Influence of caloric restriction on aging immune system

Nutrition has been shown to have a significant impact on aging. Caloric Restriction (CR), i.e., undernutrition not malnutrition, significantly increases the survival of laboratory animals by retarding/delaying the aging process. CR has beneficial effects on various physiological systems, including the immune system. Overall, the immunological status of rodents fed a restricted diet is superior to the immunological status of the non-restricted animals. It is believed that CR might retard aging and immunosenescence through a mechanism involving changes in signal transduction and gene expression. Recent studies from our laboratory support the view that the mechanism of CR involves changes in the activation of the upstream signaling molecules and cytokine gene expression that are altered with age.     

D-半乳糖致氧化损伤小鼠SOD活力及基因表达

目的　探讨D -半乳糖致氧化损伤模型鼠超氧化物歧化酶 (SOD)活性及其基因表达的相关性。方法　采用生物化学和RT- PCR方法对D -半乳糖造模小鼠、正常对照组、人参蜂王浆口服液组小鼠进行了肝组织SOD活力及SOD基因表达的测定。结果　D -半乳糖造模小鼠SOD活力和基因表达明显降低 ,与对正常照组相比差异有统计学意义 (P <0 . 0 1) ;与D -半乳糖造模组小鼠比较 ,给予不同剂量人参蜂王浆口服液小鼠SOD活力相对升高 ,低、中剂量升高幅度较大 (P <0 . 0 1) ,SOD基因表达也相对上调 ,其中中剂量上调较为明显 (P <0. 0 5 )。结论　D -半乳糖造模小鼠SOD活力降低 ,SOD基因表达也相应降低。人参蜂王浆口服液可减弱D -半乳糖对SOD活力及SOD基因表达的抑制作用。     

Leptin and anti-aging action of caloric restriction

Evolutional theories of aging and caloric restriction (CR) in animals predict the presence of neuroendocrine signals to divert the limited energy resources from energy-costly physiologic processes such as reproduction to those essential for survival in response to food shortage. The diversion of energy and subsequent molecular mechanisms might extend the lifespan. A growing body of evidence indicates that leptin, a peptide hormone secreted from adipocytes, has a key role in neuroendocrine adaptation against life-threatening stress such as fasting. The present review discusses the potential role of leptin in the anti-aging action of CR. Although several alternative signaling pathways might also mediate the anti-aging action of CR, leptin signaling could be a substantial pathway in the CR action. Research on neuroendocrine mechanisms of CR is warranted, because such efforts might provide clues to the regulation of the aging process in humans.     

Regional subcutaneous-fat loss induced by caloric restriction in obese women

OBJECTIVE: With anthropometric models using skinfolds and circumferences, we studied changes in the percentage of subcutaneous fat in the total cross-sectional area (SF%) at four body sites in obese women, before and after weight loss induced by 6 months of caloric restriction. RESEARCH METHODS AND PROCEDURES: In 61 obese women [31 African Americans and 30 whites; ages, 24 to 68 years; body mass index (BMI), > or =28 kg/m(2)], we measured SF% at the midpoint of the upper arm and thigh and the waistline and hipline, and we measured the percentage of total body fat by DXA before (Obs#1) and after (Obs#2) a 6-month nonintervention control period and then after 6 months on a 1200 kcal/d diet (Obs#3). RESULTS: The mean body weight and BMI increased (1.8 kg and 0.61 kg/m(2); p = 0.0001), but there were no significant changes in any other body composition measurements from Obs#1 to Obs#2. The means of Obs#3 for weight and BMI decreased by 11%, and the percentage of total body fat decreased by 13% of Obs#2 mean values (p = 0.0001). The mean SF% at each site decreased 7.6% to 18.0% of the Obs#2 mean values (p < 0.001). The SF% decreases were greater at mid-arm and mid-thigh than in the cross-sectional regions at the waistline and hipline (p = 0.05). There was no interaction between age or ethnicity (p > 0.2). CONCLUSIONS: In obese women, caloric restriction alone reduces anthropometrically measured subcutaneous fat proportionally more in peripheral than in central regions.     

