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Results for “Caloric Restriction”

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PubMed2004

Caloric restriction, metabolic rate, and entropy.

Caloric restriction increases life span in many types of animals. This article proposes a mechanism for this effect based on the hypothesis that metabolic stability, the capacity of an organism to maintain steady state values of redox couples, is a prime determinant of longevity. We integrate the stability-longevity hypothesis with a molecular model of metabolic activity (quantum metabolism), and an entropic theory of evolutionary change (directionality theory), to propose a proximate mechanism and an evolutionary rationale for aging. The mechanistic features of the new theory of aging are invoked to predict that caloric restriction extends life span by increasing metabolic stability. The evolutionary model is exploited to predict that the large increases in life span under caloric restriction observed in rats, a species with early sexual maturity, narrow reproductive span and large litter size, and hence low entropy, will not hold for primates. We affirm that in the case of humans, a species with late sexual maturity, broad reproductive span and small litter size, and hence high entropy, the response of life span to caloric restriction will be negligible.

Animals↗

PubMed1988

Effect of acute caloric restriction on work efficiency.

Whether caloric restriction can alter the efficiency of muscular work raises important questions regarding the control of energetic coupling processes and the efficacy of exercise as a treatment for obesity. To address these issues, oxygen uptake (VO2) was determined at rest and during incremental cycle ergometry in 13 moderately obese (133 +/- 3% ideal body weight, means +/- SEM) women during weight maintenance and after 3 wk of caloric restriction (800 kcal/d). Work efficiency was calculated from the linear portion of the VO2-work rate relationship. Caloric restriction decreased body weight 4.0 +/- 0.4 kg (p less than 0.05), VO2 at rest 32 +/- 3 mL/min (p less than 0.05), and VO2 during unloaded (0 W) cycling 47 +/- 14 mL/min (p less than 0.05). However, work efficiency was unchanged (ie, -0.3 +/- 1.2%, NS). We conclude that, despite metabolic adaptations resulting in decreased energy expenditure at rest and during zero Watt cycling, acute caloric restriction does not alter work efficiency.

Adult↗

PubMed2003

Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth.

Caloric imbalance, particularly in critical periods of growth and development, is often the underlying cause of growth abnormalities. Serum levels of leptin are elevated in obesity and are low in malnutrition and malabsorption. The aim of the present study was to determine whether leptin integrates energy levels and growth in vivo, as shown previously in our ex vivo experiments, even in the presence of caloric restriction. In the first part of the study, mice were divided into three groups. Two groups were fed ad libitum and received leptin or vehicle only, and the third group was pair-fed with the group injected with leptin to dissociate leptin's effect on growth from its effect on food consumption. Mice given leptin had a significantly greater tibial length than untreated pair-fed animals and a similar tibial length as control mice fed ad libitum despite their lower weight. In addition, leptin significantly increased the overall size of the epiphyseal growth plate by 11%. On immunohistochemistry and in situ hybridization studies, leptin stimulated both the proliferation and differentiation of tibial growth plate chondrocytes without affecting the overall organization of the plate. There was also a marked increase in the expression and level of IGF-IR. In the second part of the study, two groups of mice were fed only 60% of their normal chow; one was injected with leptin, and the other was injected with vehicle alone. Caloric deprivation by itself reduced serum levels of IGF-I by 70% and the length of the tibia by 5%. Leptin treatment corrected the fasting-induced growth deficiency, but further reduced the level of serum IGF-I. These results indicate that leptin stimulates growth even in the presence of caloric restriction independently of peripheral IGF-I.

Animals↗

PubMed2005

Analgesic effects of dietary caloric restriction in adult mice.

