Remarkably, in each example examined, restriction of infection by a given retrovirus can be abrogated at least partially by saturation with another retrovirus, provided that it is also restricted but regardless of whether it is closely related. These data suggest that restriction factors in human and non-human primate cells are able to recognize and block infection by multiple, widely divergent retroviruses and that the factors themselves may be related.

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↗

PubMed1999

Long-term calorie restriction reduces energy expenditure in aging monkeys.

Calorie restriction to produce stable long-term adult body weight for approximately 10 years prevents obesity and diabetes in middle-aged rhesus monkeys. To determine whether this dietary regimen also alters energy metabolism, the doubly labeled water method was used to measure total daily energy expenditure. Six adult male rhesus monkeys, which had been calorie-restricted for more than 10 years, were compared to 8 control adult monkeys, which had been fed ad libitum for their entire lives. The calorie-restricted monkeys weighed less than the ad-libitum fed monkeys and had a lower lean body mass and lower fat mass. Total daily energy expenditure was lower in the calorie-restricted than in the ad-libitum fed monkeys, even when corrected for differences in body size using body weight (563 +/- 64 vs 780 +/- 53 kcal/d; p < .04), surface area (547 +/- 67 vs 793 +/- 56 kcal/d; p < .05), or lean body mass (535 +/- 66 vs 801 +/- 54 kcal/d; p < .02) as covariates. Thyroxine (T4) was reduced and the free thyroxine index was suggestively lower in the calorie-restricted monkeys whereas triiodothyronine (T3) was not significantly different. Activity in calorie-restricted monkeys was similar to that of a weight-matched younger adult comparison group. We conclude that the process of preventing obesity by long-term caloric restriction causes a significant and sustained long-term reduction in energy expenditure, even when corrected for lean body mass.

Adipose Tissue↗

PubMed1980

Quantitative histologic effects on mouse thymus of controlled dietary restriction.

Specific volume fractions (VF) of cellular populations of 6-month-old mouse thymus are altered in animals dietarily restricted since weaning. The VF ratios of cortex:medulla are 2:1 for restricted animals and 1:1 for controls. Thymic cortex of restricted mice exhibits a greater VF of lymphoid cells. Dietary restriction did not alter the VF of medullary lymphoid cells. The VF of non-lymphoid cellular elements tended to decrease throughout the thymus with dietary restriction. No dietary effect on the VF of thymic vascular and connective tissues was observed. VF ratios of cortical lymphoid cells:medullary lymphoid cells show a tendency to increase in restricted mice as does the VF ratio of cortical lymphoid cells:cortical non-lymphoid cells. The VF ratio of thymic medullary lymphoid cells:medullary non-lymphoid cells also increases in restricted mice. VF ratios of cortical non-lymphoid cells:medullary non-lymphoid cells were not altered by diet.

Age Factors↗

PubMed1992

Dietary restriction alters characteristics of glucose fuel use.

A longitudinal study of plasma glucose and insulin concentrations in ad libitum fed and dietary restricted male F344 rats was carried out. The life span diurnal pattern of plasma glucose concentration was such that through most of the day dietary restricted rats have significantly lower plasma glucose levels than ad libitum fed rats. Throughout the life span, dietary restricted rats maintain mean 24-hour plasma glucose concentrations about 15% below those of ad libitum fed rats. Plasma insulin levels are maintained in dietary restricted rats at about 50% of the levels in ad libitum fed rats. Although plasma glucose and insulin levels are lower, dietary restricted rats use glucose fuel at the same rate per unit of metabolic mass per day as rats fed ad libitum. While these findings are consistent with the glycation hypothesis of aging and with our hypothesis that dietary restriction retards the aging processes by altering the characteristics of fuel use, they do not establish the validity of either. It is possible that this effect of dietary restriction on carbohydrate metabolism plays no role in its antiaging action. Further studies are required to define the role of these altered characteristics of carbohydrate metabolism in the aging processes.

Animals↗

PubMed1993

Long-term caloric restriction improves baroreflex sensitivity in aging Fischer 344 rats.

