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Effect of food restriction on acquisition and expression of a conditioned odor discrimination in mice.

Level of food restriction was manipulated in mice to assess its importance for the acquisition and expression of a conditioned odor discrimination. In training, animals were exposed to odors (either rose or lemon) presented on a piece of filter paper in a pot covered in bedding. For half of the conditioning trials, group paired received one odor (CS+) with sucrose, the unconditioned stimulus (us), under the bedding. For the remaining trials, they received the other odor (CS-) alone. Group CS-alone was also exposed to both odors, but neither odor was paired with sugar on any of the conditioning trials. During training, Group Paired mice that were food-restricted tended to dig more readily and longer in the odors, especially in the CS+ odor, than animals that were not restricted. Both restricted and nonrestricted PAIRED GROUPS dug more in the CS+ than in the CS- by the end of training, but the CS-alone mice dug very little in either. Following training, mice were exposed to both odors simultaneously in a discrimination test. Half the mice in each training food restriction condition were tested under food restriction, and half were not. Only PAIRED animals that were food-restricted in the test expressed an odor discrimination, digging only in the CS+. This occurred regardless of their previous restriction state in training. These data suggest that both food-restricted and nonrestricted mice can acquire an odor discrimination; however, expression of this odor discrimination depends on food restriction.

Animals↗

Alcohol alliesthesia: food restriction increases the palatability of alcohol through a corticosterone-dependent mechanism.

The present article analyzed the dramatic increase in alcohol ingestion that is known to occur in laboratory rats subjected to food restriction. In the first experiment, we wished to know when during the day food restricted animals consume the "extra" alcohol ration. Determinations of ethanol drinking at 3-h intervals throughout the day revealed that although food-restricted animals drink much ethanol at all times of the day, they retain a definite daily rhythm such that peak intake occurs during the dark hours. The second experiment tested the hypothesis that chronic food restriction is accompanied by positive alliesthesia for the taste of alcohol. To answer this question, we employed the taste reactivity method to measure hedonic and aversive reactions to 6% ethanol as a function of nutritional status. It was found that two weeks of food restriction, which approximately doubled the voluntary intake of ethanol, was associated with a significant increase in the hedonic response elicited by intraoral infusions of ethanol. Alcohol also elicited fewer aversive responses in food restricted subjects. Because chronic food restriction increases adrenal corticosterone secretion, we used the corticosterone synthesis inhibitor metyrapone as a tool to assess the importance of adrenal corticosterone secretion for the increased palatability of alcohol observed during food restriction. The third experiment demonstrated that attenuation of corticosterone synthesis significantly reduced the hedonic taste reactions to alcohol observed in food-restricted rats; this drop in alcohol taste reward was accompanied by a nonsignificant increase in the aversive reaction to alcohol. The final experiment investigated the effect of prolonged exposure to exogenous corticosterone on the taste reactivity to ethanol in freely fed subjects. Adrenalectomized animals bearing corticosterone implants for 3 weeks found the taste of alcohol more pleasant than did intact or adrenalectomized rats implanted with blank pellets. Taken together, the present results suggest that food restriction is associated with an apparent increase in the sensory reward--positive alliesthesia--derived from alcohol; this effect appears to be mediated by increased adrenal corticosterone secretion.

Adrenalectomy↗

The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction.

