Impact Of Caloric Restriction Research Articles

Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy.

BackgroundSevere calorie restriction (CR) is shown to improve or even reverse β-cell dysfunction in patients with obesity and type 2 diabetes mellitus. However, whether mild to moderate CR can reverse β-cell dysfunction induced by obesity and the underlying mechanism remain unclear. Autophagy plays an important role in maintaining mass, architecture and function of β-cells. While the impact of CR on β-cell autophagy is unknown. This study aims to investigate the effects of moderate CR on β-cell function and autophagy activity in diet-induced obese (DIO) mice.MethodsDIO C57BL/6 mice were subjected to 3 weeks of switching to normal chow (HF → NC group) or normal chow with 40 % CR (HF → NC CR group). Then hematoxylin-eosin and immunohistochemistry staining were performed to observe β-cell morphology. β-cell function was evaluated by intraperitoneal glucose tolerance test in vivo and static GSIS (glucose-stimulated insulin secretion) in isolated islets. β-cell autophagy activity was determined by transmission electron microscope and western blot.ResultsIn the HF → NC CR group, CR normalized body weights, completely restored glucose tolerance, early-phase and second-phase insulin secretion, insulin sensitivity, and islet size. CR also normalized insulin content and glucose-stimulated insulin secretion in isolated islets in vitro. Furthermore, β-cell autophagy level was increased in the HF → NC CR group, but AMPK phosphorylation remained unchanged. Although HF → NC mice achieved moderate weight loss and normal glucose tolerance, their insulin secretion was not improved compared with obese control mice, and additionally, β-cell autophagy was not activated in these mice.ConclusionsModerate (40 %) CR to achieve normal weight reversed β-cell dysfunction and insulin resistance, and restored glucose homeostasis in DIO mice. Furthermore, the up-regulation of β-cell autophagy may play a role in this process, independent of AMPK activation.

Impact of caloric restriction and caloric restriction-mimetics on brain structure and function in older adults and patients with mild cognitive impairment

Impact of caloric restriction and caloric restriction-mimetics on brain structure and function in older adults and patients with mild cognitive impairment

Impact of calorie restriction on epigenetic factors and metabolic pathways during senescence

Ageing is an irreversible process associated with numerous physiological alterations across multiple organ systems. It is determined by genetic and epigenetic background in addition to environmental factors associated with social structure, culture and lifestyle. Recently different studies have shown that calorie restriction (CR) plays a noticeable role in the path of delaying senescence by modulating epigenetic factors and metabolic pathways. CR elicits co-ordinated adaptive stress responses at the cellular and whole organism level by modulating epigenetic mechanisms (e.g., DNA methylation, histone modification and miRNA modification ), signaling pathways that regulate cell growth and ageing (e.g., TOR, AMPK, p53 and FOXO ) and cell-to cell signaling molecules (e.g., adiponectin ). Despite of this fact, CR appears to be one of the common ways to increase lifespan in all species. Nutrient sensing pathways are also considered as contributing factors in ageing process because several nutrients can activate different pathways directly or indirectly. Therefore, this review paper focuses on how the epigenetic factors can be influenced by CR during senescence.

Impact of caloric restriction on myocardial ischaemia/reperfusion injury and new therapeutic options to mimic its effects

Caloric restriction (CR) is the most reliable intervention to extend lifespan and prevent age-related disorders in various species from yeast to rodents. Short- and long-term CR confers cardio protection against ischaemia/reperfusion injury in young and even in aged rodents. A few human trials suggest that CR has the potential to mediate improvement of cardiac or vascular function and induce retardation of cardiac senescence also in humans. The underlying mechanisms are diverse and have not yet been clearly defined. Among the known mediators for the benefits of CR are NO, the AMP-activated PK, sirtuins and adiponectin. Mitochondria, which play a central role in such complex processes within the cell as apoptosis, ATP-production or oxidative stress, are centrally involved in many aspects of CR-induced protection against ischaemic injury. Here, we discuss the relevant literature regarding the protection against myocardial ischaemia/reperfusion injury conferred by CR. Furthermore, we will discuss drug targets to mimic CR and the possible role of calorie restriction in preserving cardiovascular function in humans.

Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects

Obesity is characterized by dysfunctional white adipose tissue (WAT) that ultimately may lead to metabolic diseases. Calorie restriction (CR) reduces the risk for age and obesity-associated complications. The impact of CR on obesity has been examined with human intervention studies, which showed alterations in circulating adipokines. However, a direct effect of CR on the human adipocyte secretome remains elusive. Therefore, the effect of a 96h low glucose CR on the secretion profile of in vitro cultured mature human SGBS adipocytes was investigated by using proteomics technology. Low-glucose CR decreased the adipocyte triglyceride contents and resulted in an altered secretion profile. Changes in the secretome indicated an improved inflammatory phenotype. In addition, several adipocyte-secreted proteins related to insulin resistance showed a reversed expression after low-glucose CR. Furthermore, 6 novel CR-regulated adipocyte-secreted proteins were identified. Since resveratrol (RSV) mimics CR we compared results from this study with data from our previous RSV study on the SGBS adipocyte secretome. The CR and RSV adipocyte secretomes partly differed from each other, although both treatment strategies lead to secretome changes indicating a less inflammatory phenotype. Furthermore, both treatments induced SIRT1 expression and resulted in a reversed expression of detrimental adipokines associated with metabolic complications.

The effects of caloric restriction and age on thyroid hormone signalling in the heart of rats

Thyroid hormones (TH) are believed to participate in adaptation of the heart to dietary caloric restriction (CR). The effect of CR on cardiac thy- roid hormone receptors α and β (TRα and TR β) has been hitherto insufficiently investigated, however, and with respect to the impact of CR on cardiac type 2 and 3 deiodinases (D2 and D3), we have not found any literature data. The aim of this study was to assess the effect of CR and age on thyroid hormone (TH) signalling (D2, D3, TR α and β) and myosin heavy chain β (BMHC) in the heart. The study was performed on 17-week- and 45-week-old male Sprague Dawley rats, fed ad libitum (AL) or restricted to 80% or 60% of AL energy intake. Plasma concentrations of TSH, total and free T3 and T4 (fT3 and fT4), protein levels of heart D2 and D3, THRα, THRβ, myosin heavy chain β (BMHC) mRNA expression and cardiac BMHC protein were determined. Morphological and endocrine parameters were influenced by age (fT3/T3, fT4/T4, THRα, BMHC protein), feeding level (TSH, T4, T3, BMHC mRNA), or by both age and feed- ing level (body weight, fT4, fT3). Caloric restriction reduced fT3, T4, and fT4 levels in both age groups, with additional decreases in TSH and T3 occurring in younger rats. Independently of age, cardiac BMHC expression was positively correlated with cardiac D3 and negatively with food intake and thyroid hor- mones. The most important finding of our study is that cardiac D3 and BMHC protein are, under conditions of differentiated dietary energy supply, directly related in both young and middle-aged rats.

Acute caloric restriction improves glomerular filtration rate in patients with morbid obesity and type 2 diabetes

AimThe role of caloric restriction in the improvement of renal function following bariatric surgery is still unclear; with some evidence showing that calorie restriction can reduce proteinuria. However, data on the impact of caloric restriction on renal function are still lacking. MethodsRenal function, as measured by glomerular filtration rate (GFR), was evaluated in 14 patients with type 2 diabetes mellitus, morbid obesity and stage 2 chronic kidney disease before and after a 7-day very low-calory diet (VLCD). ResultsAfter the VLCD, both GFR and overall glucose disposal (M value) significantly increased from 72.6±3.8mL/min/1.73m−2 BSA to 86.9±6.1mL/min/1.73m−2 BSA (P=0.026) and from 979±107μmol/min1/m2 BSA to 1205±94μmol/min1/m2 BSA (P=0.008), respectively. A significant correlation was observed between the increase in GFR and the rise in M value (r=0.625, P=0.017). ConclusionOur observation of improved renal function following acute caloric restriction before weight loss became relevant suggesting that calory restriction per se is able to affect renal function.