The effects of aging and caloric restriction on mean arterial pressure (MAP), heart rate (HR), and baroreflex sensitivity were determined in young (7-9 months) and old (22-24 months) awake, male Fischer 344 rats which had been either ad libitum fed or calorie restricted (60% of the ad libitum calories). The MAP of young rats was higher than that of old rats. The MAP of old ad libitum fed rats was higher than that of old restricted rats with no effect of diet in young rats. The HR of restricted rats was lower than ad libitum fed rats with no significant age effect. Reflex bradycardia to hypertensive episodes was greater in restricted than in ad libitum fed rats. Reflex tachycardia to hypotensive episodes was greater in young than in old rats and greater in calorie restricted than in ad libitum fed rats. These findings demonstrate that caloric restriction alters the age-associated decline in several hemodynamic parameters.

Aging↗

PubMed1981

Effect of maternal zinc deficiency of food restriction on rat fetal pancreas. 2. Insulin and glucagon.

The influence of a maternal dietary deficiency of zinc, or food restriction on the content and in vitro secretion of pancreatic hormones was measured in rat fetuses on day 19 of gestation. Pregnant Sprague-Dawley rats were fed a zinc-deficient diet (0.4 +/- 0.1 ppm zinc) ad libitum or a zinc-supplemented control diet (100 ppm zinc) either ad libitum or with restricted intake. The insulin content of the fetal pancreas was lower in fetuses from rats subjected to zinc deprivation or to food restriction than in controls. The lower insulin content of fetal pancreata from zinc-deficient rats was related to a lower than normal proportion of insulin-containing beta cells. The lower insulin content of fetal pancreata from rats subjected to food restriction was related to a less than normal amount of insulin per beta cell. Glucagon concentration in the fetal pancreas was lower than normal in response to zinc deficiency but not to food restriction. Fetal hormone release in vitro was also influenced by the maternal diet. The rate of insulin secretion in vitro was normal in fetuses from zinc-deficient rats, but was accelerated in those from females subjected to calorie restriction. The rate of glucagon secretion in vitro was lower than normal in the pancreata of zinc-deficient fetuses. We conclude that insulin and glucagon levels in the fetus were affected by maternal zinc deficiency and, to a lesser extent, by calorie restriction.

Animals↗

PubMed1982

Alterations of NADPH-generating and drug-metabolizing enzymes by feed restriction in male rats.

Two groups of weanling male Sprague-Dawley rats were fed a semisynthetic diet (ad libitum group) and 50% of that consumed by the ad libitum group (restricted group) for 49 days. Compared to the ad libitum group, the animals of the restricted group gained 55% less in body weight and had 60% smaller livers. While serum glucose, urea nitrogen, uric acid and lipids were lowered in the restricted animals, other serum biochemical parameters remained unchanged. The in vitro activities of hepatic drug-metabolizing enzymes were increased two- to threefold in the restricted animals. Feed restriction also caused a significant increase in the activities of NADPH-generating enzymes of liver and adipose tissue; however, the enzymes not concerned with the production of NADPH remained unaffected by feed restriction. It is concluded that feed restriction, unlike starvation, enhanced activities of drug-metabolizing enzymes as well as NADPH-generating enzymes.

Adipose Tissue↗

PubMed1984

Effect of caloric restriction during pregnancy on maternal and fetal body composition in the obese Sprague-Dawley rat.

The effects of 15, 30 or 50% caloric restriction during pregnancy on maternal and fetal compartments was determined in obese Sprague-Dawley rats. Pregnant and nonpregnant animals were assigned on a weight basis to one of the dietary treatments. All nutrients, except calories, were fed at levels to meet dietary requirements. Animals were killed on day 20 of treatment and fetuses were taken by Caesarian section. Pregnant animals achieved positive weight gain during 20 days of gestation at all levels of caloric restriction. Nonpregnant animals lost body weight when calories were restricted by 30 and 50%. Number of fetuses, fetal body nitrogen, and pup weight were not statistically different (P less than 0.05) among groups. Animals fed the 30 and 50% calorie-restricted diets showed a significant (P less than 0.05) decrease in total-body fat. Percent carcass protein tended to increase as dietary caloric restriction increased. The fetal compartment was apparently not affected by maternal caloric restriction up to 50% during pregnancy provided that all other nutrients were supplied in adequate amounts. Maternal stores were adversely affected at levels of 30 and 50% caloric restriction.