Nociception was studied in male mice, mostly of the C57BL/6 strain, during continuous or prolonged restriction of caloric intake (60% of ad-libitum) from midlife to senescence (up to 105 weeks). Restricted mice showed fewer licking or biting responses 20-60 min after hind paw injection of 5% formalin at 46 and 70 weeks, but not at 93 weeks. Also, they showed longer response latencies around 46 weeks of age in the 52 degrees C hot-plate test, which partial tail amputation failed to affect, although it did produce at least 2 weeks of chronic neuropathic hypersensitivity in ad libitum controls. Injection of collagen subcutaneously at 36-42 weeks led to chronic hyperalgesia in the DBA/1 but not the C57BL/6 strain, measured weekly by the barely nociceptive 50 degrees C hot-plate test to minimize damage. This collagen-induced arthritic hyperalgesia was then gradually and reversibly blocked during 9-15 weeks of caloric restriction starting at 53-58 weeks. In longitudinal trials on normal mice, performed every 2-4 weeks between 42 and 105 weeks with the 50 degrees C hot-plate, caloric restriction led to altered latencies (higher relative to controls) only in the last 10-20 weeks, perhaps because it delayed the onset of age-related peripheral neuropathies. In conclusion, long-term caloric restriction leads to significant hypoalgesia in pre-senescent mice subjected to above-threshold pain of widely different durations, the effect disappearing at later ages unless spontaneous neuropathies become influential. A reduction in cumulative food intake thus appears to generate antinociceptive signals in adult male mice, perhaps serving specifically to promote riskier behavior during prolonged food shortages.

Acute Disease↗

PubMed1997

Combined effects of caloric restriction and branched-chain amino acid supplementation on body composition and exercise performance in elite wrestlers.

Twenty-five competitive wrestlers restricted their caloric intake (28 kcal.kg-1.day-1) for 19 days, using a hypocaloric control (hC, n = 6), hypocaloric high-protein (hHP, n = 7), hypocaloric high-branched-chain amino acid (hBCAA, n = 6), hypocaloric low-protein (hLP, n = 6) diet to determine the effects of caloric restriction on body composition and performances versus control diet (C, n = 6). Anthropometric parameters (weight, percent body fat) and adipose tissue (AT) distribution measured by magnetic resonance imaging (MRI) obtained before and after diet, were compared. A significant highest body weight loss (-4 kg, p < 0.05) and decrease in the percent of body fat (-17.3%, p < 0.05) were observed for subjects of the hBCAA group. Subjects of the hBCAA group exhibited a significant reduction (-34.4%, p < 0.05) in abdominal visceral adipose tissue (VAT). There was no change in aerobic (VO2max) (p > 0.75) and anaerobic capacities (Wingate test) (p > 0.81), and in muscular strength (p > 0.82). We conclude that under our experimental conditions, the combination of moderate energy restriction and BCAA supplementation induced significant and preferential losses of VAT, and allowed maintainance of a high level of performance.

Amino Acids, Branched-Chain↗

PubMed2005

Caloric restriction prevents aging-associated changes in spike-mediated Ca2+ accumulation and the slow afterhyperpolarization in hippocampal CA1 pyramidal neurons.

In hippocampal pyramidal neurons from aged animals voltage-gated Ca2+ entry and the slow, post-burst afterhyperpolarization are enhanced. As a result, there is a decrease in neuronal excitability and, in turn, an alteration in synaptic plasticity. Restricting the caloric intake of a rodent is a well-known paradigm for increasing lifespan and ameliorating a number of neurodegenerative features of aging, including deficits in synaptic plasticity and cognition. Here we show in rat CA1 pyramidal neurons from aged animals (18-20 months old) that a restricted diet prevents the enhancement of dendritic spike-mediated Ca2+ accumulation. In contrast, no significant changes in the rates of Ca2+ recovery were observed suggesting that Ca2+ clearance mechanisms are not affected by aging or caloric restriction. Lastly, we found that caloric restriction also prevented the aging-associated increase in the slow, post-burst afterhyperpolarization. Our results suggest that caloric restriction-sensitive changes in Ca2+ accumulation and membrane excitability may in part account for the protective effects of dietary restriction on synaptic plasticity and learning deficits in aged animals.

Action Potentials↗

PubMed1998

The genetics of caloric restriction in Caenorhabditis elegans.

