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R J Feuers

Publications and source records attributed to R J Feuers.

At least 55 records · Page 3Linked to original sources
PubMed1993

Caloric restriction, aging, and antioxidant enzymes.

The basic mechanisms of aging and its retardation by caloric restriction (CR) remain unclear. One suggested means by which CR could retard aging is based on production of mitochondrial free radicals, and efficiency of their subsequent metabolism. Currently, there is little information concerning the influences of age and CR on the rates of in vivo mitochondrial free radical production. However, evidence for CR-induced modulation of free radical detoxification capacities is mounting. The direction of the influence of CR on free radical detoxification is tissue-specific. These effects are broad and appear to provide positive advantage.

Aging↗
PubMed1993

Effects of caloric restriction on rodent drug and carcinogen metabolizing enzymes: implications for mutagenesis and cancer.

Caloric restriction in rodents results in increased longevity and a decreased rate of spontaneous and chemically induced neoplasia. The low rates of spontaneous neoplasia and other pathologies have made calorically restricted rodents attractive for use in chronic bioassays. However, caloric restriction also alters hepatic drug metabolizing enzyme (DME) expression and so may also alter the biotransformation rates of test chemicals. These alterations in DME expression may be divided into two types: (1) those that are the direct result of caloric restriction itself and are detectable from shortly after the restriction is initiated; (2) those which are the result of pathological conditions that are delayed by caloric restriction. These latter alterations do not usually become apparent until late in the life of the organism. In rats, the largest direct effect of caloric restriction on liver DMEs is an apparent de-differentiation of sex-specific enzyme expression. This includes a 40-70% decrease in cytochrome P450 2C11 (CYP2C11) expression in males and a 20-30% reduction of corticosterone sulfotransferase activity in females. Changes in DME activities that occur late in life in calorically restricted rats include a stimulation of CYP2E1-dependent 4-nitrophenol hydroxylase activity and a delay in the disappearance of male-specific enzyme activities in senescent males. It is probable that altered DME expression is associated with altered metabolic activation of chemical carcinogens. For example the relative expression of hepatic CYP2C11 in ad libitum-fed or calorically restricted rats of different ages is closely correlated with the amount of genetic damage in 2-acetylaminofluorene- or aflatoxin B1-pretreated hepatocytes isolated from rats of the same age and caloric intake. This suggests that altered hepatic drug and carcinogen metabolism in calorically restricted rats can influence the carcinogenicity of test chemicals.

Animals↗
PubMed1993

Historical comments on chronobiology with emphasis on cell proliferation, the concept of free running, cancer chemotherapy and experimental design.

A brief historical summary is presented regarding the emergence, over the past several decades, of chronobiology as the newest of the integrating discipline of biology. The emphasis is on the circadian system which normally is synchronized to the 24 h environmental light-dark cycle. In the absence of a suitable synchronizer, the system free runs on its own endogenous genetically determined frequency, which usually only approximates 24 h. Since the metabolic system changes rhythmically in time it follows that an organism such as man is biochemically and physiologically a different entity at different circadian stages; therefore it reacts differently to an identical stimulus given at different times. Different stimuli such as anticancer agents are examples considered clearly timed treatment has been shown to significantly improve therapeutic efficacy, data will be presented using the L1210 mouse leukemic model. Moreover data is presented showing that to ignore such rhythmic fluctuation when designing experiments that such can bring about experimental error and false interpretation. The common "same time of day" sampling does not take care of the rhythmic problem!

Adult↗
PubMed1992

Modulation of chemical toxicity by modification of caloric intake.