Food restriction of adult rodents increases lifespan, with commensurate attenuation of age-related pathological lesions in many organs, as well as attenuation of normal ageing changes that are distinct from gross lesions. Previous work showed that chronic food restriction attenuated age-associated astrocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibility complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fed (Brown Norway x Fischer 344) F1 male rats aged three and 24 months and chronic food-restricted rats aged 24 months. In situ hybridization and immunohistochemical techniques evaluated glial expression of glial fibrillary acidic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenase-1, complement 3 receptor (OX42), OX6 and transforming growth factor-beta1. All markers were elevated in the corpus callosum during ageing and were attenuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured with glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal ganglia and hippocampus. Generally, food restriction attenuated the age-related increase in glial fibrillary acidic protein messenger RNA and immunoreactivity. Food restriction also reduced the age-related increase in apolipoprotein J and E messenger RNA and heme oxygenase-1 immunoreactivity in the basal ganglia and corpus callosum. However, astrocytes in the hilus of the hippocampus showed an age-related decrease in apolipoprotein J and E messenger RNA, which was further intensified by food restriction. The age-associated microglial activation measured by OX6 and OX42 immunoreactivity was reduced by food restriction in most subregions. The localized subsets of glial age changes and effects of food restriction comprise a mosaic of ageing consistent with the regional heterogeneity of ageing changes reported by others. In particular, age has a differential effect on astrocytic and microglial hyperactivity in gray versus white matter areas. The evident mosaic of glial ageing and responses to food restriction suggests that multiple mechanisms are at work during ageing.

Aging↗

Distinct roles of processes modulated by histone deacetylases Rpd3p, Hda1p, and Sir2p in life extension by caloric restriction in yeast.

Caloric restriction has been demonstrated to extend life span and postpone aging in a variety of species. The recent extension of the caloric restriction paradigm to yeast places the emphasis of the search for the longevity effectors at the cellular level. To narrow the range of potential effectors of the caloric restriction response, we have examined the effects of the histone deacetylases Rpd3p, Hda1p, and Sir2p, which have distinguishable but partially overlapping influences on global patterns of gene expression, on the life extension afforded by caloric restriction. Deletion of the RPD3 gene extended life span, and there was no additive effect of caloric restriction. Deletion of HDA1 had no effect of its own on longevity but acted synergistically with caloric restriction to increase life span. SIR2 deletion shortened life span but did not prevent extension of life span by caloric restriction. The results suggest that Rpd3p affects both processes that play an obligate and those that play a synergistic role in life extension by caloric restriction, while Hda1p and Sir2p affect processes that are not the obligate longevity effectors of caloric restriction but instead synergize with them, although in opposite directions. From the known patterns of gene expression elicited by rpd3delta, hda1delta, and sir2delta, we propose that the major longevity effectors of caloric restriction in yeast involve carbohydrate/energy metabolism and mitochondrial function.

Energy Metabolism↗

The sensitivity of the NTP bioassay for carcinogen hazard evaluation can be modulated by dietary restriction.

Studies were undertaken to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as by protocols employing dietary restriction. Four chemicals, using three different routes of exposure (in utero [accomplished by feeding the dam dosed feed], dosed feed, and gavage) were used to 1) evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemically-induced chronic toxicity and carcinogenicity; and 2) evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Control and chemical exposed F344 rats and B6C3F1 mice (50-60/group) were fed NIH-07 diet either ad libitum or at restricted levels such that body weights were approximately 80% of ad libitum control weights. The dietary restricted groups were either sacrificed at the end of two or 3-years. Results consistently show that feed restriction decreased the incidence of neoplastic and non-neoplastic lesions at a variety of anatomic sites in both control and chemical exposed animals. Furthermore, the sensitivity of the bioassay to detect chemical carcinogenic response were altered by dietary restriction: three of the four chemicals were found to increase the incidence of neoplastic lesions at four sites when evaluated under standard ad libitum conditions for 104 weeks. When unexposed and exposed groups were both subjected to dietary restriction, none of these 4 sites were detected as a target for carcinogenesis after two or three years. Rather, two different sites of carcinogenesis were detected. When the top dosed ad libitum fed animals were compared against their weight-matched control groups, a total of 10 sites were identified as targets for carcinogenesis. These included all four sites identified under the ad libitum protocol, both sites identified under the feed restricted protocol, and an additional four sites that were not identified under the other two protocols. These studies show that dietary restriction of all animals can be expected of decrease the sensitivity of carcinogenesis bioassays. However, restricting only unexposed groups (weight matching) of control for non-specific weight loss in chemical exposed groups yielded the most sensitivity among our comparisons.

Animals↗

The effect of moderately and severely restricted dietary magnesium intakes on bone composition and bone metabolism in the rat.

