Days Of Caloric Restriction Research Articles

Quantitative lung morphology in a regenerative lung model

Einleitung: Several lung diseases are caused by the loss of alveolar septae or alveolar remodelling. But the ability of some mammals to regenerate the lungs provides an opportunity to study regenerative mechanisms. Understanding these mechanisms will provide us with a rationale for the therapeutic purpose. The aim of our study is to decipher lung regeneration at cellular and structural levels using a stereological approach in a murine calorie restriction model. Methoden: Calorie restriction murine model, stereological methods to study structural parameters such as alveolar number, alveolar volume, alveolar wall thickness, hyperplasia (cell number), hypertrophy, total lung volume. Molecular study using real time PCR, immunohistochemistry, semi quantitative PCR. Ergebnisse: We established a calorie restriction murine model with 50% reduction in food intake. We could show that with this food regime, mice lost approx. 30% body mass within 3 days which remained constant up to 10 days. We observed reduction in lung volume measured physically and with the Cavallieri method after 10 days of calorie restriction. We also observed the reduction in alveoli number during starvation. With refeeding, we observed restoration of body mass, lung volume and alveolar number comparable to control mice receiving normal food diet. The stereological measurements are ongoing. Diskussion: Calorie restriction and refeeding has impact on lung volume and has been reported to induce alveolar regression and regeneration, respectively. Our further studies will focus on the structural details, the cell types involved and their characterisation in the lung of starved and refed mice using stereological approaches.

Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism, and plasma adiponectin levels in mice

Calorie restriction (CR) affects adipocyte function and reduces body weight. However, the effects of alternate-day fasting (ADF) on adipose biology remain unclear. This study examined the effects of ADF and modified ADF regimens on adipocyte size, triglyceride (TG) metabolism, and adiponectin levels in relation to changes in body weight and adipose mass. Twenty-four male C57BL/6J mice were randomized for 4 weeks among 1) ADF-25% (25% CR on fast day, ad libitum on alternate day), 2) ADF-50% (50% CR on fast day), 3) ADF-100% (100% CR on fast day), and 4) control (ad libitum). The body weight of ADF-100% mice was lower than that of the other groups (P < 0.005) after treatment. Adipose tissue weights did not change. Inguinal and epididymal fat cells were 35-50% smaller (P < 0.01) than those of controls in ADF-50% and ADF-100% animals after treatment. Net lipolysis was augmented (P < 0.05) in ADF-100% mice, and the contribution from glyceroneogenesis to alpha-glycerol phosphate increased in ADF-50% and ADF-100% mice, whereas fractional and absolute de novo lipogenesis also increased in ADF-50% and ADF-100% animals, consistent with an alternating feast-fast milieu. Plasma adiponectin levels were not affected. In summary, modified ADF (ADF-50%) and complete ADF (ADF-100%) regimens modulate adipocyte function, despite there being no change in body weight or adipose tissue weight in the former group.

Nutritional regulation of adipose tissue apolipoprotein E expression

Apolipoprotein E (apoE) is a multifunctional protein that is highly expressed in human and murine adipose tissue. Endogenous adipocyte apoE expression influences adipocyte triglyceride turnover and modulates the expression of genes involved in lipid synthesis and oxidation. We now demonstrate the regulation of adipose tissue apoE expression by nutritional status in lean and obese mice. Obesity induced by high-fat diet, or by hyperphagia in ob/ob mice, produces significant reduction of adipose tissue apoE expression at the protein and messenger RNA level. Fasting in C57BL/6J mice for 24 h significantly increased apoE protein and messenger RNA levels. In ob/ob mice, transplantation of adipose tissue from lean littermate controls to restore circulating leptin levels produced significant weight loss over 12 wk and also produced an increase in adipose tissue apoE expression. The increase in adipose tissue apoE expression in this model, however, did not require leptin. Adipose tissue apoE was also significantly increased in ob/ob mice after a 48-h fast or after 7 days of caloric restriction. In summary, obesity suppresses adipose tissue apoE expression, whereas fasting or weight loss increases it. From our previous observations, these changes in adipose tissue apoE expression will have significant impact on adipose tissue lipid flux and lipoprotein metabolism. Furthermore, these results suggest adipose tissue apoE participates in defending adipose tissue and organismal energy homeostasis in response to nutritional perturbation.