Glucose depletion is essential for the calorie-restriction-mediated cardiac angiogenesis via PKA/AMPK-dependent autophagy

Purpose: In last ESC meeting, we presented the impact of calorie restriction (CR) on cardiac remodeling observed in diet-induced obesity mice and pressure-over-loaded heart failure mouse model (ESC 2012, YIA runner of basic research); however, it remains unclear whether #1 the essential nutrient factor(s) that may be responsible for the CR-mediated enhanced cardiac angiogenesis and #2 the underlying molecular mechanism(s). Methods: Using both murine models of heart failure and cultured cardiomyocytes and endothelial cells, we examined mechanisms of CR-induced cardiac angiogenesis. Eighteen-week-old diet-induced obesity (DIO) mice, as a chronic heart failure model that exhibits characteristics of diabetic cardiomyopathy, were allocated into 4 week CR (DIO-CR) and ad libitum (DIO-AL) groups. Pressure overload (2 weeks) was generated by transaortic constriction (TAC) in mice, which were used as a acute heart failure induced by mechanical stress, and randomly allocated to a 4-week CR (TAC-CR and sham-CR) and ad libitum (TAC-AL and sham-AL) groups, and analyzed at 18 week-old. Cultured endothelial cells (ECs) were divided into 4 groups that exposed to culture media of 1) ordinary composition, 2) glucose-depleted, 3) amino acid-depleted, and 4) serum-depleted condition, respectively. Analyses for the changes in activities of autophagy (LC3-turnover assay and p62 level) and angiogenesis (tube formation and Akt/AMPK/eNOS activity) were evaluated. Results: Immunohistochemical analyses revealed that CR enhanced cardiac angiogenesis both in TAC and DIO mice. CR promoted increased in myocardial cyclic AMP concentration with concomitant PKA/AMPK/eNOS activation and the simultaneous increase in autophagic activity both in TAC and DIO hearts. Of note, cardiac Akt activity remains unchanged by CR. In vitro analysis revealed that glucose depletion, as well as forskolin (10 μM) and 8-bromo-cyclic AMP (1 mM), activated PKA/AMPK axis thereby facilitated angiogenesis and autophagy in ECs. The enhanced in vitro angiogenesis induced by glucose depletion and PKA enhancers was abrogated by autophagy inhibitor 3-MA treatment. PKA inhibitors (H89 and RP-cAMP) abrogated the increase in AMPK/eNOS phosphorylation levels induced by glucose depletion. Neither amino acid- nor serum-depletion had no effect on angiogenesis and autophagy. Conclusions: Glucose depletion is essential for the CR-mediated activation of cardiac angiogenesis and autophagy in a cAMP/PKA/AMPK-dependent fashion.

Caloric Restriction

While the impact of caloric restriction on human health is not fully understood, there is strong evidence to support further studies of its influence on cardiovascular health. The purpose of this review was to update the state of the science by examining the relevant literature regarding calorie-restriction effects on aging and cardiovascular health and to discuss the possible role(s) of calorie restriction in preserving cardiovascular function in humans. For purpose of this review, we have defined calorie restriction as a reduction in energy intake well below the amount of calories that would be consumed ad libitum (≥10% in humans, ≥20% in animals). We examined the relevant literature on calorie-restriction effects on longevity and cardiovascular health, with an emphasis on the state of the science regarding calorie restriction in humans. We have emphasized the importance of the preliminary and expected findings from the Comprehensive Assessment of the Long-term Effect of Reducing Intake of Energy trial. Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms. On the basis of its known benefits to cardiometabolic health, including modest calorie restriction in a combined lifestyle program is likely to improve heart health and prevent subsequent cardiovascular events in overweight and obese individuals. Additional study is needed to further illuminate its long-term applicability for older adults and for those with significant comorbidities, such as heart failure.

