Mild Caloric Restriction Research Articles

Ghrelin receptor in agouti-related peptide neurones regulates metabolic adaptation to calorie restriction.

Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain, with the highest expression in agouti-related peptide (AgRP) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that AgRP neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype-specific GHS-R knockout mouse (AgRP-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with one-quarter of food allotment given in the beginning of the light cycle and three-quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The CR-fed AgRP-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed AgRP-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these CR-fed AgRP-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP-Cre;Ghsrf/f mice revealed increased AgRP expression and a decreased expression of genes in β-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.

Age- and Experience-Related Plasticity of ATP-Mediated Signaling in the Neocortex.

There is growing recognition of the important role of interaction between neurons and glial cells for brain longevity. The extracellular ATP have been shown to bring significant contribution into bi-directional glia-neuron communications, in particular into astrocyte-driven modulation of synaptic plasticity. To elucidate a putative impact of brain aging on neuron-glia networks, we explored the aging-related plasticity of the purinoreceptors-mediated signaling in cortical neurons and astrocytes. We investigated the age- and experience-related alterations in purinergic components of neuronal synaptic currents and astroglial calcium signaling in the layer2/3 of neocortex of mice exposed to the mild caloric restriction (CR) and environmental enrichment (EE) which included ad libitum physical exercise. We observed the considerable age-related decline in the neuronal P2X receptor-mediated miniature spontaneous currents which originated from the release of ATP from both synapses and astrocytes. We also found out that purinergic astrocytic Ca2+-signaling underwent the substantial age-related decline but EE and CR rescued astroglial signaling, in particular mediated by P2X1, P2X1/5, and P2Y1 receptors. Our data showed that age-related attenuation in the astroglial calcium signaling caused a substantial decrease in the exocytosis of ATP leading to impairment of astroglia-derived purinergic modulation of excitatory synaptic currents and GABAergic tonic inhibitory currents. On a contrary, exposure to EE and CR, which enhanced purinergic astrocytic calcium signaling, up-regulated the excitatory and down-regulated the inhibitory currents in neurons of old mice, thus counterbalancing the impact of aging on synaptic signaling. Combined, our results strongly support the physiological importance of ATP-mediated signaling for glia-neuron interactions and brain function. Our data also show that P2 purinoreceptor-mediated communication between astrocytes and neurons in the neocortex undergoes remodeling during brain aging and decrease in the ATP release may contribute to the age-related impairment of synaptic transmission.

Caloric restriction induces H2O2 formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII

Caloric restriction (CR) improves endothelial function through the upregulation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, hydrogen peroxide (H2O2) is upregulated in yeast subjected to CR. Our aim was to assess if mild short-term CR increases vascular H2O2 formation as a link with AMPK and eNOS activation.Twelve-week old Zucker obese (fa/fa) and control Zucker lean male rats were fed a standard chow either ad libitum (AL, n=10) or with a 20% CR (CR, n=10) for two weeks. CR significantly improved relaxation to ACh in fa/fa rats because of an enhanced endogenous production of H2O2 in aortic rings (H2O2 levels fa/faAL=0.5 ± 0.05 nmol/mg vs. H2O2 levels fa/faCR=0.76 ± 0.07 nmol/mg protein; p<0.05). Expression of mitochondrial superoxide dismutase (Mn-SOD) and total SOD activity were increased in aorta from fa/fa animals after CR. In cultured aortic endothelial cells, serum deprivation or 2-deoxy-d-glucose induced a significant increase in: i) superoxide anion and H2O2 levels, ii) p-AMPK/AMPK and p-eNOS/eNOS expression and iii) nitric oxide levels. This effect was reduced by catalase and strongly inhibited by Ca2+/calmodulin-dependent kinase II (CamkII) silencing.In conclusion, we propose that mild short-term CR might be a trigger of mechanisms aimed at protecting the vascular wall by the increase of H2O2, which then activates AMPK and nitric oxide release, thus improving endothelium-dependent relaxation. In addition, we demonstrate that CAMKII plays a key role in mediating CR-induced AMPK activation through H2O2 increase.

High-Esterified Pectin Reverses Metabolic Malprogramming, Improving Sensitivity to Adipostatic/Adipokine Hormones.