Is eternal youth scientifically plausible?

As the popular saying goes, the only certain things in life are death and taxes. Given its inevitability, it is no surprise that death—and the ageing process that precedes it—has fascinated humans for centuries. However, it is only with the development of modern science that we are now beginning to understand why our bodies grow older and more frail until we eventually die. As theories have been put forward and refuted, the field of ageing research has oscillated between optimism and pessimism, flitting between the hope that ageing can be slowed or stopped, and the fear that it is inevitable and irreversible. The present mood is one of cautious optimism, based on studies showing that the average and maximum lifespans of rodents can be increased by 25–80% through restricting calorie intake or inhibiting the insulin growth factor 1 (IGF1) receptor (Holzenberger et al , 2003). In the worm Caenorhabditis elegans , in which increased longevity is easier to attain, the restriction of various reproductive and energy‐production pathways has increased maximum lifespan more than sixfold from 20 to 126 days (Kenyon et al , 1993; Murphy et al , 2003). According to Cynthia Kenyon from the University of California, San Francisco, USA, recent research—on C. elegans in her own laboratory, and on mammals, birds, insects, yeast and other organisms by other groups—has ushered in a new era in which significantly increasing human lifespan might be possible. “The real value of the work so far is that we now know lifespan is not a passive phenomenon. It's controlled by genes,” said Kenyon. Although some researchers are wary of drawing too many conclusions about mammalian ageing from work in lower organisms, it is now widely accepted that free radicals are the principal mediators of ageing in most species. During the synthesis of ATP, mitochondria produce …

Calorie-related rapid onset of alveolar loss, regeneration, and changes in mouse lung gene expression.

Calorie restriction, followed by ad libitum refeeding, results, respectively, in loss and regeneration of pulmonary alveoli. We now show 35% of alveoli are lost within 72 h of onset of calorie restriction ((2/3) decreased daily chow intake), and an additional 12% of alveoli are lost over a subsequent 12 days of calorie restriction. Tissue necrosis was not seen. Within 72 h of refeeding, after 15 days of calorie restriction, the number of alveoli returns to precalorie restriction values. Microarray lung gene profiling, in conjunction with Western and RNase protection assay, demonstrate an increase of granzyme and caspase gene expression 2-3 h after onset of calorie restriction. By 12 h, granzyme and caspase expression is no longer increased, but tumor necrosis factor death receptor expression is elevated. At 336 h, Fas death receptor expression is increased. Because granzymes are found only in cytotoxic lymphocytes (CTLs) and natural killer (NK) cells, we suggest calorie restriction activates these cells, initiating a series of molecular events that results in alveolar destruction. The evidence of involvement of CTLs and NK cells and the absence of necrosis are similar to alveolar destruction in chronic obstructive pulmonary disease.

Dbh(-/-) mice are hypotensive, have altered circadian rhythms, and have abnormal responses to dieting and stress.

We used mice deficient in dopamine beta-hydroxylase [Dbh(-/-)] and their littermate controls [Dbh(+/-)] to examine the role of epinephrine (Epi) and norepinephrine (NE) in the maintenance of cardiovascular parameters during 7 days of caloric restriction and acute exposure to environmental stress. Cardiovascular parameters of the mice were monitored using blood pressure radiotelemeters at an ambient temperature of 29 degrees C. Under normal conditions, Dbh(-/-) mice had a low heart rate, were severely hypotensive, and displayed an attenuated circadian blood pressure rhythm. Upon 50% caloric restriction, Dbh(+/-) mice exhibited decreases in heart rate and mean blood pressure. However, the blood pressures of Dbh(-/-) mice did not fall significantly in response to caloric restriction, and the bradycardia associated with caloric restriction was attenuated in these mice. In response to an open-field test, the blood pressure and heart rate of Dbh(+/-) mice increased substantially and rapidly, whereas Dbh(-/-) mice had blunted changes in blood pressures and no change in heart rate. These data suggest a primary role of Epi and NE in mediating the hypotension induced by dieting. Furthermore, Epi and NE play a smaller, but still significant, role in the bradycardia induced by caloric restriction. In contrast, Epi and NE are required for the tachycardia in an open field but are not required for the increase in blood pressure.