Forty 3-week-old male rats, Wistar strain, average weight 59 g, were randomized by weight into five groups of eight rats each. Three groups were fed ad libitum on a semi-purified diet containing (per kg) 400 (adequate), 200 (moderately Mg-restricted) or 20 (severely Mg-restricted) mg Mg for 3 weeks while two groups were pair-fed with the Mg-adequate diet in the same quantities as those consumed by the two Mg-restricted groups respectively. While weight gains and food conversion efficiency values for the Mg-restricted groups were similar to those of the corresponding pair-fed control groups, serum and kidney Mg, and femoral dry weight were reduced by 70, 7 and 9% respectively in the severely Mg-restricted group and were unaffected in the moderately Mg-restricted group. Significant reductions were observed in urinary pyridinoline (Pyr) (by 44 and 34%) and deoxypyridinoline (Dpyr) levels (by 40 and 33%) (markers of bone resorption), serum osteocalcin levels (by 46 and 28%) (marker of bone formation), femoral Mg levels (by 52 and 14%) and osteocalcin mRNA levels (by 46 and 22%) compared with the corresponding pair-fed controls, in the severely and moderately Mg-restricted groups respectively, and these reductions, except for those in urinary Pyr and Dpyr, were more marked in the severely Mg-restricted group. Femoral Ca and P concentrations were unaffected by dietary Mg restriction. These results show that not only severe but also moderate dietary restriction of Mg over 21 d results in qualitative changes in bone (i.e. reduced Mg concentration) as well as in aberrant bone turnover in young growing rats (i.e. severely depressed rates of bone formation and bone resorption), which may impair bone development and bone strength.

Amino Acids↗

A study on the conformation-anomeric effect-stereoselectivity relationship in anomeric radical reactions, using conformationally restricted glucose derivatives as substrates.

We previously theorized that, since the stereoselectivity of anomeric radical reactions is significantly influenced by the kinetic anomeric effect, which can be controlled by restricting the conformation of the radical intermediate, the proper conformational restriction of the pyranose ring of the substrates would therefore make highly alpha- and beta-stereoselective anomeric radical reactions possible. This theory was based on our previous results of the anomeric radical reactions with d-xylose derivatives as the substrates. We herein report the anomeric radical deuteration reactions with the conformationally restricted 1-phenylseleno-d-glucose derivatives, 2g and 3g, restricted in a (4)C(1)-conformation by an O-cyclic diketal moiety, and 4g, 5g, 6g, 7g, and 8g, restricted in a (1)C(4)-conformation by bulky O-silyl protecting groups. The radical deuterations with Bu(3)SnD, using the (4)C(1)-restricted substrates 2g and 3g, afforded the corresponding alpha-products (alpha/beta = 98:2) highly stereoselectively, whereas the (1)C(4)-restricted substrate 6g, having a trigonal (sp(2)) carbon substituent, i.e., -CHO, at the 5-position, selectively gave the beta-products (alpha/beta = 0:100). Thus, the stereoselectivity was significantly increased by the conformational restriction and was completely inverted by changing the substrate conformation from the (4)C(1)-form to the (1)C(4)-form. On the other hand, the deuterations with the (1)C(4)-restricted substrates 4g and 5g showed that the 1,5-steric effect due to the tetrahedral carbon substituent (-CH(2)OTIPS or -CH(2)OH) at the 5-axial position dominantly prevented the hydride transfer from the beta-face competing with the kinetic anomeric effect. This study suggests that, depending on the restricted conformation of the substrates to the (4)C(1)- or the (1)C(4)-form, the alpha- or beta-products would be obtained highly stereoselectively via anomeric radical reactions of hexopyranoses.

Chemistry, Organic↗

Modification of age-related immune decline in mice dietarily restricted from or after midadulthood.