Detrimental metabolic programming has become a determinant factor in obesity propensity and the development of metabolic disorders; therefore, the search of nutritional strategies to reverse it is very relevant. Pectin is a prebiotic with health-promoting effects, such as control of glucose homeostasis and lipid metabolism, although other possible health effects and the prevention of obesity have been poorly studied. We studied the effects of chronic physiological supplementation with high-esterified pectin (HEP) in the reversion of metabolic nutrition-sensitive malprogramming associated with gestational undernutrition. As a model of nutrition-sensitive malprogramming, we used the progeny of rats with mild calorie restriction (CR) during pregnancy and analyzed their performance under metabolic stress (high-sucrose diet). We focused on the study of the sensitivity to the main adipostatic/adipokine hormones, i.e., leptin, insulin, and adiponectin, at both peripheral (liver and circulating parameters) and central (hypothalamus) levels. Our main findings suggest that chronic HEP supplementation is able to prevent weight/fat gain, to substantially reverse the detrimental malprogramming caused by the CR condition, to improve general health circulating markers, to modulate oxidative/lipogenic balance in the liver and energy metabolism regulators in the hypothalamus, and to restore/improve adipostatic/adipokine sensitivity affected by maternal calorie restriction, both peripherally and centrally. HEP stands out as a food component potentially useful against the development of metabolic disorders and obesity.

Differential Metabolic Responses to Adipose Atrophy Associated with Cancer Cachexia and Caloric Restriction in Rats and the Effect of Rikkunshito in Cancer Cachexia.

Despite the similar phenotypes, including weight loss, reduction of food intake, and lower adiposity, associated with caloric restriction (CR) and cancer cachexia (CC), CC is a progressive wasting syndrome, while mild CR improves whole body metabolism. In the present study, we compared adipose metabolic changes in a novel rat model of CC, mild CR (70% of the food intake of control rats, which is similar to the food consumption of CC rats), and severe CR (30% of the food intake of controls). We show that CC and severe CR are associated with much smaller adipocytes with significantly lower mitochondrial DNA content; but, that mild CR is not. CC and both mild and severe CR similarly upregulated proteins involved in lipolysis. CC also downregulated proteins involved in fatty acid biosynthesis, but mild CR upregulated these. These findings suggest that CC might impair de novo fatty acid biosynthesis and reduce mitochondrial biogenesis, similar to severe CR. We also found that rikkunshito, a traditional Japanese herbal medicine, does not ameliorate the enhanced lipolysis and mitochondrial impairment, but rather, rescues de novo fatty acid biosynthesis, suggesting that rikkunshito administration might have partially similar effects to mild CR.

Diversity of Astroglial Effects on Aging- and Experience-Related Cortical Metaplasticity

Activity-dependent regulation of synaptic plasticity, or metaplasticity, plays a key role in the adaptation of neuronal networks to physiological and biochemical changes in aging brain. There is a growing evidence that experience-related alterations in the mechanisms of synaptic plasticity can underlie beneficial effects of physical exercise and caloric restriction (CR) on brain health and cognition. Astrocytes, which form neuro-vascular interface and can modulate synaptic plasticity by release of gliotransmitters, attract an increasing attention as important element of brain metaplasticity. We investigated the age- and experience-related alterations in astroglial calcium signaling and stimulus-dependence of long-term synaptic plasticity in the neocortex of mice exposed to the mild CR and environmental enrichment (EE) which included ad libitum physical exercise. We found out that astrocytic Ca2+-signaling underwent considerable age-related decline but EE and CR enhanced astroglial signaling, in particular mediated by noradrenaline (NA) and endocannabinoid receptors. The release of ATP and D-Serine from astrocytes followed the same trends of age-related declined and EE-induced increase. Our data also showed that astrocyte-derived ATP and D-Serine can have diverse effects on the threshold and magnitude of long-term changes in the strength of neocortical synapses; these effects were age-dependent. The CR- and EE-induced enhancement of astroglial Ca2+-signaling had more stronger effect on synaptic plasticity in the old (14–18 months) than in the young (2–5 months) wild-type (WT) mice. The effects of CR and EE on synaptic plasticity were significantly altered in both young and aged dnSNARE mice. Combined, our data suggest astrocyte-neuron interactions are important for dynamic regulation of cortical synaptic plasticity. This interaction can significantly decline with aging and thus contributes to the age-related cognitive impairment. On another hand, experience-related increase in the astroglial Ca2+-signaling can ameliorate the age-related decline.