FABPPB CONTENT DECREASES WITH 20 DAY CALORIC RESTRICTION IN MUSCLE OF YOUNG FISCHER 344 RATS

779 Long-term caloric restriction has been shown to prolong life span in rats. However, the effects of short-term caloric restriction on younger animals has not been examined. It has been shown that long-term caloric restriction increases glucose transport in adult rat muscle tissue, but the effects of caloric restriction on free fatty acid (FFA) transport have not been examined. Therefore, we examined the effect of short-term caloric restriction on changes in the muscle content of the plasma membrane fatty acid-binding protein(FABPPM) in young adult rats. Male Fischer 344 rats were randomly assigned to either an ad libitum (AL) or a 20 day caloric restriction (CR) feeding group. The CR diet consisted of a 40% reduction from baseline food intake supplemented with minerals and vitamins. At 5.5 months of age, blood samples were taken and the flexor digitorum brevis (FDB) muscles were rapidly excised. Crude membrane fractions were prepared and analyzed for FABPPM by SDS PAGE analysis. CR resulted in a significant decrease in body weight (AL: 330 ± 6 g vs. CR: 280 ± 4 g, p<0.01), but no difference in FDB muscle weights (68.5 ± 5 mg, p>0.05) was observed. Blood glucose (G) and plasma FFA concentrations were significantly lower in CR rats (G: 95.8 ± 3.6 mg/dl, FFA: 350 ± 30 μmol/L) than in AL rats (G: 113.3 ± 4.4 mg/dl, FFA: 520 ± 60 μmol/L, p<0.05). FABPPM content was significantly decreased in CR rats versus AL rats(AL: 36.4 ± 1.1 units vs. CR: 30.7 ± 2.6 units, p<0.05). It is concluded that 20 days of caloric restriction results in significant decreases in FABPPM content in FDB muscles and plasma FFA concentration. These findings indicate that short-term caloric restriction induces rapid changes in FFA metabolism in young adult rats.

II: the effects of recombinant human insulin-like growth factor-1 on immunological recovery in the malnourished alcoholic rat.

Immunological abnormalities are frequently observed in alcoholics with severe liver disease and are typically in association with immune abnormalities. Concomitantly, serum levels of insulin-like growth factor-1 (IGF-1) are frequently very low in these patients. Because IGF-1 is known to modulate both nutrition and immune status, the present study was undertaken to evaluate an in vivo rat model of alcoholism and malnutrition, the possibility of a therapeutic application for IGF-1. Controlled injury was induced by 14 days of calorie restriction and alcohol feeding that resulted in a 9% loss of body mass. Changes were compared with normal unrestricted control rats that gained 28% above their pretreatment body mass during the same period. Immunological impairment was assessed using thymus and spleen mass, cellularity and spleen T-lymphocyte function. Recovery was evaluated after 28 days of treatment using various combinations of: (1) high calorie intake, (2) cessation from alcohol feeding, and (3) IGF-1. The thymus was most severely affected, losing 52.3% of its mass and 55.7% of its cellularity. The spleen was diminished, losing 31.2% of its mass and 41.9% of its cellularity. All of the spleen T-lymphocyte subsets were diminished, with CD5 affected the least (37.1 %) and CD8 affected the most severely (51.7%). During recovery, only the group treated with high calorie intake, no alcohol intake, and IGF-1 (group 8) had complete restoration of all immunological parameters, including a recovery of T-lymphocyte function. Continuous consumption of alcohol, even in the presence of high calories and IGF-1, produced an incomplete recovery. Cessation of alcohol coupled with high calorie nutrition and IGF-1 treatment produced an accelerated improvement in host immunity. These animal studies suggest that IGF-1 is efficacious for this condition and supports the need for additional clinical studies.

I: the effects of recombinant human insulin-like growth factor-1 on nutritional recovery in the malnourished alcoholic rat.