Animal Nutritional Physiological Phenomena↗

PubMed1986

Consequences of restricted feeding/refeeding cycles in lean and obese female Zucker rats.

Lean and obese female Zucker rats underwent four, 6-wk cycles of restricted feeding/refeeding. Restricted-fed, lean (RL) rats lost and then regained sufficient weight in each cycle to weigh the same amount as ad libitum-fed, lean (AL) rats at the end of each refeeding period. After the final period of restricted intake, RL rats had significantly lower parametrial and retroperitoneal pad weights and fat cell sizes than AL rats, but their organ growth and lipogenic enzymes were not affected. After the final refeeding period, there were no differences between RL and AL rats except in cumulative food intake. During the first period of restricted intake restricted-fed, obese (RO) rats did not lose weight; however, they were unable to attain the body weight of ad libitum-fed, obese (AO) rats during the subsequent refeeding period. In later cycles, RO rats lost and regained weight, but always weighed significantly less than AO rats. Following the final restricted feeding and refeeding periods, fat pad weights and cell numbers were significantly lower in RO than AO rats, but fat cell size was not affected. Liver weight and lipogenic enzymes were lower in RO than in AO rats after the final period of restricted intake, but were similar to AO rats after the final refeeding period. Permanent effects on heart and kidney growth were found in RO rats. Obese rats appeared to respond differently than lean rats to this form of dietary intervention.

Adipose Tissue↗

PubMed1990

Effect of dietary restriction on the age-dependent changes in the expression of antioxidant enzymes in rat liver.

The effects of aging and dietary restriction on the expression of several enzymes (superoxide dismutase, catalase and glutathione peroxidase) that are involved in free radical detoxification were studied in liver tissue from male Fischer F344 rats. The expression (i.e., activities and mRNA levels) of superoxide dismutase (Cu-Zn) and catalase decreased with age in liver. Dietary restriction (40% restriction of energy intake) increased the activities of superoxide dismutase (24 to 38%) and catalase (64 to 75%) in liver at 21 and 28 mo of age. Glutathione peroxidase activity in liver of diet-restricted rats was significantly higher (37%) at 28 mo of age than that of rats fed ad libitum. The age-related changes in the relative levels of mRNA for superoxide dismutase, catalase and glutathione peroxidase paralleled the changes in the activities of these enzymes in rats fed ad libitum or rats fed the restricted diet. Thus, the changes in the activities of superoxide dismutase, catalase and glutathione peroxidase with age and dietary restriction appear to arise from changes in the levels of mRNAs coding for these enzymes. Free radical damage, as measured by thiobarbituric acid-reactive material and lipofuscin accumulation, was lower in diet-restricted rats than in rats fed ad libitum.

Aging↗

PubMed1992

Exercise and food restriction in rats.

A number of studies have shown that exercised rats live longer than sedentary freely eating controls. There is disagreement regarding whether exercise results in extension of maximal life span. However, in two studies of the effect of voluntary wheel running on longevity of male specific-pathogen-free Long-Evans rats it was found that, although the runners had a longer average survival than sedentary freely eating controls, they did not have an increase in maximal life span. This is in contrast to the effect of food restriction. Sedentary rats that were food restricted to keep their body weights in the same range as those of the runners lived longer than the runners and showed an extension of life span. When exercise, in the form of voluntary wheel running was combined with food restriction (approximately 30% below ad libitum), the runners had an increased mortality rate over the first approximately 50% of their mortality curve up to age approximately 900 d. However, in those food-restricted runners that survived past approximately 900 d survival became similar to that of food-restricted sedentary controls, with a similar increase in maximal life span. Thus, although exercise has a deleterious effect on food-restricted rats, it does not counteract the increase in maximal life span induced by food restriction.