Effects of 8-hour time restricted feeding on body weight and metabolic disease risk factors in obese adults: A pilot study

BACKGROUND:Time restricted feeding decreases energy intake without calorie counting and may be a viable option for weight loss. However, the effect of this diet on body weight in obese subjects has never been examined.OBJECTIVE:This study investigated the effects of 8-h time restricted feeding on body weight and metabolic disease risk factors in obese adults.DESIGN:Obese subjects (n = 23) participated in an 8-h time restricted feeding intervention (ad libitum feeding between 10:00 to 18:00 h, water fasting between 18:00 to 10:00 h) for 12 weeks. Weight loss and other outcomes were compared to a matched historical control group (n = 23).RESULTS:Body weight and energy intake decreased in the time restricted group (–2.6% ± 0.5; –341 ± 53 kcal/d) relative to controls over 12 weeks (P < 0.05). Systolic blood pressure decreased in the time restricted feeding group (–7 ± 2 mm Hg) versus controls (P < 0.05). Fat mass, lean mass, visceral fat mass, diastolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose, fasting insulin, HOMA-IR, and homocysteine were not significantly different from controls after 12 weeks (no group×time interaction).CONCLUSION:These findings suggest that 8-h time restricted feeding produces mild caloric restriction and weight loss, without calorie counting. It may also offer clinical benefits by reducing blood pressure.

Characterizing the physiologic effects of exogenous ketone supplements – an alternative or adjuvant to the ketogenic diet

The ketogenic diet (KD) is a high fat, adequate protein, low carbohydrate diet that is used clinically for refractory pediatric epilepsy, and is under investigation as a treatment for a wide variety of disorders, including many neurological diseases, cancer, obesity, and diabetes. Studies suggest that many of the beneficial effects associated with the KD are mechanistically attributable to the ketone bodies, leading our lab and others to develop and test exogenous ketone supplements (KS). KS elevate blood ketones without the need for dietary restriction of carbohydrate. In order to further our understanding of this new technology, we sought to characterize the metabolic effects, safety, and toxicity of KS in healthy rats. KS tested include the R,S‐1,3‐butanediol acetoacetate diester, 1,3‐butanediol, medium chain triglyceride oil, caprylic acid, and beta‐hydroxybutyrate mineral salts, alone and in various combinations. Healthy rats were administered KS by oral gavage or in their food in an acute (once, or 7 days), sub‐chronic (1 month) or chronic (4 months) fashion and analyzed for a variety of metabolic and physiologic biomarkers. KS rapidly elevate blood ketones to therapeutic levels (2–5mM), and simultaneously decrease blood glucose. Some types of KS induce a mild calorie restriction effect, and preliminary evidence suggests ketone ester treatment during CR may preserve lean muscle mass in this catabolic state via a non‐insulin dependent mechanism. Satiety may be increased by KS as demonstrated by an elevation in leptin following KE administration, even when animals were self calorie‐restricting. KS significantly alters the global metabolome, indicating a shift from carbohydrate‐based to fat‐based metabolism. Some markers of this were an elevation in medium chain fatty acids, an increase in acetyl coA and acetylcarnitine suggestive of enhanced mitochondrial LCFA oxidation, and an increase in Kreb's cycle intermediates such as citrate, succinate, and fumarate. Inflammatory profiling following chronic, but not acute, KS administration revealed decreases in many pro‐inflammatory cytokines, including IL‐1β, IL‐6, IFN‐γ, MCP‐1, and RANTES. KS appears safe as there were no signs of toxicity or adverse changes in total cholesterol, HDL, LDL, triglycerides, or markers of liver/kidney function over the chronic treatment protocol. KS may be a useful alternative or adjuvant to the KD for disorders where nutritional ketosis is therapeutic.Support or Funding InformationOffice of Naval Research, Scivation Inc, Disruptive Nutrition, Epigenix FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of weight loss on circulating fatty acid profiles in overweight subjects with high visceral fat area: a 12-week randomized controlled trial

