Effects of calorie restriction on life span of microorganisms

Calorie restriction (CR) in microorganisms such as budding and fission yeasts has a robust and well-documented impact on longevity. In order to efficiently utilize the limited energy during CR, these organisms shift from primarily fermentative metabolism to mitochondrial respiration. Respiration activates certain conserved longevity factors such as sirtuins and is associated with widespread physiological changes that contribute to increased survival. However, the importance of respiration during CR-mediated longevity has remained controversial. The emergence of several novel metabolically distinct microbial models for longevity has enabled CR to be studied from new perspectives. The majority of CR and life span studies have been conducted in the primarily fermentative Crabtree-positive yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, but studies in primarily respiratory Crabtree-negative yeast and obligate aerobes can offer complementary insight into the more complex mammalian response to CR. Not only are microorganisms helping characterize a conserved cellular mechanism for CR-mediated longevity, but they can also directly impact mammalian metabolism as part of the natural gut flora. Here, we discuss the contributions of microorganisms to our knowledge of CR and longevity at the level of both the cell and the organism.     

Effect of long-term somatotropin treatment on body composition and life span in aging obese Zucker rats

The objective of this work was to test the hypothesis that a somatotropin (STH)-induced reduction in body fat would prolong the life span of the obese Zucker rat. Two experiments were conducted. In the first experiment, male and female, lean and obese Zucker rats were treated with STH (0 or 2 mg/d bovine STH) for 4 weeks, beginning at 7 months of age. Across phenotypes, STH treatment increased the growth rate by 159%, muscle weights by 14%, and circulating insulin-like growth factor (IGF)-1 by 23%, and decreased carcass fat by 21% (P < 0.05). The second experiment was a longevity trial to determine whether these changes in body composition would increase the life span of the obese rat. Beginning at 7 months of age, individually housed, male and female, lean and obese rats were assigned to daily STH treatments (0 or 2 mg/d). Rats were monitored daily, and sick or moribund rats were euthanized and necropsied to determine existing pathologies. The average life span of the lean rats was 661 days and was unaffected by STH treatment (639 days, NS) or gender. Average life span of the vehicle-injected obese rats (435 days) was less than that of the lean group (P < 0.001). STH treatment of the obese rats resulted in a further reduction of life span (349 days, P < 0.02). The predominant pathology observed across the treatment groups was renal disease, characterized by progressive glomerulonephropathy. Thus, although exogenous STH was able to reduce carcass lipid and to increase lean tissue mass in obese rats, there was no improvement in longevity. In contrast to the hypothesis, STH actually reduced the life span of the obese rat. It is likely that STH treatment accelerated the development of progressive glomerulonephropathy in the obese rat.     

Effect of very low calorie diet on body composition and exercise response in sedentary women.

The effect of very low calorie diet (VLCD) on fat-free mass (FFM) and physiological response to exercise is a topic of current interest. Ten moderately obese women (aged 23-57 years) received VLCD (1695 kJ.day-1) for 6 weeks. FFM, estimated by four conventional techniques, and heart rate (fc), blood lactate (la(b)), mean arterial pressure (MAP), respiratory exchange ratio (R) and rating of perceived exertion (RPE) were measured during a submaximal cycle ergometry test 1 week before, in the 2nd and 6th week, and 1 week after VLCD treatment. Strength and muscular endurance of the quadriceps and hamstrings were tested by isokinetic dynamometry. The 11.5-kg reduction in body mass was approximately 63% fat and 37% FFM. The latter was attributed largely to the loss of water associated with glycogen. Whilst exercise fc increased by 9-14 beats.min-1 (P < 0.01), there were substantial decreases (P < 0.01) in submaximal MAP (1.07-1.73 kPa), la(b) (0.75-1.00 mmol.l-1 and R (0.07-0.09) during VLCD. R and fc returned to normal levels after VLCD. Gross strength decreased (P < 0.01) by 9 and 13% at 1.05 rad.s-1 and 3.14 rad.s-1, respectively. Strength expressed relative to body mass (Nm.kg-1) increased (P < 0.01) at the lower contraction velocity, but there was no change at the faster velocity. Muscular endurance also decreased (P < 0.01) by 62 and 82% for the hamstrings and quadriceps, respectively. We concluded that the strength decrease was a natural adaptation to the reduction in body mass as the ratio of strength to FFM was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cold adaptation on the feeding behavior of genetically obese Zucker rats