Caloric restriction increases maximum achievable lifespan and offsets the time to development of degenerative disease. Part of these desirable effects may result from positive modulation of toxic events. We have shown that when rodents are placed on a diet that is reduced in total calories by 40%, several beneficial changes on biochemical systems which impact on toxicologic processes are positively enhanced. Lipid metabolism is reduced and, therefore, the potential for lipoperoxidation is reduced. Additionally, activity of enzymes that produce free radicals as byproducts (cytochrome P4502C11) are also reduced. Concurrently, we have shown that the "effective" activity of catalase and the activity of superoxide dismutase (which are required for the detoxification of toxic oxygen radicals) are significantly increased by caloric restriction. The activities of enzymes of drug and xenobiotic metabolism are also altered by caloric restriction. The effect upon activity may be to either decrease or increase activity, dependent upon whether the enzyme activates compounds to intermediates which may be more toxic or whether the enzyme acts to reduce toxicity. We have also shown that caloric restriction may affect the initiation stage of carcinogenesis. Aflatoxin B1 binding to hepatic nuclear DNA was reduced by caloric restriction (caloric restriction reduced both major adducts that are formed upon exposure to aflatoxin B1). caloric restriction also reduced cytochrome P4502C11 which converts aflatoxin B1 to its toxic epoxide, and may partly explain the reduction in binding. These results suggest that caloric restriction may, in part, extend the time to development of degenerative disease by altering basic biochemical mechanisms of toxicity.

Animals↗
PubMed1992

The high mobility group of nuclear proteins as biomarkers of age and caloric restriction in rats.

The quantitative levels and phosphorylation states of the high mobility group (HMG) of proteins were investigated in bone marrow, brain, heart, kidney, liver, pancreas, spleen, testis and thymus of three groups of male Fischer 344 rats. Two groups of rats, young ad libitum (Y/AL - 1 1/2 mo.) and old ad libitum (O/AL - 28 mo.), had free access to rat chow, and a third group of old rats were maintained on a caloric restricted intake (O/CR - 28 mo.). The quantities of HMGs 1,2,14 and 17 were significantly reduced in O/AL rats compared with Y/AL rats in all tissues examined, and in many cases, the amount of HMGs of O/CR rats were increased by varying degrees from O/AL animals. In G2-phase nuclei of bone marrow, spleen and testis, phosphorylation of HMG proteins was reduced significantly in O/AL rats, but was enhanced in O/CR animals (especially HMG14). These levels of HMGs in O/CR animals, altered by age and diet dependent factors, reflect a condition which is more reminiscent of Y/AL than O/AL animals.

Aging↗
PubMed1991

Circadian variation in alloxan sensitivity of mice as indicated by mortality and blood glucose alteration.

The objective of this study was to determine in mice if a time-dependent pancreatic beta-cell susceptibility to alloxan could be correlated to daily changes in blood glucose levels and to monitor the pattern of blood glucose at various times of day as mice became diabetic. Food was removed from mice standardized to a 12-h light:dark cycle (lights on at 0600 h CST, during the month of June) at 12 h before subcutaneous injection with 0.27 mg/g of alloxan. Six groups of 30 fasted mice were injected at 4-h intervals. Blood glucose levels were measured from each group immediately prior to injection, and at 2, 4, 8, 12, 24, 48, and 216 h after treatment. Animals receiving alloxan during the early- to middark period had an increase in blood glucose after 2 h, followed by a decline to hypoglycemic levels between 4 and 8 h, and recovery to hyperglycemic levels 48 h after alloxan exposure. Three and 30% of these animals were dead at 8 and 48 h, respectively. Mice treated during the midlight span had decreased blood glucose levels 2 h after alloxan treatment followed by an increase to diabetic hyperglycemia within 48 h. Twenty-three and 70% of the animals treated at 1430 h were dead at 8 and 48 h, respectively. At 216 h, total mortality was 45.6% and 81 of the 98 surviving mice were hyperglycemic. These data suggest a greater sensitivity to alloxan during the midlight resting period of the mice. This may be the result of increased sensitivity to the insulin released from the beta cells when alloxan was given during the light span.

Alloxan↗
PubMed1991

Biomarkers of aging: changes in circadian rhythms related to the modulation of metabolic output.