BackgroundSignificant associations between visceral fat and alterations in plasma fatty acids have been identified in overweight individuals. However, there are scant data regarding the relationships of the visceral fat area (VFA) with the plasma fatty acid profiles and desaturase activities following weight loss. We investigated the effect of weight loss with mild calorie restriction on the circulating fatty acid profiles and desaturase activities in nondiabetic overweight subjects with high VFA.MethodsEighty overweight subjects with high VFA (L4 VFA ≥100 cm2) were randomized into the 12-week mild-calorie-restriction (300 kcal/day) or control groups.ResultsComparison of the percent of body weight changes between groups revealed that the weight-loss group had greater reductions in body weight. The VFA decreased by 17.7 cm2 from baseline in the weight-loss group (P < 0.001). At follow-up, the weight-loss group showed greater reductions in serum triglycerides, insulin, and HOMA-IR than the control group. Significantly greater reductions in total saturated fatty acids, palmitic acid, stearic acid, total monounsaturated fatty acids, palmitoleic acid, oleic acid, eicosadienoic acid, and dihomo-γ-linolenic acid levels were detected in the weight-loss group compared with the control group after adjusting for baseline values. Following weight loss, C16 Δ9-desaturase activity was significantly decreased and Δ5-desaturase activity was significantly increased, and the changes were greater in the weight-loss group than in the control group.ConclusionsThe results suggest that mild weight loss improves abdominal obesity, overall fatty acid profiles, and desaturase activities; therefore, mild calorie restriction has potential health benefits related to obesity-related diseases in overweight subjects with high VFA.Trial registrationNCT02992639. Retrospectively registered 11 December 2016.

Whitening and Impaired Glucose Utilization of Brown Adipose Tissue in a Rat Model of Type 2 Diabetes Mellitus

Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by 18F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic 18F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. 18F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased 18F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.

Less is more: Caloric regulation of neurogenesis and adult brain function.

Calorie intake is essential for regulating normal physiological processes and is fundamental to maintaining life. Indeed, both extremes of calorie intake result in increased morbidity and mortality. In this review, we discuss the effect of calorie intake on adult brain function, with an emphasis on the beneficial effects of mild calorie restriction. Recent findings relating to the regenerative and protective effects of the gastrointestinal hormone, ghrelin, suggest that it may underlie the beneficial effects of calorie restriction. We discuss the putative cellular mechanisms underlying the action of ghrelin and their possible role in supporting healthy brain ageing.

Exercise initiated after the onset of insulin resistance improves trabecular microarchitecture and cortical bone biomechanics of the tibia in hyperphagic Otsuka Long Evans Tokushima Fatty rats

The present study extends our previous findings that exercise, which prevents the onset of insulin resistance and type 2 diabetes (T2D), also prevents the detrimental effects of T2D on whole-bone and tissue-level strength. Our objective was to determine whether exercise improves bone's structural and material properties if insulin resistance is already present in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF rat is hyperphagic due to a loss-of-function mutation in cholecystokinin-1 receptor (CCK-1 receptor), which leads to progressive obesity, insulin resistance and T2D after the majority of skeletal growth is complete. Because exercise reduces body mass, which is a significant determinant of bone strength, we used a body-mass-matched caloric-restricted control to isolate body-mass-independent effects of exercise on bone. Eight-wk old, male OLETF rats were fed ad libitum until onset of hyperglycemia (20weeks of age), at which time they were randomly assigned to three groups: ad libitum fed, sedentary (O-SED); ad libitum fed, treadmill running (O-EX); or, sedentary, mild caloric restriction to match body mass of O-EX (O-CR). Long-Evans Tokushima Otsuka rats served as the normophagic, normoglycemic controls (L-SED). At 32weeks of age, O-SED rats had T2D as evidenced by hyperglycemia and a significant reduction in fasting insulin compared to OLETFs at 20weeks of age. O-SED rats also had reduced total body bone mineral content (BMC), increased C-terminal telopeptide of type I collagen (CTx)/tartrate resistant acid phosphatase isoform 5b (TRAP5b), decreased N-terminal propeptide of type I procollagen (P1NP), reduced percent cancellous bone volume (BV/TV), trabecular number (Tb.N) and increased trabecular separation (Tb.Sp) and structural model index (SMI) of the proximal tibia compared to L-SED. T2D also adversely affected biomechanical properties of the tibial diaphysis, and serum sclerostin was increased and β-catenin, runt-related transcription factor 2 (Runx2) and insulin-like growth factor-I (IGF-I) protein expression in bone were reduced in O-SED vs. L-SED. O-EX or O-CR had greater total body bone mineral density (BMD) and BMC, and BV/TV, Tb.N, Tb.Sp, and SMI compared to O-SED. O-EX had lower CTx and CR greater P1NP relative to O-SED. O-EX, not O-CR, had greater cortical thickness and area, and improved whole-bone and tissue-level biomechanical properties associated with a 4-fold increase in cortical bone β-catenin protein expression vs. O-SED. In summary, EX or CR initiated after the onset of insulin resistance preserved cancellous bone volume and structure, and EX elicited additional benefits in cortical bone.