Genetic differences in effects of food restriction on aging in mice

Lifelong food restriction to two-thirds of normal ad libitum consumption extended mean and maximum life spans more than 200 d in male B6CBAF1 hybrid mice, already a long-lived genotype. The following biological systems were improved by food restriction, with values for older mice being similar to those previously found for younger individuals: tight wire clinging, a measure of neuromuscular performance; open field movement, a measure of voluntary activity; tail tendon denaturation rate, a measure of collagen solubility; urine concentrating ability, a measure of renal function, and hair regrowth rate, a measure of the frequency of hair follicle cycling. However, wound healing was slower in food-restricted mice than in ad libitum-fed controls. The same food restriction treatment had entirely different effects on longevities of a different genotype, male B6 (C57BL/6J) mice, reducing mean and maximum life spans 265 and 27 d, respectively. This surprising deleterious effect was not predicted by tests of tight wire clinging, open field movement and tail tendon denaturation, but was predicted by hair regrowth rates, as these were lower in restricted B6 mice than in fed controls. In genetically obese (ob/ob) B6 mice, food restriction extended mean and maximum longevities 327 and 440 d, yet no biological systems tested performed better than those of food-restricted normal (+/+) mice whose life spans were reduced. Thus the food restriction regimen that increased longevities for individuals of two genotypes decreased them for individuals of a third genotype tested in the same set of experiments.     

Gene expression profiling in bone tissue of osteoporotic mice

Ovaricetomized (OVX) animals represent an optimal model to investigate bone loss in osteoporosis. To further elucidate the underlying mechanisms of decreased bone formation and increased bone resorption following OVX, we conducted gene expression profiling experiments using bone samples of ovariectomized C57BL/6J mice. Following OVX, genes involved in immune response, cell cycle regulation, growth, apoptosis and bone resorption were upregulated, while genes that are important for regular cell processes, mitosis, metabolism of carbohydrates, extracellular matrix structure, angiogenesis, skeletal development and morphogenesis were downregulated. Among bone specific genes we observed upregulation of interleukin 7 (IL-7), IL-7 receptor and matrix metallopeptidase 8, while genes such as transforming growth factor-beta 3, procollagen type I and procollagen type VI exhibited marked decrease in expression. We also observed downregulation of two genes, parathyroid hormone receptor 1 and WD repeat domain 5, that are involved in skeletal development but were not previously reported to be altered in osteoporosis. We further performed gene set enrichment analysis (GSEA) in order to calculate enrichment of pathways specifically altered in murine bones following ovariectomy. In conclusion, OVX greatly influences expression of various genes involved in diverse biological processes confirming the notion that numerous pathways play an important role in pathophysiology of osteoporosis.     

Monitoring human radiation exposure by gene expression profiling: possibilities and pitfalls

Advances in high throughput analysis of mRNA expression have made it possible to establish gene expression profiles for different cells, tissues, diseases and exposure states. For instance, recent studies have demonstrated the utility of such an approach to classify sub-types of cancers with more detail than was previously possible. In addition, gene expression studies of ionizing radiation exposure both in vitro and in vivo are affording insight into the molecular mechanisms of mammalian radiation response. We have demonstrated that radiation expression profiles are a good predictor of p53 function in cell lines, and such profiles also indicate a major role for p53-regulated genes in the in vivo radiation response. Gene expression can be a sensitive indicator of radiation response as we have shown linear dose-responses for induction of several genes down to doses as low as 2 cGy. As profiles are established from radiation studies, it is hoped that they may be useful for identifying individuals with specific exposures or predisposition to negative outcome of exposure. Although this technology holds great promise, some obstacles remain to be overcome before it can be successfully applied to population studies.     

