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Biomedical subjects

P H Duffy

Publications and source records attributed to P H Duffy.

18 recordsLinked to original sources
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

Oxidative DNA damage levels in rats fed low-fat, high-fat, or calorie-restricted diets.

Increased fat and caloric content of the diet has been associated with increased mammary tumor incidence. The dietary modulation of cellular redox state may be one mechanism behind this association. We have examined the effects of changes in dietary fat and caloric intake on the levels of 5-hydroxymethyluracil in DNA from rat liver and mammary gland. Female Fischer 344 rats, 40 days old, were maintained on 3% (low-fat), 5% (control), or 20% (high-fat) corn oil diets for 2 weeks. A fourth group of rats had the same daily fat intake as the control group, but total caloric intake was restricted by 40%. As a measure of oxidative DNA damage, 5-hydroxymethyluracil levels were measured in the DNA extracted from liver and mammary gland by gas chromatography-mass spectrometry. 5-Hydroxymethyluracil levels in the liver DNA of the low-fat, high-fat, and calorie-restricted groups were decreased relative to that of control, but the only significant decrease was in the calorie-restricted group (p less than 0.01). In the mammary gland DNA, statistically significant decreases in damage were found in each group relative to control (p less than 0.05). The relationship between fat in the diet and oxidative stress is thus complex. These results show that changes in dietary intake of both fat and calories can modulate oxidative DNA damage levels, and the effect of diet was more clearly evident in the DNA from mammary gland than in DNA from liver.

Animals↗
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

Effect of chronic caloric restriction on the synchronization of various physiological measures in old female Fischer 344 rats.

A variety of physiological and behavioral parameters which relate to metabolism were continuously monitored in 18 month old female Fischer 344 rats which were maintained on either ad libitum or reduced calorie diets. Caloric restriction (CR) stimulated average motor activity per day, the duration of each feeding episode, food consumed per episode, and water consumed per gram lean body mass (LBM). However, CR limited total food consumption, feeding time, number of feeding episodes per day, total eating and drinking time, and the daily ratio of food consumed to water consumed, CR also decreased average body temperature per day, O2 consumption, CO2 production, and respiratory quotient. A variety of parameters concerning water consumption were not affected. CR rats ate their food immediately when food was presented during the light span, while ad libitum fed animals ate numerous small meals throughout the entire dark span. An anticipatory response to restricted feeding was also noted. Total motor activity, metabolism, and body temperature increased just prior to scheduled feeding and reached maximum values shortly after feeding, suggesting that these parameters were highly synchronized to feeding. Females and males were found to respond to caloric restriction in a similar fashion. Dramatic changes in respiratory quotient and body temperature suggest rapid shifts between metabolic pathways (glycolysis to gluconeogenesis) to obtain optimal efficiency. Lower body temperature and metabolism may provide protection against DNA damage, thereby increasing the survival potential of restricted rats. These responses may provide insight into the mechanisms by which caloric restriction acts to extend life span.

Aging↗
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↗
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↗
PubMed1989

Effect of chronic caloric restriction on hepatic enzymes of intermediary metabolism in the male Fischer 344 rat.

It is well established that caloric restriction extends life span and significantly retards the rate of occurrence of most age-associated degenerative disease processes. A paucity of data exists relative to the mechanisms by which caloric restriction accomplishes these events. We have examined the effect of caloric restriction in rats on several hepatic enzymes of intermediary metabolism. The activities of glycolytic and supporting enzymes including lactate dehydrogenase, pyruvate kinase, sorbitol dehydrogenase, and alcohol dehydrogenase were all decreased in response to caloric restriction. Fructose 1-phosphate aldolase and creatine phosphokinase were not altered. Likewise, enzymes associated with lipid metabolism (malic enzyme and glycerokinase) were reduced (fatty acid synthetase was reduced, but not to a statistically significant degree). Activities of enzymes supporting gluconeogenesis (glutamate oxaloacetate transaminase, tyrosine aminotransferase, glutamate pyruvate transaminase, glutamate dehydrogenase, amino acid oxidase, malate dehydrogenase, and glucose 6-phosphatase) were either unchanged or increased significantly by caloric restriction. Glucagon levels were decreased. Comparisons between young ad libitum fed and older calorically restricted rats revealed similar but not identical metabolic activity. These results suggest that caloric restriction produces an effect on intermediary metabolism, favoring the role of glucagon and glucose synthesis; but limiting the role of insulin and glucose catabolism in the liver. The former observation provides for the efficient support of peripheral tissues and the latter a level of energy production necessary only for self maintenance. Limited lipid metabolism suggests decreased potential for fatty acid epoxide formation and free radical damage to cellular macromolecules. Additionally, caloric restriction may delay the progressive age associated changes in the activities of some of the enzymes investigated.

Age Factors↗
PubMed1989

The effect of dietary restriction on myc protooncogene expression in mice: a preliminary study.