Effects of mild calorie restriction on lipid metabolism and inflammation in liver and adipose tissue

Calorie restriction (CR) has been reported to improve lipid metabolism and to decrease inflammatory diseases. However, most existing CR models use 30–50% calorie reduction, which is hard to achieve in humans. We investigated the effects of mild CR on lipid metabolism and inflammatory responses. Male C57BL/6 mice were fed control diet (10% kcal fat, Control) or high fat diet (60% kcal fat, HFD) ad libitum or reduced amount of control diet to achieve 15% CR for 16 wks. Body weights, white adipose tissue weights, liver triacylglycerol levels, and serum fetuin-A levels were lower in CR than in the Control. Serum adiponectin levels were higher in CR and lower in HFD compared with the Control. Liver and adipose tissue Mcp-1 mRNA levels were significantly lower in CR compared with the Control. Adipose tissue mRNA levels of Mcp-1, Il-6, Tnf-α and Socs3 were significantly higher in HFD than in the Control and CR, and levels of these negatively correlated with serum adiponectin levels. CR group had the lowest leptin levels and the highest liver Lepr expression, and Lepr mRNA levels positively correlated with liver Socs3 mRNA levels. Our findings showed that mild CR lowered adiposity which resulted in higher adiponectin and lower fetuin-A levels, and might have contributed to alleviation of inflammatory status in the liver and adipose tissue. Furthermore, mild CR might have affected leptin sensitivity by up-regulating Lepr expression.

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice.

There is increasing evidence that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling (collectively referred to as somatotropic signaling) during development has a profound influence on aging and longevity. Moreover, the absence of GH action was shown to modify responses of adult mice to calorie restriction (CR) and other antiaging interventions. It was therefore of interest to determine whether GH resistance in GH receptor knockout (GHR-KO) mice would modify the effects of mild pre-weaning CR imposed by increasing the number of pups in a litter (the so-called litter crowding). In addition to the expected impact on body weight, litter crowding affected glucose homeostasis, hepatic expression of IGF-1 and genes related to lipid metabolism, and expression of inflammatory markers in white adipose tissue, with some of these effects persisting until the age of 2years. Litter crowding failed to further extend the remarkable longevity of GHR-KO mice and, instead, reduced late life survival of GHR-KO females, an effect opposite to the changes detected in normal animals. We conclude that the absence of GH actions alters the responses to pre-weaning CR and prevents this intervention from extending longevity.

Mild and Short-Term Caloric Restriction Prevents Obesity-Induced Cardiomyopathy in Young Zucker Rats without Changing in Metabolites and Fatty Acids Cardiac Profile.

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30–65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile.