运动对脑老化小鼠铁调节蛋白-2基因表达影响

目的 以铁调节蛋白-2(iron regulatory protein-2,IRP-2)基因表达观测点探讨运动抗脑老化的机制.方法 将40只雄性ICR小鼠按体重随机分为4组:对照组、脑老化组、运动组、脑老化+运动组.脑老化及运动干预的实验造模期为10周.造模期结束后,以Morris水迷宫试验检测小鼠的学习记忆能力,逆转录-聚合酶链反应(RT-PCR)检测小鼠大脑IRP-2基因表达水平.结果 脑老化组小鼠脑IRP-2基因表达水平(0.738±0.221)显著低于对照组(3.938±2.357)(P<0.05);脑老化+运动组小鼠脑IRP-2基因表达水平(2.938±0.468)显著高于脑老化组(P<0.05);与对照组之间差异无统计学意义;运动组IRP-2基因表达水平(2.595±0.822)与对照组之间差异无统计学意义.结论 脑老化小鼠IRP-2基因表达水平降低,运动可以防止脑老化小鼠的IRP-2基因表达下调.运动具有抗脑老化的效应.     

Expectations,validity, and reality in gene expression profiling

ObjectiveTo provide a critical overview of gene expression profiling methodology and discuss areas of future development.ResultsGene expression profiling has been used extensively in biological research and has resulted in significant advances in the understanding of the molecular mechanisms of complex disorders, including cancer, heart disease, and metabolic disorders. However, translating this technology into genomic medicine for use in diagnosis and prognosis faces many challenges. In addition, gene expression profile analysis is frequently controversial, because its conclusions often lack reproducibility and claims of effective dissemination into translational medicine have, in some cases, been remarkably unjustified. In the last decade, a large number of methodological and technical solutions have been offered to overcome the challenges.Study Design and SettingWe consider the strengths, limitations, and appropriate applications of gene expression profiling techniques, with particular reference to the clinical relevance.ConclusionSome studies have demonstrated the ability and clinical utility of gene expression profiling for use as diagnostic, prognostic, and predictive molecular markers. The challenges of gene expression profiling lie with the standardization of analytic approaches and the evaluation of the clinical merit in broader heterogeneous populations by prospective clinical trials.     

The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake

We sought to clarify the impact of dietary restriction (undernutrition without malnutrition) on aging. Female mice from a long-lived strain were fed after weaning in one of six ways: group 1) a nonpurified diet ad libitum; 2) 85 kcal/wk of a purified diet (approximately 25% restriction); 3) 50 kcal/wk of a restricted purified diet enriched in protein, vitamin and mineral content to provide nearly equal intakes of these essentials as in group 2 (approximately 55% restriction); 4) as per group 3, but also restricted before weaning; 5) 50 kcal/wk of a vitamin- and mineral-enriched diet but with protein intake gradually reduced over the life span; 6) 40 kcal/wk of the diet fed to groups 3 and 4 (approximately 65% restriction). Mice from groups 3-6 exhibited mean and maximal life spans 35-65% greater than for group 1 and 20-40% greater than for group 2. Mice from group 6 lived longest of all. The longest lived 10% of mice from group 6 averaged 53.0 mo which, to our knowledge, exceeds reported values for any mice of any strain. Beneficial influences on tumor patterns and on declines with age in T-lymphocyte proliferation were most striking in group 6. Significant positive correlations between adult body weight and longevity occurred in groups 3-5 suggesting that increased metabolic efficiency may be related to longevity in restricted mice. Mice from groups 3-6 ate approximately 30% more calories per gram of mouse over the life span than did mice from group 2. These findings show the profound anti-aging effects of dietary restriction and provide new information for optimizing restriction regimes.     

Effect of moderate caloric restriction and/or weight cycling on mammary tumor incidence and latency in MMTV-Neu female mice