Twenty-four hour (circadian) rhythmicity is an important component of biological variability associated with studies relating to biomarkers of aging. Chronobiological testing techniques must be utilized because (1) many variables that are related to the modulation of metabolic output vary dramatically at different times of the day; (2) various experimental variable and treatment groups must be synchronized with environmental cues that control circadian rhythms; and (3) multiple circadian variables may interact together to modulate the rate of aging. The rhythm for physiological factors such as whole animal metabolic output, body temperature, heart rate, urine flow, potassium, etc. were found to be dissociated or altered by the senescence process; behavioral variables such as spontaneous activity, wheel running, feeding and drinking, verbal performance, as well as sleep-wakefulness rhythms, seem to be accurate predictors of biological age. Circadian rhythms for a variety of enzymes of intermediary metabolism which are directly associated with energy metabolism have been well documented. These well-defined rhythms of enzyme activity have also been shown to degenerate with aging. Rhythms tend to lose amplitude as activity falls with age and as a general loss of regulation (especially time of day where maximal activity might be found) of activity across the 24-h span occurs. As with behavioral variables, changes in enzyme rhythms appear to accurately predict aging. Generally speaking, the loss of temporal organization with age, characterized by decreased circadian amplitude, loose internal synchronization, and poor response to external environmental time queues, is associated with poor health states and decreased longevity. Temporal rhythms for whole animal parameters are highly correlated with molecular events, such as regulation of cellular metabolism. DNA repair, and gene expression. Automated data acquisition and process control systems will be required for future chronobiological studies to develop biomarkers of aging.

Aging↗
PubMed1990

Effect of chronic caloric restriction on the circadian regulation of physiological and behavioral variables in old male B6C3F1 mice.

The circadian rhythms of food and water consumption, the number of feeding and drinking episodes, oxygen consumption, carbon dioxide production, respiratory quotient, gross motor activity, and body temperature were measured in male B6C3F1 mice that were fed ad libitum (AL) or fed a caloric-restricted diet (CR). The CR regimen (60% of the normal AL consumption) was fed to mice during the daytime (5 hr after lights on). CR animals exhibited fewer feeding episodes but consumed more food per feeding bout and spent more total time feeding than AL mice. It appears that CR caused mice to change from their normal "nibbling behavior" to meal feeding. Compared to AL animals, the mean body temperature was reduced in CR animals, while the amplitude of the body temperature rhythm was increased. Spans of reduced activity, metabolism, and body temperature (torpor) occurred in CR mice for several hours immediately before feeding, during times of high fatty acid metabolism (low RQ). The acute availability of exogenous substrates (energy supplies) seemed to modulate metabolism shifting metabolic pathways to promote energy efficiency. CR was also associated with lower DNA damage, higher DNA repair, and decreased proto-oncogene expression. Most of the circadian rhythms studied seemed to be synchronized primarily to the feeding rather than the photoperiod cycle. Night-time CR feeding was found to be better than daytime feeding because the circadian rhythms for AL and AR animals were highly synchronized when this regimen was used.

Aging↗
PubMed1990

A preliminary report of circadian effects of interleukin-2 (IL-2) on the activity of enzymes of intermediary metabolism of mice.