Alcoholics with severe liver disease (ALD) typically demonstrate the findings of protein calorie malnutrition. Such an occurrence might be anticipated with insulin-like growth factor-1 (IGF-1) deficiency. Furthermore, serum levels of IGF-1 are frequently very low in patients with alcoholic liver disease. The present study was undertaken to evaluate in an in vivo rat model of alcoholism and malnutrition, the possibility of a therapeutic application for IGF-1. Controlled injury was induced by 14 days of calorie restriction and alcohol feeding (phase 1), which induced a 9% loss of body mass. Changes were compared with pair-fed, calorie-restricted controls that lost 7.8% of body mass and to unrestricted control rats that gained 28% above their pretreatment body mass during the same period. Recovery was evaluated after 28 days of treatment using various combinations of: (1) high calorie intake, (2) cessation from alcohol feeding, and (3) IGF-1. Liver injury was minimal, but protein calorie malnutrition was moderately severe after phase 1 treatments. During recovery (phase 2), continuous consumption of alcohol--even in the presence of high calories and IGF-1 treatment--produced an incomplete nutritional recovery and, compared with normal rats, was associated with lower serum IGF-1 levels. The group treated with all three modalities (high calories, IGF-1, and abstinence from ethanol) had the most rapid and complete restoration of body weight. Recovery of nutritional status in the malnourished rat correlates significantly with serum IGF-1 levels. In the absence of ethanol and with sufficient caloric intake, IGF-1 treatment increased serum IGF-1 concentrations and accelerated nutritional recovery. Even with adequate calories, ethanol negated this recovery and was associated with lower serum IGF-1 concentrations. Further studies, both basic and clinical, are needed to better understand the mechanisms involved and to establish whether in patients with severe liver disease IGF-1 treatment would produce an accelerated improvement in nutritional status and improve both morbity and mortality. These animal studies suggest that this is the case.

Use of Very-Low-Calorie Diets in the Treatment of Obese Persons with Non-Insulin-Dependent Diabetes Mellitus

This article discusses the use of very-low-calorie diets (VLCDs) in the treatment of obese persons with non-insulin-dependent diabetes mellitus (NIDDM). Research using VLCDs with overweight participants with and without diabetes is reviewed. In both groups of participants, it has been shown that VLCDs used in combination with behavior therapy increase initial weight loss. However, to date, it has not been possible to develop treatment programs that maintain this weight loss long term. Neither intensive maintenance sessions nor intermittent VLCDs have been successful in maintaining the benefits of VLCDs long term. Thus, from the perspective of producing long-term weight loss, balanced low-calorie diets appear to be as effective as VLCDs. However, VLCDs may be useful in treating obese persons with NIDDM, because caloric restriction independent of notable weight loss has marked effects on glycemic control. Several studies have shown that just 7 days of caloric restriction can produce dramatic improvements in glycemic control; moreover, VLCDs produce greater improvements in glycemic control than more moderate diets, even if weight losses are the same. Research is needed to explore new ways to use VLCDs and other approaches to caloric restriction in the treatment of obese persons with NIDDM. J Am Diet Assoc. 1995; 95:569-572.

The Relationship Between Daytime and Nighttime Food Intake in an Obese Night‐Eater

Some obese individuals consume food during awakenings from nighttime sleep. Three studies were conducted on a 28-year-old morbidly obese male with chronic sleeping complaints and insignificant weight loss, despite self-reported daily caloric restriction: I. For 3 mo, the subject recorded food intake for 24-h periods. Mean daytime intake was 1286 kcal +/- 386 (SD), and mean nighttime intake was 1036 kcal +/- 487 (SD). Caloric values of daytime and nighttime intake were negatively correlated, r = -0.22, df= 82, p < .05. II. Seven consecutive 24-h food intake recordings were obtained with an automated formula dispenser when the subject was an inpatient on a metabolic ward and received ad libitum formula as his sole food source. Mean daytime intake was 1245 +/- 662 (SD), and mean nighttime intake was 231 +/- 236 (SD). There was a non-significant negative correlation between daytime and nighttime intake, r = -0.32, df = 5, NS. III. The subject underwent polysomnographic studies on 2 non-consecutive nights, following the administration of either a low (600 kcal) or high (1800 kcal) daytime caloric condition. The subject, upon awakening from nighttime sleep, could eat from a platter of sandwich quarters placed at his bedside. The addition of 1200 kcal to daytime intake decreased nighttime intake by 654 kcal, or by 55% of the additional calories delivered during the day. The three studies (I, II, and III) show that daytime food intake can be negatively correlated with nighttime intake, and that daytime intake can influence nighttime intake in a documented obese night-eater.

Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus.

In obese patients with noninsulin-dependent diabetes mellitus (NIDDM), reducing calorie intake improves glycemic control, often more rapidly than weight loss. Conversely, after weight loss has been achieved, metabolic control can deteriorate once calorie intake is increased, even if there is no regaining of weight. The current study, therefore, tested the hypothesis that restricting calorie consumption has an important role, independent of weight loss, in metabolic regulation of NIDDM patients. Isotopic determinations of hepatic glucose production (HGP), post-absorptively and after ingestion of 75 g glucose (dual glucose isotope method), were made in conjunction with measurement of insulin secretion and insulin sensitivity in seven obese NIDDM volunteers after four periods of controlled calorie intake: 1) 7 days of a baseline weight maintenance diet, 2) followed immediately by 7 days of calorie restriction (800 Cal/day); 3) followed by a weight loss program that consisted of 2 months of a very low calorie diet (400 Cal/day) and then 4 weeks of gradual refeeding and 7 days on a weight maintenance diet; and 4) a final week of calorie restriction (800 Cal/day). The initial brief interval of calorie restriction produced substantial decreases in fasting plasma glucose, HGP, and fasting plasma triglyceride and increases in insulin sensitivity and secretion. After a substantial weight loss (12.7 +/- 2 kg), each parameter improved further, with the effect of weight loss approximately equal to that obtained with initial calorie restriction. Reimposing calorie restriction after weight loss had little effect, except that fasting plasma glucose and HGP improved slightly further. In obese NIDDM subjects, a 7-day period of calorie restriction produces approximately half of the overall improvement in HGP, insulin sensitivity, and insulin secretion that is obtained after a substantial loss of weight. These findings indicate that calorie restriction has an important regulatory effect on the metabolism of obese patients with NIDDM that is independent of weight loss.

Differential Regulation of IGF-1 and IGF-Binding Protein-1 by Dietary Composition in Humans

Although it is known that circulating levels of the insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) fluctuate in response to changes in nutritional status, there is little information regarding either relative contributions from different dietary components or regulation by insulin in nondiabetic subjects. To define dietary contributions to IGF regulation, the authors examined the effects of fasting and hypocaloric diets of differing nutritional composition on serum IGF-1 and a IGFBP-1 in 16 healthy, obese adult women. Subjects received an isocaloric diet for 6 days, followed by 14 days of calorie restriction (fasting or a hypocaloric diet enriched in either protein, fat, or carbohydrate), and by 4 days refeeding. All diets produced 6-8% weight loss over 14 days with little difference between groups. The "protein-sparing" diet sustained nitrogen balance (+1.2 g/d, versus -4.5 g/d for the other three groups; p < 0.05). Serum IGF-1 levels decreased during calorie restriction with fasting or with diets high in fat or carbohydrates (CHO; combined mean 40 +/- 7%) but showed little change with the high protein regimen (3 +/- 16%; p < 0.05 compared to the other diets). In contrast, IGFBP-1 increased during calorie restriction in all four groups but significantly less with the high CHO diet (43 +/- 17% above baseline) than with the other diets (168 +/- 31%; p < 0.05). Levels of IGF-1 were correlated with nitrogen balance (r = 0.51; p < 0.05) but levels of IGFBP-1 were not. Although IGFBP-1 levels inversely correlated with measures of insulin secretion, IGF-1 levels did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations in β-adrenergic sensitivity and platelet α2-adrenoceptors in obese women: effect of exercise and caloric restriction