A diurnal hyperphagia is certainly the main factor of adiposity in the genetically obese Zucker fa/fa rat. In a previous experiment it was observed that cold-acclimatization suppressed hyperphagia and stopped the increase in obesity. In this work, the chronology of modification in the feeding pattern is studied during the first month of cold exposure (10 degrees C). The main cold-induced modifications are observed after 2 weeks of cold exposure. Possibly the decrease in metabolic efficiency of food could parallel the cold-induced enhancement of energetic capacity of brown adipose tissue which has been described elsewhere. This tissue could play a role in the obesity of the Zucker rat.     

Adrenal hydroxylations in genetically obese and hypertensive rats.

The separate steps in the formation of aldosterone from cholesterol were studied in a strain of spontaneously hypertensive rats in which phenotypic obesity is inherited as a recessive trait (Koletsky rats). The obese and hypertensive state had little or no effect on side-chain cleavage of cholesterol, formation of progesterone from pregnenolone or 21-hydroxylation. Mitochondrial 18-hydroxylation of endogenous and exogenous corticosterone, however, as well as 18- and 11 beta-hydroxylation of deoxycorticosterone, were increased in obese hypertensive rats, both when compared with non-obese hypertensive siblings and when compared with healthy Sprague-Dawley rats. 18-Hydroxylation of corticosterone was increased more than 18-hydroxylation of deoxycorticosterone. In non-obese hypertensive rats, the adrenal content of mitochondrial cytochrome P-450 was lower than that in obese hypertensive rats but higher than that in rats of the conventional Sprague-Dawley strain. The results are discussed with respect to possible heterogeneity of adrenal cytochrome P-450 and to possible explanations for the changes observed.     

Fructose 2,6-bisphosphate in livers of genetically obese rats.

Livers of genetically obese (fa/fa) rats, starved for 24 h, contained more fructose 2,6-bisphosphate, glucose 6-phosphate, fructose 6-phosphate and glycogen, and more pyruvate kinase and phosphofructokinase 2 activities, than livers of control lean rats. These changes may be explained in terms of cyclic AMP concentration, which was decreased in livers of obese starved rats.     

Effect of low protein and low energy diet on physiological status and digestibility of F344 rats.

A long-term raising study was carried out on male F344/DuCrj rats with three low protein (Crude Protein (CP); 14.5, 11.5, 8.5%) and low energy (Digestible Energy (DE); 2.0 kcal/g) diets from 4 to 104 weeks of age. In rats fed the 8.5% CP diet, body weight and digestible crude protein (DCP) consumption at 10 weeks of age were lower (P < 0.05) but the body weight at 50 weeks of age was higher (P < 0.05) than in the other groups. In rats fed the 8.5% CP diet the crude fat digestibility was higher (P < 0.05), and the CP/nitrogen-corrected metabolizable energy (MEn) ratio was low. On the other hand, the mean survival time at 80 weeks of age was shorter in rats fed the 8.5% CP diet (P < 0.05).     

Effects of nicotine on the fertility, cytology and life span of male rats

Contrary to an earlier opinion that nicotine has no effect on the fertility of male animals or humans, the present experimental study using male inbred Fisher rats demonstrates that the reproductive capacity of the animals is greatly reduced when injected with nicotine, and that the effect is much greater in male than in female Fisher rats similarly injected with nicotine. This is in accord with some earlier histological and morphological studies which have shown that female rodents have a greater tolerance to nicotine than their male counterparts. It is also confirmed by the cytologic observations of the present study. These observations show that, similar to female rats, inflammatory processes, as evidenced by an increased number of lymphocytes and/or polymorphonuclear leukocytes, are responsible for the decrease in fertility. However, the cytological profile is profoundly different in the two sexes: virulent inflammatory conditions begin much earlier in male rats, they are more frequent and, whereas the condition is reversible in the female animal when nicotine treatment is discontinued, it is not in some male rats, and inflammatory conditions persist for the entire life as does infertility. However, the life span of nicotine-treated male rats is greater than in female nicotine-treated rats, although it is shorter in both sexes than in their respective controls; in some male nicotine-treated rats, the life span is greater not only than in their male controls but even than in their female counterparts. Possible explanations for this apparently paradoxical life-prolonging effect of nicotine treatment are reviewed, but the evidence is either conflicting or insufficiently established and requires further study.     