Calorie restriction and cancer prevention: a mechanistic perspective

Calorie restriction (CR) is one of the most potent broadly acting dietary interventions for inducing weight loss and for inhibiting cancer in experimental models. Translation of the mechanistic lessons learned from research on CR to cancer prevention strategies in human beings is important given the high prevalence of excess energy intake, obesity, and metabolic syndrome in many parts of the world and the established links between obesity-associated metabolic perturbations and increased risk or progression of many types of cancer. This review synthesizes findings on the biological mechanisms underlying many of the anticancer effects of CR, with emphasis on the impact of CR on growth factor signaling pathways, inflammation, cellular and systemic energy homeostasis pathways, vascular perturbations, and the tumor microenvironment. These CR-responsive pathways and processes represent targets for translating CR research into effective cancer prevention strategies in human beings.

Carolic Restriction Ameliorates Cardiac Steatosis by Activation of Autophagy via Cyclic AMP/AMPK/PKA Axis

Caloric restriction (CR) promotes beneficial cardiovascular effects and enhances autophagy partly via the cyclic-AMP elevation. Cardiac steatosis impairs cardiac function associated with myocardial lipid accumulation and lipotoxic injury. However, the impact of CR on the cardiac steatosis remains unclear.

Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study

Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.

Abstract A94: Effects of different modes of calorie restriction on mammalian target of rapamycin (mTOR) and IGF-I signaling pathways in mammary fat pads and tumors

Abstract Chronic calorie restriction (CCR) is an effective experimental intervention to prevent spontaneous and carcinogen-induced mammary tumor (MT) development in rodents. The prevailing wisdom has been that protection is proportional to the degree of restriction, however, we have reported that intermittent calorie restriction (ICR) provides greater protection in breast and prostate cancer models than CCR despite the same overall amount of restriction. One pathway of interest with respect to the impact of calorie restriction and cancer development is the mammalian target of rapamycin (mTOR) signaling pathway. Modulation of mTOR signaling proteins by calorie restriction has been reported in various tissues and cancer models. Here the impact of ICR versus CCR on MT development and proteins associated with mTOR and IGF-I signaling pathways in mammary fat pads (MFP) and MTs from MMTV-TGF-α mice were determined. Mice were enrolled at 10 wks of age into ad-libitum-fed (AL), CCR (25% reduction) and ICR (cycles of 3 weeks of 50% reduced intake and 3 weeks of AL intake resulting in overall reduction of 25%). Groups were followed until 37/38 or 73/74 wks of age. Time points 37 and 73 followed three wks of 50% calorie restriction for ICR mice (ICR-Restricted), while 38 and 74 followed one wk of refeeding of ICR mice (ICR-Refed).At 37/38 wks, 1/11, 2/10 and 0/15, AL, CCR and ICR mice had histopathologically confirmed MTs and at 73/74 wks the values were 9/17, 5/15 and 5/22, respectively. Both protocols significantly reduced serum IGF-I levels compared to AL mice. At 37/38 wks, IGF-I receptor (IGF-IR) expression levels from MFP of ICR-Restricted and CCR mice were significantly (∼20%) lower than AL mice, while .there were no differences for IGF-IR levels between ICR-Refed and AL mice. Further at 37/38 IGFBP3 protein expression levels in MFP were significantly higher in ICR-Restricted and CCR mice compared to AL mice while for ICR-Refed mice expression was similar to AL mice. Both types of calorie restriction decreased p70S6K, HIF-1, EGFR protein expression levels and Erk and Akt protein activation, although it increased p4EBP1 and VEGF protein expression levels. At wk 73/74 there were no differences for IGF-IR levels in MFP tissue and AMPK activation was similar in AL, ICR-Restricted and ICR-Refed mice. Erk1/2 protein activation level was significantly higher only in ICR-Restricted compared to the AL group. At 73/74 wks sufficient MT tissue was available for analyses. Both modes of calorie restriction lowered IGF-I protein expression levels and Akt activation in MTs and IGF-IR expression levels were significantly lower in all calorie restricted groups compared to the AL mice. In contrast only CCR increased mTOR, p70S6K, p4EBP1, and HIF-1 protein expression levels in MTs. On the other hand, ICR had inconsistent effects on these proteins in MTs at the 73/74 time point. In MTs from ICR-Restricted mice AMPK activation was significantly lower compared to the AL mice while the value for ICR-Refed mice was similar to AL mice. These findings confirm that calorie restriction, particularly intermittent calorie restriction delays the early development of MTs and that mTOR signaling proteins are modulated by tissue, age and type of calorie restriction. (Support CA101858 (MPC), DK16105 (JPG), The Breast Cancer Research Foundation and The Hormel Foundation). Citation Information: Cancer Prev Res 2010;3(12 Suppl):A94.

Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle

Sarcopenia is the age-related loss of skeletal muscle mass and function and is characterized by a reduction in muscle mass and fiber cross-sectional area, alterations in muscle fiber type and mitochondrial functional changes. In rhesus monkeys, calorie restriction (CR) without malnutrition improves survival and delays the onset of age-associated diseases and disorders including sarcopenia. We present a longitudinal study on the impact of CR on early stage sarcopenia in the upper leg of monkeys from ~ 16 years to ~ 22 years of age. Using dual-energy X-ray absorptiometry we show that CR delayed the development of maximum muscle mass and, unlike Control animals, muscle mass of the upper leg was preserved in CR animals during early phase sarcopenia. Histochemical analyses of vastus lateralis muscle biopsies revealed that CR opposed age-related changes in the proportion of Type II muscle fibers and fiber cross-sectional area. In contrast the number of muscle fibers with mitochondrial electron transport system enzyme abnormalities (ETS ab) was not significantly affected by CR. Laser capture microdissection of ETS ab fibers and subsequent PCR analysis of the mitochondrial DNA revealed large deletion mutations in fibers with abnormal mitochondrial enzyme activities. CR did not prevent stochastic mitochondrial deletion mutations in muscle fibers but CR may have contributed to the maintenance of affected fibers.

Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research

Calorie restriction (CR) is arguably the most potent, broadly acting dietary regimen for suppressing the carcinogenesis process, and many of the key studies in this field have been published in Carcinogenesis. Translation of the knowledge gained from CR research in animal models to cancer prevention strategies in humans is urgently needed given the worldwide obesity epidemic and the established link between obesity and increased risk of many cancers. This review synthesizes the evidence on key biological mechanisms underlying many of the beneficial effects of CR, with particular emphasis on the impact of CR on growth factor signaling pathways and inflammatory processes and on the emerging development of pharmacological mimetics of CR. These approaches will facilitate the translation of CR research into effective strategies for cancer prevention in humans.

Resistance Training Does Not Contribute to Improving the Metabolic Profile after a 6-Month Weight Loss Program in Overweight and Obese Postmenopausal Women

Limited data are available regarding the impact of caloric restriction (CR) in combination with resistance training (RT) on the metabolic profile of postmenopausal women. The objective of the study was to determine whether RT adds to CR in improving body composition and the metabolic profile. This was a 6-month, randomized, clinical trial. Patients included 107 postmenopausal women (body mass index >27 kg/m(2)). The intervention was a 6-month CR alone or in combination with a RT program. Fat mass (FM), lean body mass (LBM), abdominal sc fat and visceral fat, fasting lipids, insulin sensitivity, resting blood pressure, and inflammation markers were measured. Both groups were similar at baseline and significantly decreased body weight, body mass index, FM, percent FM, abdominal sc fat, and visceral fat after the study (P < 0.001), with greater losses of percent FM and trunk FM in the CR + RT group (P < 0.05). LMB significantly decreased in the CR (-0.9 +/- 2.4 kg) and the CR+RT (-0.4 +/- 2.2 kg) groups (P < 0.005), with no difference between them. Both groups significantly improved plasma triglycerides, fasting insulin level, glucose disposal, and markers of the inflammation profile after weight loss (P < 0.05), with no difference between groups. No improvements were observed for the other variables of interest in both groups. CR+RT was associated with greater losses in percent FM and trunk FM compared with CR alone. However, CR+RT was not associated with additional improvements in the metabolic profile compared with CR alone.