1. Peripheral adrenergic responses were studied in eight obese women before and after 15 days of caloric restriction (2500 kJ/day) and in eight sex- and age-matched lean controls. 2. beta-Adrenergic sensitivity (defined as the dose of isoprenaline required to increase resting heart rate by 25 beats/min) was evaluated before and after the diet. Density and affinity (determined as the apparent dissociation constant) of platelet alpha 2-adrenergic receptors, and plasma adrenaline and noradrenaline levels, were measured after overnight bed-rest and after 9 min of standardized exercise performed before and after the low caloric diet. 3. Before the diet basal antecubital venous plasma noradrenaline concentrations were lower in obese women when compared with lean women (0.94 +/- 0.06 vs 1.27 +/- 0.17 nmol/l, P less than 0.02). Isoprenaline sensitivity did not differ between lean and obese women. 4. At rest, platelet alpha 2-adrenoceptor density was lower in overweight than in lean women (129 +/- 21 vs 168 +/- 16 fmol/mg of protein, P less than 0.02). Exercise significantly increased platelet alpha 2-adrenoceptor density and decreased affinity in lean women. This decrease correlated with the rise in plasma noradrenaline. 5. In obese women exercise did not modify platelet alpha 2-adrenoceptor density or affinity, despite a significant increase in plasma catecholamines. However, the increase in plasma noradrenaline during exercise was lower in obese women. 6. The low caloric diet produced a beta-adrenergic supersensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of calorie restriction and weight loss on glucose and insulin levels in obese humans.

The relative contributions of weight loss vs calorie restriction in the improvement of glucose tolerance in obese subjects has not been well studied. We measured fasting and stimulated glucose and insulin levels in seven obese subjects at 4 time periods: on a regular diet before weight loss, on a very low calorie ketogenic diet (VLCKD) after 4 days and after 6 weeks, and after 4 days back on a regular diet. Fasting glucose and insulin levels fell significantly after only 4 days of calorie restriction and did not change after 6 weeks. With return to a regular diet, these levels rose toward baseline even through body weight remained well below baseline. Stimulated glucose and insulin levels during an insulin tolerance test, intravenous glucose tolerance test, and standard meal demonstrated a similar pattern, although the changes due to either diet or weight loss were minimal. We conclude that calorie restriction has a greater effect on glucose and insulin levels than does weight loss in obese subjects who are losing weight.

Effects of Physical Exercise and a High Protein Diet on Various Physiological and Biochemical Functions in Calorie-restricted Overweight Subjects

This study was undertaken to investigate the effects of a combined action of regular dynamic exercise, caloric restriction and a high protein diet on weight reduction, endurance capacity and certain metabolic and biochemical parameters on blood in four middle aged males including two overweight subjects during and after a 30-day reduction period.The reducing diet provided 1, 650 kcal, 125gm protein, 80gm fat and 100gm carbohydrate. The exercise progam consisted of a 2hr-daily walk on a treadmill at the speed of 4.8km/hr and the inclination of 8.75%.The weight loss was 3.4kg throughout the 30-day reduction period. The weight was restored by 1kg two months after realimentation. The body composition of the tissues lost by the obese subjects were calculated as 79% of fat and 21% of water and protein.The daily walking exercise which corresponded to 40-60% of VO2 max resulted in increases of VO2 max and of the distances of a 5 minute running test both by 10%. The combination of exercise and a high protein diet did not prevent both the lowering of the basal metabolic rate and the occurrence of deficiency anemia during weight loss, though these symptons were recovered within a week of ad libitum feeding.Serum cholesterol and triglyceride levels showed a sharp decline within the first 7 days of caloric restriction and thereafter maintained low levels throughout the reduction period. Realimentation, however, brought about a rapid rise of serum lipid levels toward the initial individual values.These results indicated that a high protein diet (2gm of protein/kg body weight) did not exert any additional effects in preventing the physiological deficits which had previously appeared during the treatment of obesity by both exercise and a moderate protein diet (1.5gm of protein/kg body weight).