Adipogenic activity in the plasma of genetically obese Zucker rats

The potential of plasma to stimulate differentiation and lipid filling of adipose precursors in primary culture was investigated in the groups of genetically obese Zucker rats (fafa) and their lean littermates (FaFa). The effect of age, feeding status and possible role of growth hormone in the process of adipogenesis was also studied. Differences in lipid-filling activity of the tested plasma samples were much more dependent on age than the genotype of plasma donors were. The plasma taken from the oldest (20-week-old) rats stimulated the accumulation of triglycerides in the cells to significantly higher levels than the plasma from other rats. The influence of the feeding status on the lipid-filling activity of plasma was not significant. The differentiation potential of plasma in terms of the stimulation of glycerophosphate dehydrogenase activity measured in adipocyte precursors was 30-50% higher when the culture medium contained plasma from obese rats. Furthermore, glycerophosphate dehydrogenase activity in the growing cells declined with age and tended to be higher in the presence of plasma from fed rats. It was the growth hormone that was in a considerable degree responsible for the differentiation potential of Zucker rat plasma. This effect of growth hormone seemed to be less dependent on fafa genotype. It is, therefore, suggested that in addition to growth hormone, other factors in the plasma of genetically obese Zucker rats might be important in the development of obesity in this rat strain.     

Effects of 2G exposure on lean and genetically obese Zucker rats

Changes in the ambient force environment alter the regulation of adiposity, food intake and energy expenditure (i.e., energy balance). Lean (Fa/Fa) and obese (fa/fa) male Zucker rats were exposed to 2G (twice Earth's normal gravity) for eight weeks via centrifugation to test the hypothesis that the Fa/Fa rats recover to a greater degree from the effects of an increased ambient force environment on body mass and food intake, than do the fa/fa rats which have a dysfunctional leptin regulatory system. The rats (lean and obese exposed to either 1G or 2G) were individually housed in standard vivarium cages with food and water provided ad libitum. The acute response to 2G included a transient hypophagia accompanied by decreased body mass, followed by recovery of feeding to new steady-states. In the lean rats, body mass-independent food intake had returned to 1G control levels six weeks after the onset of centrifugation, and body mass increased towards that of the 1G rats. In contrast, food intake and body mass of the 2G obese rats plateaued at a level lower than that of the 1G controls. Although percent carcass fat was reduced more in the 2G leans vs. 2G obese rats, the latter lost significantly more grams of fat than did the leans. Our data suggest that with respect to food intake and body mass, the lean rats recover from the initial effects of 2G exposure to a greater degree than do the fatty rats, a difference that likely reflects the functionality of the leptin regulatory system in the leans.     

Effect of ionizing radiations on the life span of non-transformed human fibroblasts.

We studied in vitro the influence of ionizing radiations on the life span of non-transformed HF 19 human fibroblasts. The life span of surviving clones was found to be reduced when the cells had received two or three doses of 6 Gy separated by an interval of 15 doublings. In addition, this reduction in life span was greater when the cells were older at the time of irradiation.     

Insulin binding in the hypothalamus of lean and genetically obese Zucker rats

Recent reports have suggested that the obesity and hyperphagia of the genetically obese Zucker rat may be related to defective insulin action or binding in the hypothalamus. We used quantitative autoradiography to determine if insulin binding is altered in specific hypothalamic nuclei associated with food intake. Insulin binding was measured in the arcuate (ARC), dorsomedial (DMN), and ventromedial (VMN) hypothalamic nuclei of 3–4-month-old lean (Fa/Fa) and genetically obese (fa/fa) Zucker rats. A consistently reproducible 15% increase in the total specific binding of 0.1 nM [¹²⁵I]-insulin was found in the ARC of the obese genotype. A slight increase in insulin binding in the DMN was also found. No difference in specific insulin binding was found between genotypes in the VMN. Nonlinear least squares analysis of competitive binding studies showed that the K_d of the ARC insulin binding site was 33% higher in the lean rats than in the obese rats, indicating an increased affinity for insulin. No difference in site number (B_max) was found in the ARC, DMN or VMN, and no evidence was found for reduced insulin binding in the hypothalamus of the obese (fa/fa) genotype. The results suggest that hyperphagia and obesity of the obese (fa/fa) Zucker rat genotype may be associated with increased insulin binding in the arcuate nucleus.     