1103 Cardiovascular magnetic resonance assessment of epicardial fat volume: impact of weight reduction in obese males

Introduction Epicardial fat covers 80% of the heart and constitutes 20% of its weight. Epicardial fat and its known relationship with abdominal obesity and coronary atherosclerosis, may render this a sensitive risk predictor of adverse cardiovascular events. The aim of this study was to effectively evaluate the impact of caloric restriction and associated weight reduction on epicardial fat volume via cardiac magnetic resonance imaging (CMR).

Identifying the Genes and Genetic Interrelationships Underlying the Impact of Calorie Restriction on Maximum Lifespan: An Artificial Intelligence-Based Approach

Novel artificial intelligence methodologies were applied to analyze gene expression microarray data gathered from mice under a calorie restriction (CR) regimen. The data were gathered from three previously published mouse studies; these datasets were merged together into a single composite dataset for the purpose of conducting a broader-based analysis. The result was a list of genes that are important for the impact of CR on lifespan, not necessarily in terms of their individual actions but in terms of their interactions with other genes. Furthermore, a map of gene interrelationships was provided, suggesting which intergene interactions are most important for the effect of CR on life extension. In particular our analysis showed that the genes Mrpl12, Uqcrh, and Snip1 play central roles regarding the effects of CR on life extension, interacting with many other genes (which the analysis enumerates) in carrying out their roles. This is the first time that the genes Snip1 and Mrpl12 have been identified in the context of aging. In a follow-up analysis aimed at validating these results, the analytic process was rerun with a fourth dataset included, yielding largely comparable results. Broadly, the biological interpretation of these analytical results suggests that the effects of CR on life extension are due to multiple factors, including factors identified in prior theories of aging, such as the hormesis, development, cellular, and free radical theories.

Gene Expression Profiling of Cardiac Aging: Impact of Caloric Restriction and Other Nutritional Interventions

Gene Expression Profiling of Cardiac Aging: Impact of Caloric Restriction and Other Nutritional Interventions

Energy expenditure of calorically restricted rats is higher than predicted from their altered body composition

Debate exists over the impact of caloric restriction (CR) on the level of energy expenditure. At the whole animal level, CR decreases metabolic rates but in parallel body mass also declines. The question arises whether the reduction in metabolism is greater, smaller or not different from the expectation based on body mass change alone. Answers to this question depend on how metabolic rate is normalized and it has recently been suggested that this issue can only be resolved through detailed morphological investigation. Added to this issue is the problem of how appropriate the resting energy expenditure is to characterize metabolic events relating to aging phenomena. We measured the daily energy demands of young and old rats under ad libitum (AD) food intake or 40% CR, using the doubly labeled water (DLW) method and made detailed morphological examination of individuals, including 21 different body components. Whole body energy demands of CR rats were lower than AD rats, but the extent of this difference was much less than expected from the degree of caloric restriction, consistent with other studies using the DLW method on CR animals. Using multiple regression and multivariate data reduction methods we built two empirical predictive models of the association between daily energy demands and body composition using the ad lib animals. We then predicted the expected energy expenditures of the CR animals based on their altered morphology and compared these predictions to the observed daily energy demands. Independent of how we constructed the prediction, young and old rats under CR expended 30 and 50% more energy, respectively, than the prediction from their altered body composition. This effect is consistent with recent intra-specific observations of positive associations between energy metabolism and lifespan and theoretical ideas about mechanisms underpinning the relationship between oxygen consumption and reactive oxygen species production in mitochondria.