Although weaning-initiated dietary restriction of rodents is known to increase maximum survivorship and inhibit spontaneous late-life disease and immunologic aging, restriction begun in adulthood has been much less thoroughly evaluated. In the present studies, male mice of a long-lived F1 hybrid strain were gradually restricted dietarily beginning at 12 mo or older until their body weights stabilized at 60-70% of controls. Underfeeding decreased the number of nucleated cells per spleen but increased the percentage of T cells. For mice restricted at 12, 17, or 22 mo and tested at various ages thereafter, the [3H]thymidine uptake of spleen cells after phytohemagglutinin stimulation significantly exceeded values for age-matched unrestricted controls. Restriction did not, however, alter either splenocyte responses to concanavalin A or to B-cell mitogens or phytohemagglutinin responses of peripheral lymph node cells. In the splenic plaque-forming cell response to injected sheep erythrocytes, restricted and control mice differed more clearly in response kinetics than in peak levels. The splenic cell-mediated lymphocytotoxic response to alloantigens was comparable in old mice (27-29 mo) restricted since 12 mo of age with that of young (5- to 6-mo) controls and was greater than that of age-matched old controls. Spontaneous tumors were observed less frequently in 19- to 25-mo-old mice restricted at 12 mo of age than in mice restricted at 17 mo or in controls. Our results indicate that appropriate food restriction initiated in adulthood influences immunosenescence and spontaneous tumor incidence in a fashion not unlike its weaning-initiated counterpart.

Aging↗

Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice.

Dietary restriction, especially caloric restriction, is a major modifier in experimental carcinogenesis and is known to decrease significantly the incidence of neoplasms. Gross and Dreyfuss [Gross, L. & Dreyfuss, Y. (1984) Proc. Natl. Acad. Sci. USA 81, 7596-7598; Gross, L. & Dreyfuss, Y. (1986) Proc. Natl. Acad. Sci. USA 83, 7928-7931] reported that a 36% restriction in caloric intake dramatically decreased the radiation-induced solid tumors and/or leukemias. Their protocol predominantly produced lymphatic neoplasms. It is of interest to observe the effect of caloric restriction on radiation-induced myeloid leukemia, because the disease was observed to have been increased in the survivors of the atomic bombs in Hiroshima and Nagasaki. The spontaneous incidence of myeloid leukemia in C3H/He male mice is 1%, and the incidence increased to 23.3% when 3 Gy of whole-body x-ray irradiation was given. However, the incidence of myeloid leukemia was found to be significantly decreased by caloric restriction; it was reduced to 7.9% and 10.7% when restriction was started before (6 weeks old) and after (10 weeks old) irradiation, respectively. In addition, the onset of the myeloid leukemia in both restricted groups was prolonged to a greater extent as compared with the control diet group. Caloric restriction demonstrated a significant prolongation of the life span in the groups on a restricted diet after having been exposed to irradiation, either before or after dietary restriction, in comparison with mice that were only irradiated.

Aging↗

Comparison of vitamin C deficiency with food restriction on collagen cross-link ratios in bone, urine and skin of weanling guinea-pigs.

Mild-to-moderate vitamin C depletion in weanling guinea-pigs affects pyridinoline:deoxypyridinoline (collagen cross-link) ratios in femur shaft and urine, attributed to impairment of hydroxylation of collagen lysine. We investigated: (1). whether the picture at two time points is compatible with progressive accumulation of abnormal collagen; (2). whether any changes are seen in skin, where little deoxypyridinoline occurs; (3). whether total food restriction has similar effects. Male weanling Dunkin-Hartley guinea-pigs were fed diets containing either 0.5 (vitamin C-restricted) or 160.0-320.0 (vitamin C-adequate) mg vitamin C/d. Two groups receiving the vitamin C-adequate diet received it ad libitum. Two other groups received the vitamin C-adequate diet in a restricted amount, limited to that which permitted nearly the same growth rate as in the vitamin C-restricted groups. Animals were fed for 4 or 8 weeks; urine was collected, and vitamin C and collagen indices were measured. In the femur shaft, the hydroxyproline content per unit weight was unaffected by vitamin C restriction or by total food restriction. Deoxypyridinoline was increased and the pyridinoline:deoxypyridinoline ratio was decreased in vitamin C-restricted groups, but not in food-restricted groups. Changes in the value of the ratio were greater after 8 than after 4 weeks. Urine indices mirrored bone indices. In skin, the main effect of vitamin C restriction was to reduce hydroxyproline. Here, the cross-link ratios changed less markedly than in bone, and there was less deoxypyridinoline. We conclude that the picture at two time points is compatible with a progressive accumulation of pyridinoline-enriched collagen in vitamin C-deprived animals, that the picture in skin differs from that of bone and urine, and that cross-link changes are not produced by total food restriction.