Animals↗

PubMed1994

Restricting food intake does not exacerbate the effects of a choline-deficient diet on tissue carnitine concentrations in rats.

Previous reports in animals indicate that choline deficiency alters carnitine metabolism. Recent studies in humans suggest that choline deficiency occurs in individuals during long term total parenteral nutrition. Malnutrition is also a frequent complication in this population. We therefore examined the effect of restricting the intake of a choline-deficient diet on carnitine concentrations in plasma and tissues. Adult male rats were randomly assigned to one of four dietary regimens: control, choline deficient, restricted control (85% of control), or restricted choline deficient for 42-43 d. At the end of the experimental period, restricted animals weighed significantly less than their respective controls (P < 0.01). Liver weight relative to body weight and fat concentration were greater in choline-deficient animals (P < 0.01 and 0.001, respectively). Choline-deficient rats fed free access had elevated plasma carnitine concentration (P < 0.01). Urinary carnitine excretion was elevated in both groups of choline-deficient rats (P < 0.01), while liver, heart and muscle carnitine concentrations were lower than in controls (P < 0.05). Restricting dietary intake reduced plasma carnitine concentration in choline-deficient animals (P < 0.01), but did not alter tissue or urine carnitine concentrations in either group. Restricted, choline-deficient animals did not exhibit a worsening of the sequelae of choline deficiency. We conclude that choline deficiency alters carnitine concentrations in plasma and tissues and that restricting the intake of a choline-deficient diet does not alter this effect in tissues.

Animals↗

PubMed1994

Protein restriction specifically decreases the abundance of serum albumin and transthyretin nuclear transcripts in rat liver.

The expression of the genes for serum albumin and several other plasma proteins is decreased in animals consuming inadequate amounts of dietary protein. To define the specificity of this phenomenon, we examined the effect of dietary protein restriction on the abundance of the mRNA for nine genes in rat liver. The results of this and previous studies indicate that genes in liver can be divided into two classes based on their response to protein restriction. Group I genes (albumin, transthyretin, carbamyl phosphate synthetase-I, class I alcohol dehydrogenase, insulin-like growth factor-I) exhibit decreased expression in response to protein restriction. In contrast, the expression of group II genes (hypoxanthine-guanine phosphoribosyl transferase, ubiquitin, H-ferritin, insulin-like growth factor binding proteins-1, -2 and -4) is either unchanged or increased in response to protein restriction. To investigate the molecular mechanism(s) leading to the decreased level of albumin and transthyretin mRNA in protein-restricted animals, the effect of protein restriction on the abundance of albumin and transthyretin nuclear transcripts was examined. The results demonstrated that protein restriction specifically decreased the abundance of albumin and transthyretin nuclear transcripts, indicating that the reduction in mRNA levels is caused at least partly by a decrease in gene transcription.

Animals↗

PubMed1995

Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction.

The objective of this study was to determine how food restriction (40% restriction of food intake) altered the age-related changes in the activities of Cu,Zn superoxide dismutase, catalase and glutathione peroxidase in liver, brain cortex, heart, kidney and intestinal mucosa obtained from 6-, 16- and 26-mo-old male Fischer 344 rats. Food restriction increased the activity of one or more of the antioxidant enzymes in the liver, brain cortex, heart and kidney of the rats. However, the magnitude of the effect and the antioxidant enzyme(s) affected by food restriction varied from tissue to tissue, and food restriction had no significant effect on the activities of these enzymes in intestinal mucosa. Interestingly, the four tissues in which food restriction increased the activity of one or more of the antioxidant enzymes showed reduced lipid peroxidation as measured by thiobarbituric acid-reactive material. These data suggest that food restriction might enhance the survival of rodents by altering the levels of the antioxidant enzymes and hence reducing free radical damage.