Low caloric intake (caloric restriction) can lengthen the life span of a wide range of animals and possibly even of humans. To understand better how caloric restriction lengthens life span, we used genetic methods and criteria to investigate its mechanism of action in the nematode Caenorhabditis elegans. Mutations in many genes (eat genes) result in partial starvation of the worm by disrupting the function of the pharynx, the feeding organ. We found that most eat mutations significantly lengthen life span (by up to 50%). In C. elegans, mutations in a number of other genes that can extend life span have been found. Two genetically distinct mechanisms of life span extension are known: a mechanism involving genes that regulate dauer formation (age-1, daf-2, daf-16, and daf-28) and a mechanism involving genes that affect the rate of development and behavior (clk-1, clk-2, clk-3, and gro-1). We find that the long life of eat-2 mutants does not require the activity of DAF-16 and that eat-2; daf-2 double mutants live even longer than extremely long-lived daf-2 mutants. These findings demonstrate that food restriction lengthens life span by a mechanism distinct from that of dauer-formation mutants. In contrast, we find that food restriction does not further increase the life span of long-lived clk-1 mutants, suggesting that clk-1 and caloric restriction affect similar processes.

Aging↗

PubMed2001

Caloric restriction in primates.

Caloric restriction (CR) remains the only nongenetic intervention that reproducibly extends mean and maximal life span in short-lived mammalian species. This nutritional intervention also delays the onset, or slows the progression, of many age-related disease processes. The diverse effects of CR have been demonstrated many hundreds of times in laboratory rodents and other short-lived species, such as rotifers, water fleas, fish, spiders, and hamsters. Until recently, the effects of CR in longer-lived species, more closely related to humans, remained unknown. Long-term studies of aging in nonhuman primates undergoing CR have been underway at the National Institute on Aging (NIA) and the University of Wisconsin-Madison (UW) for over a decade. A number of reports from the NIA and UW colonies have shown that monkeys on CR exhibit nearly identical physiological responses as reported in laboratory rodents. Studies of various markers related to age-related diseases suggest that CR will prevent or delay the onset of cardiovascular disease, diabetes, and perhaps cancer, and preliminary data indicate that mortality due to these and other age-associated diseases may also be reduced in monkeys on CR, compared to controls. Conclusive evidence showing that CR extends life span in primates is not presently available; however, the emerging data from the ongoing primate studies strengthens the possibility that the diverse beneficial effects of CR on aging in rodents will also apply to nonhuman primates and perhaps ultimately to humans.

Aging↗

PubMed1985

Caloric restriction does not alter thyrotropin secretion in hypothyroidism.

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.

Adult↗

PubMed1997

Effect of caloric restriction on pre-malignant and malignant stages of mammary carcinogenesis.

Caloric restriction has documented beneficial effects on numerous diseases including cancer, yet the mechanism(s) that accounts for these wide ranging benefits is unknown. Part of the difficulty in defining mechanisms has been the long-term nature of experimental protocols in which these beneficial effects have been observed and the inherent difficulty of investigating mechanisms in such studies. The experiments reported were designed: (1) to determine if caloric restriction would inhibit mammary carcinogenesis in a model for this disease process that is 35 days in duration; (2) to determine if progression from pre-malignant to malignant stages of mammary carcinogenesis was affected by caloric restriction; and (3) to explore whether the effects of caloric restriction were associated with changes in adrenal function. Mammary carcinogenesis was induced in female Sprague-Dawley rats by the i.p. administration of 1-methyl-1-nitrosourea (50 mg/kg body weight) at 21 days of age. Rats were randomized to one of four dietary treatment groups: ad libitum fed, or restriction of food intake to 90, 80 or 60% of the ad libitum intake. Rats were palpated for detection of mammary tumors and all mammary lesions excised at necropsy were histologically classified. Twenty-four-hour collections of urine were obtained at weekly intervals throughout the 35-day experiment. Urine was assayed for corticosterone by direct radioimmunoassay. Caloric restriction resulted in both a dose dependent prolongation of latency to palpable carcinomas (P < 0.01) and a reduction in final incidence of mammary cancer; the dose response was linear (P < 0.05). The percentage of pre-malignant mammary lesions in a group increased with increasing degree of caloric restriction, whereas the percentage of carcinomas decreased (P < 0.05). The level of cortical steroid increased linearly with increasing caloric restriction (P < 0.01) an effect that was not attenuated over time. Poisson regression analyses with the number of cancers per rat as the dependent variable, level of caloric restriction as the independent variable and urinary cortical steroid excretion as a co-variate were performed. These analyses indicated that the variation in cancers per rat, irrespective of the treatment group to which an animal was assigned, could be accounted for by urinary cortical steroid excretion (P<0.05); i.e. urinary cortical steroid excretion was an independent predictor of an animal's carcinogenic response. The data reported in this study support the use of a short term model to study the mechanism(s) by which caloric restriction inhibits mammary carcinogenesis and point to both a stage in the disease process, the conversion of pre-malignant to malignant cells, and a target tissue (adrenal gland) and chemical species (adrenal cortical steroid) that may be involved in mediating the protective effects of energy restriction. These data indicate the feasibility of identifying a chemical basis for the protective effect of caloric restriction that is independent of energy restriction per se and this, in turn, indicates that it may be possible to circumvent the practical problem of implementing a program of chronic energy restriction in human populations, yet still achieve the wide-ranging health benefits of such a program.