The effect of chronic dietary restriction on the expression of the c-myc protooncogene was determined in the livers of a hybrid mouse strain (C57Bl6 x C3H F1 hybrid) at three time points during a 24-h period: 1 h after lights on (1 HALO), 5 h prior to feeding (12 HALO), and 2 h after feeding (19 HALO). In addition, in whole animals studies, changes in core body temperature were monitored. In mice which had been subjected to a chronic diet restriction (60% of the intake of ad libitum controls), c-myc expression was significantly reduced at 1 HALO and 19 HALO compared to corresponding ad libitum animals. In addition, significant differences in c-myc expression were found between time points, in both the ad libitum and restricted groups, suggesting that myc protooncogene expression in the liver may be regulated in a circadian fashion. C-myc expression may correlate with body temperature, suggesting a possible association with metabolic output.

Animals↗
PubMed1987

The turnover of radiolabeled nuclear proteins in rats exposed to environmental and chemical stress.

Exposure to a 12 h light/12 h dark (L/D) cycle for 1 month, followed by reversal to a 12 h D/12 h L (D/L) cycle stimulated within 18 h the incorporation of [3H]leucine and [32P]orthophosphoric acid into new proteins (130-25 kDa) in the G0 phase of the cell cycle of the non-regenerating and regenerating rat liver as observed in two-dimensional gel autoradiograms. Six additional proteins from the rat submaxillary gland (130-20 kDa) revealed labeling with 32P within 3 h following combined administration of isoproterenol and sodium arsenite. Labeling disappeared within 7 days for all stressed proteins.

Animals↗
PubMed1987

Effect of age and torpor on the circadian rhythms of body temperature, activity, and body weight in the mouse (Peromyscus leucopus).

Age-related alterations in homeostatic mechanisms, as measured by changes in circadian rhythms, have been reported in the literature. The purpose of the present study was to determine if changes in the circadian rhythms of motor activity, body temperature, and body weight occur with age in the long-lived mouse, Peromyscus leucopus, and to determine if the incidence of torpor (hypothermia) was age-dependent. Young and old mice were entrained to an LD 12:12 cycle, and then physiological and behavioral performance was monitored by a data-acquisition system. The major differences between the 6-month and 60-72-month age groups were the following. Significant episodes of torpor occurred in a high percentage of old mice at 0600 hr on consecutive days, but young mice showed no evidence of torpor when food was provided ab libitum. Torpor in young mice was found to occur only during starvation conditions. Old animals phase in and out of torpor over an interval of several days; high-amplitude rhythms and good synchronization of activity and temperature occurred when torpor was expressed, and low-amplitude rhythms, poor synchronization between temperature and activity, and a phase shift of body-weight acrophase occurred on days when torpor was not expressed. Significant changes in acrophase and amplitude occurred between individual animals and days in the old group; no significant change in acrophase and amplitude was observed in the young group. Population-mean cosinor analysis revealed a significant age-related decrease in amplitude and mesor, but no significant change in acrophase was found.

Aging↗
PubMed1979

Odontomas in Peromyscus leucopus.

A colony of Peromyscus leucopus was established 15 years ago from animals trapped in the deciduous forest at Argonne National Laboratory, Argonne, Illinois. A roentgenographic survey of the skeletons of 189 of these untreated animals dying during a 13-month period disclosed 48 odontogenic growths in 21 of the mice. These growths were diagnosed on histopathologic examination as complex odontomas, the incidence of which was higher in males than in females. In this relatively small sample, these benign tumors appeared to be associated with youth rather than old age.

Age Factors↗
PubMed1979

Genetic relation of life span to metabolic rate for inbred mouse strains and their hybrids.

Average life spans were estimated for the male progeny from 21 of the 25 possible matings of 5 inbred mouse strains. Oxygen consumption was measured in an open system over a 48-hour interval. Resting metabolism, Mre, and average metabolism, Mav, were determined at 6-8 months of age, and at 24-34 months. Body weight, W, was determined at the time metabolism was measured. Life span, L, is negatively correlated with Mre and Mav, and positively correlated with W at both ages of measurement. This is in accord with the metabolic wear factor that had previously been established among 85 different species of mammals. A new metabolism variable, the energy partition coefficient, defined as the ratio of average to resting metabolic rate, Mav/Mre, has a parabolic relation to body weight, i.e., is maximal at an intermediate body size. The squared body weight deviation in turn has a negative correlation with life span. The correlation of L with Mav/Mre is positive, as expected, but not significant. These data suggest the existence of a longevity factor dependent on the partition of energy between the phasic metabolism of activity and the continuous maintenance metabolism.

Aging↗
PubMed1976

Age-dependence of body weight and linear dimensions in adult Mus and Peromyscus.

Head plus body length (HBL), tail length (TL) and body weight (BW) were measured on two species of small myomorph rodents, Mus musculus and Peromyscus leucopus, throughout adult life. Both sexes of Mus show about a 15 per cent increase of HBL and TL between 5 and 24 months of age, and a BW increase of about 47 per cent. There is no age-trend of HBL in either sex of Peromyscus between 5 and 67 months of age, while TL increases about 7 per cent. In both species, cessation of skeletal growth is followed by a steady decrement of body mass, which averages about 0.23 per cent per month throughout adult life for the two sexes of Peromyscus, and over two per cent per month after cessation of skeletal growth in Mus. The weight loss in Mus in the last half of the lifespan is shown to be associated with age, rather than with the duration of subsequent survival. This evidence against the hypothesis that the late weight loss in Mus is due to terminal disease.

Age Factors↗