Aging↗

PubMed1995

Expression of heat shock genes in hepatocytes is affected by age and food restriction in rats.

The objective of this study was to determine how food restriction altered the age-related changes in the basal and heat-induced expression of heat shock genes (hsc70, grp78, and ubiquitin) by hepatocytes isolated from young (4 to 6 mo old) and old (26 to 28 mo old) male Fischer 344 rats. The basal levels of the mRNA transcripts for hsc70 and ubiquitin were similar for hepatocytes isolated from young and old rats fed with free access to the diet (control) or from rats fed a restricted diet (40% restriction of food intake). However, the induction of the mRNA transcripts for hsc70 and ubiquitin by a heat shock (42.5 degrees C for 30 min) was significantly higher for hepatocytes isolated from old rats fed the restricted diet compared with old rats fed with free access to the diet. The changes in hsc70 mRNA levels were paralleled by similar changes in hsc70 transcription by isolated nuclei; therefore, the greater induction of hsc70 expression by food restriction results from changes in the transcription of hsc70 gene. In contrast with hsc70 and ubiquitin, the basal levels of grp78 were reduced with age and by food restriction. Therefore, the effect of aging and food restriction on the basal and heat-induced expression of heat shock genes varies considerably from gene to gene.

Aging↗

PubMed1995

Aging and food restriction alter some indices of bone metabolism in male rhesus monkeys (Macaca mulatta).

Food restriction increases life span, reduces aging rate and affects a wide variety of biological functions. In rats, food restriction delays bone growth and reduces bone density and mineral content. We report the effects of aging and long-term (> 6.0 y) food restriction on several indices of bone growth and metabolism in rhesus monkeys (Macaca mulatta). Food allotments for controls approximated free access consumption, whereas food-restricted monkeys received 30% less food on a body weight basis. Cross-sectional and longitudinal age effects on serum alkaline phosphatase paralleled those reported for humans. Food restriction induced a significant delay in the developmental decline (to adult levels) in total alkaline phosphatase and significantly suppressed serum interleukin 6 concentrations, particularly in younger monkeys. Also, food restriction slowed skeletal growth, as reflected by shorter crown-rump length, and significantly reduced total body bone mineral content, but not bone mineral density, measured by dual energy X-ray absorptiometry. Analyses of serum parathyroid hormone, calcium, phosphate and osteocalcin concentrations suggested that the effects on skeletal growth were not related to alterations in calcium and phosphate homeostasis or a primary defect in bone formation. These findings suggest that long-term food restriction delays skeletal development in male rhesus monkeys while allowing the development of a reduced but otherwise normal skeleton.

Aging↗

PubMed1996

Dietary energy restriction in mice negatively regulates hepatic glucose-regulated protein 78 (GRP78) expression at the posttranscriptional level.

Dietary energy restriction delays age-related physiologic changes, increases maximum life span, and reduces cancer incidence. We showed previously that 50% energy restriction in mice reduces hepatic expression of glucose-regulated protein mRNA by 50 to 80%. Changes in glucose-regulated protein 78 (GRP78) levels can either decrease or increase the rate of secretion of specific proteins. Therefore, energy restriction probably produces a global change in the spectrum of proteins secreted by the liver. These studies were initiated to investigate the molecular basis for the negative regulation of the gene. By use of transfection and nuclear run-on techniques, the strong induction of GRP78 gene transcription in cultured cells subjected to acute, extreme glucose deprivation has been well characterized. However, negative regulation of GRP78 gene expression in vivo by energy restriction is not as well understood. In our studies, a reduction in GRP78 protein levels determined using Western blotting closely paralleled a reduction in hepatic GRP78 mRNA measured by Northern and dot blotting. In each case the changes were statistically significant. This close correspondence indicates that energy restriction does not influence the translation rate or the stability of GRP78 protein. No statistically significant difference in the rate of transcription of the gene was detected in energy-restricted mice by use of transcription run-on assays. These results strongly suggest that energy restriction results in destabilization of GRP78 mRNA, thereby repressing hepatic expression of the gene.

Animals↗