Since it previously has been reported that IL-2 has profound circadian dependent effects upon DNA synthesis in the liver of mice (Scheving et al., 1988; Tsai et al., 1988) the effects of IL-2 on enzyme activities were studied. The objective was to determine the effect of IL-2 when administered at different times to mice who were fed ad libitum, and standardized to 12 h of light alternating with 12 h of dark. Three groups were injected intraperitoneally with either 1 or 4 mg/kg of IL-2, one group was given the vehicle only. The treatment time for each dose and the vehicle was a 2 h into the light for one group and the other was at 2 h into the dark span. Subgroups of 5 mice were killed 4, 8, 12, 16, 20, 24, and 30 h after each treatment, livers were taken and frozen to await preparation and analysis of enzyme activities by our standard procedures. When treatment was in the light span IL-2 had no statistically significant effect on enzymes of lipid, carbohydrate or amino acid metabolism. On the contrary when treatment was given in the dark span IL-2 produced statistically significant increases in enzymes of glycolysis, and lipid synthesis beginning 8 h after treatment (changes ranged from 20 to 43%) with both the higher and lower doses (higher doses always yielded higher activities), and these activities continued to increase through the 24 h post-treatment span (changes ranged from 42 to 64%). At 30 h, activities were returning to normal levels. Amino acid metabolism, on the other hand, was decreased during these post-treatment times (the range of decrease was from 18 to 44%). Thus, we report for the first time that the duration of time, pathway affected, as well as the magnitude of the effect seen and the dosage of IL-2 were all circadian-stage dependent even with two time point samplings. We believe, however, that these two time points represent different critical extremes in liver metabolism, but studies with denser sampling are planned. Interleukin-2 was generously supplied by Cetus Corp. of Emeryville, CA.

Alanine Transaminase↗
PubMed1990

Effect of chronic caloric restriction on hepatic enzymes of intermediary metabolism in aged B6C3F1 female mice.

Caloric restriction (CR) extends maximum life span and significantly retards the rate of occurrence of most age-associated degenerative diseases. The effect of CR in female mice on several hepatic enzymes was examined after 33 month old mice were killed at either the onset of dark, the onset of light or the mid-dark span. Animals had been singly caged with 12 hr of light followed by 12 hr of dark. All feeding was in the early dark span. CR mice were given 60% of the caloric intake of ad libitum fed mice throughout their lives (CR was initiated at 14 weeks of age). Livers were frozen to await preparation and then analysis for 14 enzymes of intermediary metabolism by our standard procedures. Enzymes of gluconeogenesis and amino acid metabolism were increased at all times due to CR. Enzymes of glycolysis and lipid metabolism were decreased at all times. However, maximum differences between ad libitum and CR mice occurred during the mid-dark span (this is the time of normal acrophase in younger mice). Circadian variation was lost and mesors changed for nearly all enzymes measured from mice that had been fed ad libitum. CR mice were found to maintain circadian variation of activities and activity profiles were similar to those seen in younger ad libitum fed mice. These observations suggest that the mechanism through which CR elicits its effects may involve a circadian component.

Aging↗
PubMed1990

Chronobiology of exercise: the influence of scheduling upon glycemic responses of control and of subjects with diabetes mellitus.

Exercise programs contribute significantly to: a) improve cardiovascular fitness; b) lower blood pressure in hypertension; and c) facilitate glycemic control in subjects with Diabetes Mellitus (DM). The mechanisms involved in promoting the above responses remain undetermined. Circadian phases at which exercise is applied could play a major role in optimizing the individual's physiological responses to exercise. In a pilot study, controls and a subject with Insulin Dependent Diabetes Mellitus (IDDM) were exercised at 0800 and 2000 hours: pedaling on an exercycle for 30 minutes at rates that maintained tachycardia at 70% of maximum reserve heart rates (Karvomen et al., 1957). All subjects were on "standard" rest-activity schedules (rest 2300-2400 to 0600-0700) and were allowed a single 360 ml Sustacal meal either at 2400 hours or at 1200 hours; i.e., 8 hours preceding the exercise program. Blood samples were obtained for determinations of glucose (finger tip) just before exercise (0 time) and at 10, 20, 30, 40 and 60 minutes of exercise/post exercise periods. The results suggest that non-diabetics experience a rapid decrease in blood glucose levels which does not recover during the 60 minute sampling time when exercise was in the morning. However, when these individuals exercised during the evening, glucose levels did not fall as much on a percentage basis and full recovery was obtained within 40-60 minutes. In the case of the diabetic patient, after morning exercise, glucose levels did not decline and after 40 minutes had risen above resting glucose levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1989

Circadian variation of epidermal growth factor receptor in mouse liver.