Effects of low calorie diet-induced weight loss on post-exercise heart rate recovery in obese men

[Purpose]

Heart Rate Recovery (HRR) after maximum exercise is a reactivation function of vagus nerve and an independent risk factor that predicts cardiovascular disease and mortality. Weight loss obtained through dietary programs has been employed as a therapy to reduce risks of cardiovascular disease and obesity.

[Methods]

Eighteen subjects of middle aged obese men (age 44.8 ± 1.6 yrs, BMI 29.7 ± 0.5 kg/m²) were selected for this study. As a weight loss direction, the nutritional direction of low-calorie diet mainly consisted of carbohydrate, protein, and fat has been conducted for 3 months. Blood pressure was measured after overnight fasting, and blood samples were collected from the antecubital vein before and after weight loss program. All the pre- and post-exercise ‘HRR decay constant’s were assessed by using values of HRR (heart recovery rate; 2 minutes) and HR measured after reached to the maximal oxygen uptake (VO₂max) exploited the bicycle ergometer.

[Results]

After the completion of weight loss program, body weight and BMI were significantly decreased, but the Heart Rate (HR) after maximum exercise and in steady state were not changed significantly (p > 0.05). The post-exercise HRR after the weight loss did not show significant changes in perspectives of 30 seconds (-16.6 ± 2.3 to -20.2 ± 2.1 beats/min, p > 0.05) and 60 seconds (-33.5 ± 3.4 to -34.6 ± 2.8 beats/min, p > 0.05) respectively but in perspectives of 90 seconds (-40.9 ± 2.6 to -48.1 ± 3.1 beats/min, p < 0.05) and 120 seconds (-48.6 ± 2.6 to -54.3 ± 3.5 beats/min, p < 0.05), they were decreased significantly. Pre-’HRR decay constant’s of 0.294 ± 0.02 %/second were significantly increased to post-values of 0.342 ± 0.03 %/second (p = 0.026). Changes in ‘HRR decay constant’ were significantly correlated with changes in blood glucose (r = -0.471, p < 0.05) and maximal oxygen consumption (VO₂max, r = 0.505, p < 0.05) respectively.

[Conclusions]

The low-calorie diet directed to obese middle aged men for 3 months significantly improved the HRR after maximum exercise, and this improvement in cardiovascular autonomic nerve system was estimated to be involved with improvements in blood glucose and maximal oxygen consumption.     

四氢生物蝶呤对大鼠低密度脂蛋白氧化修饰的作用及其机制探讨

目的:探讨四氢生物蝶呤(BH4)治疗高脂血症(HL)大鼠对低密度脂蛋白(LDL)氧化修饰作用及其机制。方法:选用8周龄雄性Wistar大鼠54只,随机分为对照组(普通饮食)、高脂饮食组(HL组)和高脂饮食并腹腔注射BH4组(HL+BH4组)(n=18)。于实验前、实验8周和16周时每组各杀死6只大鼠测定血脂和血清BH4水平,测定主动脉血管活性氧(ROS)、脂质过氧化代谢终产物丙二醛(MDA)和LDL氧化修饰水平。结果:至实验8周和16周时,HL组和HL+BH4组血脂水平较对照组均明显升高(P<0.01),但HL组和HL+BH4组之间无明显差异(P>0.05);ROS和MDA明显降低(P<0.01);HL+BH4组较对照组和HL组BH4水平均明显升高(P<0.01);与对照组相比,HL组大鼠主动脉匀浆中BH4含量明显降低(P<0.01),但总喋呤水平(TB=BH4+BH2+B)无明显差异(P>0.05);HL组大鼠血清硫代巴比妥酸反应物(TBARS)生成量随周龄的增加有逐渐升高的趋势,而HL+BH4组大鼠血清TBARS生成量较HL组明显降低(P<0.01)。结论:BH4可以减轻LDL氧化修饰,其机制可能与纠正NOS脱偶联、ROS生成减少及LDL脂质过氧化降低有关。