Recently, we reported that intermittent caloric restriction-refeeding reduces mammary tumor (MT) incidence and extends latency in murine mammary tumor virus (MMTV)-transforming growth factor (TGF)-a mice to a greater extent than does chronic caloric restriction. Here, this same weight-cycling protocol was applied to MMTV-Neu female mice, which develop MTs at a much younger age than do TGF-a mice. This study consisted of three experimental groups: mice fed an AIN-93M diet ad libitum, mice intermittently fed an AIN-93 modified diet (2-fold increase in protein, fat, vitamins, and minerals) at 50% of the amount fed to the ad libitum-fed mice for 3-wk intervals and then fed an AIN-93M diet ad libitum for 3-wk intervals, and mice chronically restricted, pair fed to the intermittently restricted mice by feeding 2:1 mixtures of AIN-93M-AIN-93 modified diets for each 6-wk feeding interval. Mice were euthanized when MTs reached a length of 20 mm or at 80 wk of age. Cumulative caloric intake was 10% lower (not significant) for intermittently restricted mice and 16% lower (P < 0.05) for chronically restricted mice than for ad libitum-fed mice. Final body weights were significantly different as follows: ad libitum-fed > intermittently restricted > chronically restricted. Fat pad weights were greater in ad libitum-fed than in intermittently restricted and chronically restricted mice. MT incidence of ad libitum-fed mice was 37% compared with 22% for intermittently restricted mice and 33% for chronically restricted mice (not significant). There were no differences in MT weight or number among the groups. These results indicate that intermittent caloric restriction-refeeding provides a moderate protective effect, whereas chronic caloric restriction provides no significant protection against MT development in transgenic Neu mice.     

Regional fat pad growth and cellularity in obese zucker rats: modulation by caloric restriction

OBJECTIVE: To investigate, in young obese male Zucker rats, the effects of chronic food restriction and subsequent refeeding on: 1). parameters of nonadipose and adipose growth, 2). regional adipose depot cellularity [fat cell volume (FCV) and number], and 3). circulating leptin levels. RESEARCH METHODS AND PROCEDURES: Obese (fa/fa) and lean (Fa/?) male Zucker rats were studied from age 5 to 19 weeks. After baseline food intake monitoring, 10 obese rats were subjected to 58 days of marked caloric restriction from ad libitum levels [obese-restricted (OR)], followed by a return to ad libitum feeding for 22 days. Ten lean control rats and 10 obese control rats were fed ad libitum for the entire experiment. All rats were fed using a computer-driven automated feeding system designed to mimic natural eating patterns. RESULTS: After food restriction, OR rats weighed significantly less than did lean and obese rats and showed a significant diminution in body and adipose growth as compared with obese rats. Relative adiposity was not different between obese and OR rats and was significantly higher than that of lean rats. The limitation in growth of the adipose tissue mass in OR rats was due mostly to suppression of fat cell proliferation because the mean FCV in each of the four depots was not affected. Serum leptin levels of OR and obese rats were not different from each other but were significantly higher than those of lean rats. DISCUSSION: Marked caloric restriction affects obese male Zucker rats in a manner different from that of nongenetic rodent models (i.e., Wistar rats). In comparison with the response to caloric deprivation of Wistar rats, these calorically restricted obese male Zucker rats appeared to defend their relative adiposity and mean FCV at the expense of fat cell number. These findings indicate that genetic and/or tissue-specific controls override the general consequences of food restriction in this genetic model of obesity.     

The effect of caloric restriction and glycemic load on measures of oxidative stress and antioxidants in humans: Results from the calerie trial of human caloric restriction

Decreasing oxidative stress and increasing antioxidant defense has been hypothesized as one mechanism by which caloric restriction (CR) increases longevity in animals. A total of 46 moderately overweight volunteers (BMI: 252-30 kg/m²), ages 20–42 yr were randomized to either high glycemic (HG) or low glycemic (LG) dietary load CR regimen at either 10% (n=12) or 30% (n=34) of basal caloric intake. All food was provided to participants for 6 mo. Overall, after controlling for CR levels and dietary regimen for 6 mo, plasma glutathione peroxidase activity increased (p=0.04) and plasma protein carbonyl levels decreased (p=0.02) and a non-significant decrease in plasma 8-epi-prostaglandin F2α level was observed (p=0.09). No significant change was observed in other plasma antioxidants such as superoxide dismutase and catalase. These findings indicate that short term CR (10% or 30%) in moderately overweight subjects modulates some but not all measures of antioxidant defense and oxidative stress.