Amino Acids↗

Chronic dietary restriction influences tumor metastasis in the rat: parametric considerations.

Chronic dietary restriction is a well-documented means of inhibiting tumor growth. This study examines the effects of chronic dietary restriction on tumor metastasis in the rat. We investigate the effect of 1) the degree of food restriction, 2) the effect of preexposure to food restriction, and 3) the duration of food restriction after tumor inoculation on tumor metastasis. We also compare two methods of dietary restriction: 1) the time that food is available and 2) the amount of food available. Our findings demonstrate that rats restricted to 50% of ad libitum diet for one week before inoculation with MADB106 tumor cells and for three weeks after inoculation exhibit a significant (p < 0.001) reduction in lung colonization compared with animals fed ad libitum. Animals restricted to access to food for 4 hrs/day (60% of ad libitum) for the same period of time exhibit significantly (p < 0.005) greater lung tumor colonization than animals fed ad libitum. Preadaptation to the feeding regimen for one week before tumor inoculation proved to be critical in inhibiting tumor metastasis. The tumor-inhibitory effect was not significantly influenced by the duration of restriction after inoculation or by the manner in which food restriction was implemented. Finally, we demonstrate that inhibition of tumor colonization may be mediated by enhanced natural killer cell activity in the early postinoculation period.

Adenocarcinoma↗

The influence of functional limitations and various demographic factors on self-reported activity restriction at older ages.

PURPOSE: The study analysed some differentials in self-reported restrictions for personal care activities. Activity restrictions are the result of basic functional limitations (vision, mobility...), but such limitations do not evenly reduce activity performance. We assessed how age, sex and the place of residence (household or institutions) changed the risk of reporting restrictions for similar functional problems. METHOD: We used the French disability survey data on personal care activity restrictions and functional limitations (physical, visual, time orientation) for people aged 55 years and older (n=16961). A logistic regression model shows the separate impact of the nature of functional limitations and of age, gender and residence on the risk of reported restrictions. RESULTS: Half of the people aged 55 and older reported functional problems; 20% of them also reported personal care activity restrictions. The probability of reporting restrictions was higher for people with several types of limitations, especially orientation and physical controlling for such limitations, the probability of restriction increased with age beyond 70, was higher for men than women below 70, and was higher in institutions than in households. CONCLUSION: Self-reported activity restrictions are not solely related to functional limitations but also to various demographic variables likely to modify the impact of these limitations on activity performance. These findings suggest studying differentials in the resources allowing to compensate limitations and to prevent reported restrictions.

Activities of Daily Living↗

H2-M3-restricted T cells in bacterial infection: rapid primary but diminished memory responses.

Major histocompatibility complex (MHC) class Ib molecules have been implicated in CD8(+) T cell-mediated defenses against intracellular bacterial infection, but the relative importance of MHC class Ib-restricted T cells in antimicrobial immunity is unknown. In this report, we use MHC tetramers to characterize T cell responses restricted by H2-M3, an MHC class Ib molecule that selectively presents N-formyl peptides. We find that sizeable H2-M3-restricted T cell responses, occurring earlier than MHC class Ia-restricted T cell responses, are mounted after primary infection with the intracellular bacterium Listeria monocytogenes. These H2-M3-restricted T cells are cytolytic and produce interferon gamma. However, after a second L. monocytogenes infection, H2-M3-restricted memory T cell responses are minor in comparison to the much larger MHC class Ia-restricted responses. This first direct characterization of an MHC class Ib-restricted T cell response indicates that CD8(+) T cells responding to L. monocytogenes infection can be divided into two groups: H2-M3-restricted responses, which provide rapid and quantitatively substantial effector function during primary infections but contribute relatively little to memory responses, and MHC class Ia-restricted responses, which expand later during primary infection but form memory T cells that respond rapidly and dramatically in response to subsequent infections by the same pathogen.