Adenocarcinoma↗

PubMed2001

Parasite infection and caloric restriction induce physiological and morphological plasticity.

To investigate the effects of parasitism and caloric restriction on morphology (body composition, organ mass) and physiology (resting metabolism, intestinal glucose transport capacity), we gave laboratory mice intestinal parasites (Heligmosomoides polygyrus, Nematoda), 30% caloric restriction, or both. Calorically restricted mice had smaller body mass, enhanced glucose transport capacity, and lower resting metabolism than ad libitum-fed mice. Parasitized mice maintained body mass, had diminished intestinal glucose transport capacity, and greater resting metabolism than unparasitized mice. Parasitized, calorically restricted mice had smaller organ masses than parasitized, ad libitum-fed mice and did not increase their glucose uptake rate as much as unparasitized, calorically restricted mice. There was a significant interaction between caloric restriction and parasite status for morphological variables but not for physiological variables. Knowing the types of phenotypic changes that occur with simultaneous parasitism and caloric restriction will provide insight into understanding human helminthiasis in food-restricted communities and also how wild animals cope with environments where parasitism and seasonal food restriction are common.

Animals↗

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↗

PubMed2004

Sexual dimorphism in the response of adipose mass and cellularity to graded caloric restriction.

OBJECTIVE: To investigate the effects of mild to moderate caloric restriction on parameters of body growth, fat mass, and adipose tissue cellularity in female and male Wistar rats. RESEARCH METHODS AND PROCEDURES: Three-month-old female and male Wistar rats were subjected to a chronic, mild to moderate caloric restriction paradigm (5%, 10%, or 20% reduction in caloric intake from ad libitum values) for 6 months. This was accomplished using a unique automated feeder system tailored to the food consumption levels of individual rats. Body weight and length, weight of lean organs, regional adipose mass, and adipose cellularity were measured before and after the diet restriction. RESULTS: Caloric restriction produced proportional decelerations in body weight increases in both genders, without significant changes in body length or lean organ mass. Marked and disproportional reductions in regional adipose tissue mass were produced at all levels of food restriction (even at 5% restriction). An unexpected finding was that in response to graded caloric restriction, female rats preserved adipose fat cell number at the expense of fat cell volume, whereas the converse was seen for male rats. DISCUSSION: These studies demonstrate a sexual dimorphism in the response to mild to moderate degrees of chronic caloric restriction. At low levels of caloric restriction, it is possible to affect regional adipose mass and cellularity while preserving lean organ mass.

Adipocytes↗

PubMed2003

Increased hepatic apoptosis during short-term caloric restriction is not associated with an enhancement in caspase levels.

Long-term caloric restriction extends lifespan, probably through a reduction in radical production and attenuation of oxidative stress. In addition, caloric restriction is associated with a reduction and incidence in tumor pathology, probably, in part, via an enhanced rate of apoptosis. We examined whether short-term (2-month) caloric restriction (40% reduction compared to ad libitum controls) increased hepatic apoptosis and if this was associated by an enhancement in various proteolytic caspase (-3, -7, -9, -12) levels and/or a decrease in two potential inhibitors of apoptosis (the x-linked inhibitor of apoptosis protein XIAP and heat shock protein 70). Short-term caloric restriction resulted in a significant decline, compared to ad libitum controls, in both body mass (30%) and liver mass (46%). While hepatic apoptosis (DNA fragmentation) was significantly higher in the caloric restricted rats, this was not associated with any increase in caspase (-3, -7, -9, -12) levels in the liver. Indeed, the levels of caspase-3, -7 and -12 were significantly lower in the caloric restricted group compared to the ad libitum controls and no differences were observed between groups in either XIAP or HSP70 levels. These findings suggest that enhanced hepatic apoptosis observed after 2-months of caloric restriction is not a result of elevated caspase levels at this time, thereby suggesting that an alternative, caspase-independent pathway may be involved.