The liver undergoes a biochemical and morphological circadian transformation. In this paper, we document circadian variation in the binding parameters of the hepatic epidermal growth factor receptor (EGFR). Liver membranes were prepared from ad libitum fed or fasted male CD2F1 mice killed at different circadian phases at 4 h intervals. Bmax (maximum binding) and Kd (dissociation constant) varied in a rhythmic fashion. The range of change for Bmax along the 24 h time scale was 423%. For Kd, it was 162%. Both peaked late in the dark span, and decreased late in the light span. Fasting and EGF treatment reduced Bmax and the amplitude of circadian variation.

Animal Nutritional Physiological Phenomena↗
PubMed1989

Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat.

In the present study, a number of physiological and behavioral measures that are related to metabolism were continuously monitored in 19-month-old male Fischer 344 rats that were fed ad libitum or fed a caloric restricted diet. Caloric restricted rats ate fewer meals but consumed more food during each meal and spent more time eating per meal than did rats fed ad libitum. Therefore, the timing and duration of meals as well as the total number of calories consumed may be associated with life extension. Average body temperature per day was significantly lower in restricted rats but body temperature range per day and motor activity were higher in restricted rats. Dramatic changes in respiratory quotient, indicating rapid changes in metabolic pathway and lower temperature, occurred in caloric restricted rats when carbohydrate reserves were depleted. Lower body temperature and metabolism during this time interval may result in less DNA damage, thereby increasing the survival potential of restricted rats. Nighttime feeding was found to synchronize physiological performance between ad libitum and caloric restricted rats better than daytime feeding, thereby allowing investigators to distinguish the effects of caloric restriction from those related solely to the time-of-day of feeding.

Animals↗
PubMed1989

Effects of aging and caloric restriction on hepatic drug metabolizing enzymes in the Fischer 344 rat. I: The cytochrome P-450 dependent monooxygenase system.

The effects of long-term caloric restriction on the hepatic cytochrome P-450 dependent monooxygenase system were investigated in the 22-month-old Fischer 344 rat. Caloric restriction decreased the age-related changes in hepatic testosterone metabolism, which are associated with demasculinization of the liver. Caloric restriction also increased hepatic microsomal testosterone 6 beta-hydroxylase, lauric acid 12-hydroxylase and 4-nitrophenol hydroxylase activities over corresponding values in both ad libitum fed 22-month and 60-day-old control male rats. This suggests that cytochrome P-450 isozymes, P-450 pcn1&2, P-452 and P450j may be induced by caloric restriction. Such changes in cytochrome P-450 isozyme profiles could result in altered carcinogen activation, radical formation or drug detoxication in the calorically restricted rat.

Aging↗
PubMed1989

Effects of aging and caloric restriction on hepatic drug metabolizing enzymes in the Fischer 344 rat. II: Effects on conjugating enzymes.

The effects of long-term caloric restriction on the hepatic phase II drug metabolizing enzymes were investigated in the male Fischer 344 rat. Rats that had been restricted to 60% of their pair-fed control consumption from 14 weeks post-partum exhibited altered conjugating enzyme activities at 22 months. Caloric restriction significantly reduced the age-related decrease in glutathione-S-transferase activity towards 1,2-dichloro-4-nitrobenzene, but did not significantly alter the age-related changes in UDP-glucuronyltransferase or sulfotransferase activities towards hydroxysteroids. Caloric restriction appeared to increase hepatic microsomal UDP-glucuronyltransferase activity toward bilirubin and gamma-glutamyltranspeptidase activities. These observations suggest that caloric restriction has multiple effects on the hepatic phase II drug metabolizing enzymes in the rat. Such effects may alter hepatic metabolism and activation or detoxification of drugs and carcinogens.

Aging↗