Animals↗

Digestive responses during food restriction and realimentation in nestling house sparrows (Passer domesticus).

We used nestling house sparrows (Passer domesticus) under laboratory conditions to test for modulation of digestive efficiencies during periods of low and high food intake and tested the hypothesis that nestlings would exhibit compensatory changes in digestive efficiency following a period of food restriction. During the low intake period, nestlings were held at constant body mass for 48 h beginning on either day 3 or day 6 of life by feeding them at 50% of control rations. After 48 h of food restriction, nestlings were fed as much as they could consume, allowing the nestlings restricted at day 6 (early restriction not assessed) to consume 14% more food than control nestlings. For nestlings restricted at day 6 apparent dry mass assimilation of the entire diet was found to be 5% and 8% lower during food restriction and realimentation, respectively, compared with control nestlings that were not under- or overfed. There were no significant differences in radiolabeled starch assimilation efficiencies between control and restricted nestlings. Starch assimilation efficiencies remained constant from 3 d of age onward in control nestlings. Total starch extracted was lower during food restriction but reached a rate similar to that of control nestlings during the realimentation period. Passage times (time of first defecation, mean retention time, and mode passage time) measured with an indigestible marker were longer during food restriction and shorter during realimentation, relative to control nestlings. During realimentation there was no difference in intestinal rates of hydrolysis or mediated uptake of L-leucine compared with control nestlings. The main effect of changing food intake was apparently to alter flow rate, and hence retention time, causing slight changes in digestive efficiency. Thus, nestlings did not exhibit compensatory changes in digestion rates as implied by the hypothesis. Our finding of a lower dry mass assimilation efficiency and similar total starch assimilation during realimentation (relative to controls) helps explain why nestling house sparrows do not display compensatory growth, despite higher food intake. Our results indicate that the gut has little spare capacity to deal with increased food intake during growth following food restriction.

Adaptation, Physiological↗

Enforcing a policy for restricting antimicrobial drug use.

An institution's experience in enforcing a policy for restricting the use of antimicrobial agents is described. A policy to restrict the use of eight intravenous antimicrobial agents had been in place for two years at a large county teaching hospital but had never been enforced. In 1994 an organized effort to enforce the policy was begun. Memorandums were sent to all medical staff, residents, pharmacists, and nurses informing them that the policy would be diligently enforced. Before a restricted antimicrobial could be dispensed, the approval of a physician specializing in infectious diseases was required. Under the direction of the pharmacy and therapeutics committee and an antimicrobial subcommittee, a specially hired team of pharmacists started to encourage more effective and economical prescribing of antimicrobials. During a nine-month period after enforcement began, use of the restricted antimicrobials declined, and use of nonrestricted antimicrobials increased. After two months, acquisition costs for the restricted drugs had been reduced by more than $82,000; however, a similar increase in acquisition costs for nonrestricted antimicrobials occurred. As a result, one nonrestricted agent was reclassified as restricted, and inservice sessions were held to teach prescribes about the appropriate use of another agent. In general, physicians were very compliant with the antimicrobial-restriction policy; the greatest resistance was encountered from surgical residents. Some-pharmacists needed warnings beyond the initial memorandum. Enforcement of an antimicrobial-restriction policy led to decreased use of the restricted drugs and substantial cost avoidance. As new patterns of antimicrobial use emerged, the restriction policy was modified as necessary.

Anti-Bacterial Agents↗

Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat.