Animals↗

PubMed1997

The increase in the induction of IL-2 expression with caloric restriction is correlated to changes in the transcription factor NFAT.

The objective of this study was to determine if the increase in the induction of interleukin-2 (IL-2) expression with caloric restriction correlates with changes in binding activity of the IL-2-specific transcription factor NFAT (nuclear factor of activated T cells) and/or the ubiquitous transcription factor AP-1 in T cells from male Fischer 344 rats. Splenic T cells were isolated from young (6-month) and old (24-month) rats fed ad libitum and from old (24-month) rats fed a restricted diet (40% caloric restriction) that began at 6 weeks of age. T cells were stimulated with concanavalin A (Con A) and the expression of IL-2 and the DNA binding activity of the transcription factors NFAT and AP-1 were measured in these cells. We found that the induction of IL-2 activity and mRNA levels decreased with age and that caloric restriction significantly (P < 0.05) reduced the age-related decline in IL-2 expression. The ability of nuclear extracts from T cells isolated from old rats fed ad libitum and restricted old rats to bind to the NFAT oligonucleotide or AP-1 oligonucleotide decreased with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in NFAT but had no significant effect on AP-1 binding activity. We also measured the induction of c-fos and c-jun expression by Con A in T cells from young and old rats fed ad libitum or caloric-restricted diet. The induction of c-fos protein and mRNA levels but not c-jun protein or mRNA levels decreased significantly with age. Caloric restriction significantly (P < 0.05) reduced the age-related decline in c-fos expression but had no significant effect on c-jun expression. Therefore, the increase in IL-2 expression with caloric restriction correlates with an increase in binding activity of transcription factor NFAT and an increase in the expression of c-fos, which is a component of the NFAT-protein complex.

Aging↗

PubMed2006

Gene expression and physiologic responses of the heart to the initiation and withdrawal of caloric restriction.

Aging increases and caloric restriction (CR) decreases morbidity and mortality associated with the cardiovascular system. Using Affymetrix microarrays, we identified changes in heart gene expression induced by aging and CR in male mice. Eight weeks of CR (CR8) reproduced 19% of the long-term CR (LTCR)-related expression changes. Because CR8 begins to extend the life span of these mice, these genes may be keys to its cardioprotective effects. CR8 and LTCR changed gene expression in a manner consistent with reduced remodeling and fibrosis, and enhanced contractility and energy production via lipid beta-oxidation. Molecular and histochemical studies indicated that CR reduced natriuretic peptide precursor type B and collagen expression, and reduced perivascular collagen deposition. We found smaller cardiomyocytes in the left ventricle of old-LTCR mice, suggesting reduced age-related cell death. Eight weeks of control feeding returned 97% of the LTCR-responsive genes to control expression levels. Thus, key CR-induced effects are rapidly responsive to diet, suggesting reduced caloric intake has rapid, positive effects on the heart.

Aging↗

PubMed2004

Fructose metabolizing enzymes from mouse liver: influence of age and caloric restriction.

The influence of caloric restriction (CR) on the activities of liver fructose metabolizing enzymes and metabolite levels were studied in young (3 months) and old (30 months) mice. Fructokinase activity was increased (P<0.05) in both young and old CR mice when compared to controls while triokinase activity was increased (P<0.05) only in old CR versus control mice. Aldolase was not altered by CR in either old or young mice. No age-related differences in activities were observed in controls although a trend towards an increase was observed for triokinase, while significant age-related increases were observed for fructokinase and triokinase, but not aldolase, in CR mice. Both young and old mice on CR showed significant decreases in fructose and fructose-1-phosphate, however, no age-related changes in metabolite levels were observed for either control or CR mice. A fructose-1-phosphate kinase activity was also measured and found to be unchanged in both young and old mice on CR, but the activity was significantly lower in the old mice compared with young. We show here that the enzymes involved in fructose metabolism are influenced by CR and that this could contribute to alterations in gluconeogenesis and glycolysis observed with CR.

Adaptor Proteins, Signal Transducing↗

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↗