Thiamin, riboflavin, and pyridoxine excretion during acute starvation and calorie restriction

Daily excretion of thiamin and vitamin B6in micrograms per gram creatinine were in the low-to-deficient ranges established by the ICNND during the calorie restriction period, indicating rapid depletion of body stores. Although riboflavin excretion decreased during the latter days of calorie restriction (studies I and II), these values remained in the high range of acceptability. The elevated excretions of riboflavin are indicative of adequate reserves and catabolism of body protein for use as energy, or both. These data suggest that under conditions of calorie restriction, the daily minimal allowances of vitamins B1, B2, and B6are influenced by the calorie, vitamin, and protein intakes, the degree of negative nitrogen balance, and the subsequent protein catabolism.

Tissue Changes During Intermittent Starvation and Caloric Restriction as Treatment for Severe Obesity

Changes in body weight, nitrogen, water, and total body fat were evaluated, with two independent techniques, in four obese patients during seven consecutive 16-day periods during which each patient was starved for 16 days and then fed an 800-calorie liquid diet for 16 days before again being fasted. The major component of the body weight loss during every starvation period was not fat, but water and protein. The periods of caloric restriction which followed each starvation period were characterized by minimal change in body weight and rapid reaccumulation of water and nitrogen. Fat loss, although variable in magnitude, was constant throughout starvation and caloric restriction. The average cumulative fat loss during 48 days of total starvation was not significantly different from the average fat loss during 48 days of caloric restriction.

Cellular Response in Rats during Malnutrition at Various Ages

Malnutrition retards growth in animals and children. Recovery of normal stature on refeeding depends, in part, on age at onset of deprivation. To investigate the cellular events underlying this time-dependence, rats were exposed to 21 days of caloric restriction at birth, at weaning and at age 65 days and then refed normally until adulthood. Total organ weight, protein, RNA, and DNA were measured during the periods of caloric restriction and subsequent refeeding. Total organ DNA and weight/DNA, protein/DNA, and RNA/DNA ratios in test and control animals reared in the usual manner served as indexes of changes in organ cell size and number. Malnutrition from birth to weaning resulted in a proportional decrease in weight, protein, RNA, and DNA, indicating a reduction in cell number without alteration in cell size. These animals did not recover normal growth when adequately refed. Malnutrition from weaning to 42 days of age resulted in a proportional reduction in weight, protein, RNA, and DNA in all organs except brain and lung. Although weight, protein, and RNA were reduced in these 2 organs, DNA was unaffected. Refeeding was accompanied by recovery in weight of these 2 organs only, resulting in an animal retarded in overall growth with normal-size brain and lung. Finally, malnutrition from 65 to 86 days of age resulted in maintenance of DNA values in all organs except spleen and thymus, whereas weight, protein, and RNA were reduced. The reduced ratios coupled with normal DNA suggest decrease in cell size with retention of cell number. All organs in the animals except thymus recovered normal size on refeeding and all ratios returned to normal. These data suggest that cellular effects of malnutrition depend on the phase of growth in the animal at the time of malnutrition. Early malnutrition impeded cell division and the animal did not recover. Malnutrition at a later stage of growth resulted in reduction of cell size from which the animal could recover.

Some Relationships between Caloric Restriction and Body Weight in the Rat: IV. Fecal Nitrogen, Fat, Energy, and Ash and Urinary Creatinine

The relationship between the caloric restriction adaptation and fecal excretion of nutrients was investigated in ad libitum and caloric-restricted rats. Both ad libitum controls and restricted animals excreted approximately 4 to 6% as much nitrogen in the feces as ingested in the diet, indicating similar efficiencies of absorption. The fecal fat was about 5% of the total fat intake in both groups, and the fecal excretion of I131 following intragastric administration of I131-labeled triolein was also about 5% of that administered. Feces of both groups contained approximately 5% as much energy, measured by combustion in a bomb calorimeter, as was ingested in the diet. However, feces of restricted rats contained about 30% as much mineral ash as did the ingested diet, whereas, feces from rats fed ad libitum contained only about 20% of the ingested mineral. Urinary creatinine excretion by restricted animals was constant over the 44 days of caloric restriction but gradually increased in the ad libitum controls.