Because of the suggested role of energy consumption and the well-documented role of estrogens in the etiology of breast cancer, we have examined the effect of a 40% restriction of dietary energy consumption on the ability of administered 17beta-estradiol (E2) to induce mammary tumorigenesis in female ACI rats. Experiments herein test the hypothesis that at least part of the inhibitory effect of energy restriction on mammary tumorigenesis is exerted downstream of potential effects of dietary manipulation on the production of estrogens by the ovaries. Ovary-intact ACI rats were fed a control or a 40% energy-restricted diet and were either treated continuously with E2 from subcutaneous Silastic tubing implants or received no hormone treatment. Mammary cancers rapidly developed in E2-treated rats fed the control diet; within 216 days of initiation of E2 treatment 100% of the population at risk exhibited palpable mammary tumors. Dietary energy restriction markedly inhibited E2-induced mammary tumorigenesis, as evidenced by significant reductions in cancer incidence and tumor burden as well as a significant increase in the latency to the appearance of the first palpable cancer. The inhibitory actions of dietary energy restriction on E2-induced mammary tumorigenesis were associated with an inhibition of E2-stimulated mammary cell proliferation. However, this inhibition was insufficient to block induction of lobuloalveolar hyperplasia or appearance of focal regions of atypical epithelial hyperplasia. These data suggest that dietary energy restriction inhibits E2-induced mammary cancer by attenuating or retarding the progression of atypical hyperplasia to carcinoma. Expression of progesterone receptor (PR) was up-regulated within the focal regions of atypical hyperplasia and the carcinomas induced by E2, regardless of whether the rats were fed the control or energy-restricted diet. However, circulating progesterone was reduced by dietary energy restriction, suggesting a possible mechanism for inhibition of mammary tumorigenesis. Dietary energy restriction did not inhibit the ability of administered E2 to induce prolactin (PRL)-producing pituitary tumors and associated hyperprolactinemia, indicating that the inhibitory effects of dietary energy restriction on mammary tumorigenesis are tissue specific and independent of circulating E2 and PRL.

Animals↗

Modulation of age-related changes in serum 1,25-dihydroxyvitamin D and parathyroid hormone by dietary restriction of Fischer 344 rats.

The purpose of this study was to determine the effect of food restriction on age-related changes in serum 1,25-dihydroxyvitamin D and PTH, two important regulators of Ca metabolism. Starting at 6 wk, male F344 rats were fed a purified diet either ad libitum (non-restricted) or 60% of ad libitum (restricted). Rats from each group were killed at 5, 13, 22 and 28 mo of age. Dietary restriction increased the median lifespan from 24 to 31 mo. It delayed the rapid decrease in serum 1,25-dihydroxyvitamin D from 1.5-5.0 mo in the non-restricted group to 5-13 mo in the restricted group. It also completely suppressed the marked rise in serum PTH which occurred at 22 and 28 mo in the non-restricted group. Dietary restriction had these effects even though both groups of animals consumed the same amount of Ca per gram body weight. Diet had no effect on serum Ca and P, except at 28 mo. These effects of dietary restriction on serum 1,25-dihydroxyvitamin D and PTH may result in altered Ca metabolism in dietary restricted F344 rats.

Aging↗

Changes in plasma thyroid hormone concentrations in chronically food-restricted female rats and their offspring during suckling.

To examine the joint effects of lactation and dietary restriction on thyroid function, we studied chronically food-restricted rat dams at conception and dams and their pups during the nursing period compared with controls that had free access to food. As expected, both dietary restriction [plasma thyroxine and 3,3',5-triiodothyronine (T3) values were lower and reverse T3 (rT3) values were higher in food-restricted than in control rats] and stage of lactation (T3 values decreased in both groups) had independent effects on maternal thyroid function. There also were interactive effects: rT3 values decreased during lactation among the food-restricted dams but remained constant among controls. Maternal dietary restriction also did not have a consistent effect on pup thyroid function during the nursing period: in offspring of food-restricted compared with control dams, plasma thyroxine values were lower only at d 14, T3 values were lower at d 7-21, and rT3 values were higher from birth to d 14. These data demonstrate that dietary restriction and lactation have synergistic negative effects on thyroid status in lactating rats and their pups and that thyroid hormone ontogeny is retarded in the offspring of food-restricted rats. These hormonal effects may contribute to the impaired milk production of food-restricted rats and to altered growth characteristics of their offspring.

Animals↗