Age-related alterations in the sarcolemmal environment are attenuated by lifelong caloric restriction and voluntary exercise

Age-related loss of skeletal muscle mass and function, referred to as sarcopenia, is mitigated by lifelong calorie restriction as well as exercise. In aged skeletal muscle fibers there is compromised integrity of the cell membrane that may contribute to sarcopenia. The purpose of this study was to determine if lifelong mild (8%) caloric restriction (CR) and lifelong CR+voluntary wheel running (WR) could ameliorate disruption of membrane scaffolding and signaling proteins during the aging process, thus maintaining a favorable, healthy membrane environment in plantaris muscle fibers. Fischer-344 rats were divided into four groups: 24-month old adults fed ad libitum (OAL); 24-month old on 8% caloric restriction (OCR); 24month old 8% caloric restriction+wheel running (OCRWR); and 6-month old sedentary adults fed ad libitum (YAL) were used to determine age-related changes. Aging resulted in discontinuous membrane expression of dystrophin glycoprotein complex (DGC) proteins: dystrophin and α-syntrophin. Older muscle also displayed decreased content of neuronal nitric oxide synthase (nNOS), a key DGC signaling protein. In contrast, OCR and OCRWR provided significant protection against age-related DGC disruption. In conjunction with the age-related decline in membrane DGC patency, key membrane repair proteins (MG53, dysferlin, annexin A6, and annexin A2) were significantly increased in the OAL plantaris. However, lifelong CR and CRWR interventions were effective at maintaining membrane repair proteins near YAL levels of. OAL fibers also displayed reduced protein content of NADPH oxidase isoform 2 (Nox2) subunits (p67phox and p47phox), consistent with a perturbed sarcolemmal environment. Loss of Nox2 subunits was prevented by lifelong CR and CRWR. Our results are therefore consistent with the hypothesis that lifelong CR and WR are effective countermeasures against age-related alterations in the myofiber membrane environment.

ZMIANY MASY CIAŁA I STĘŻENIA LIPIDÓW PACJENTÓW PODDANYCH RESTRYKCJOM KALORYCZNYM – DONIESIENIE WSTĘPNE

Caloric restriction is the only well-documented nutritional intervention prolonging the life of mammals. This method modifies the lipid levels in blood, controlling obesity and delaying the onset of many medical conditions associated with metabolic disorders. The aim of the study was to carry out a comparative analysis of lipid profile in patients on Mediterranean or CRON (Caloric Restriction with Optimal Nutrition) diets, before and after six weeks of dieting. The following parameters were compared: total cholesterol, total lipids, triglycerides, LDL cholesterol, HDL cholesterol, and BMI. Additionally, we measured the levels of insulin, HOMA score, and anthropometric parameters. The comparative analysis demonstrated a statistically significant correlation between mild caloric restriction and blood lipid profile. Results from studies on patients who underwent six-week dietetic intervention indicated statistically significant changes in biochemical parameters due to caloric restrictions. Such changes were not found in subjects following the Mediterranean diet. The greatest decrease in the blood level of triglycerides was found in subjects on the CRON diet, LDL cholesterol, total cholesterol and total lipid levels also decreased. No significant changes if biochemical parameters were found in patients on the Mediterranean diet. A comparative analysis of all parameters demonstrated that the use of mild caloric restrictions with ensured supply of all necessary nutrients seems to be the most effective solution for reducing fatty tissue.

Association of endothelial proliferation with the magnitude of weight loss during calorie restriction.

Substantial weight loss through intense dietary regimens is thought to ameliorate endothelial dysfunction in obesity. It is less clear whether similar improvements can be achieved with modest dietary interventions. This study aimed to identify the parameters of endothelial cell status in obesity that are affected by mild calorie restriction. Human umbilical vein endothelial cells (EA.hy926 line) in culture were exposed pairwise to serum from 57 individuals with simple obesity (BMI>30kg/m(2)) collected before and after 8-week dietary intervention with energy deficit of 300-500kcal/day. Analysis of endothelial transcriptome suggested that the intervention could impact on endothelial cell growth. Cell proliferation was measured with the MTT test and verified by [(3)H]-thymidine incorporation. The participants were categorized according to a change in proliferation over time. Significant decrease in endothelial cell proliferation correlated with the extent of weight loss in men, but not in women. This effect corresponded with changes in serum levels of leptin and adiponectin, but was not related to serum concentrations of several known angiogenic mediators (VEGF, MCP-1, TSP-1, MMP-9, angiopoietin-2). Direction and magnitude of changes in serum-induced endothelial cell proliferation identifies patients with the greatest weight loss in response to modest calorie restriction.

Age‐Related Perturbations in the Sarcolemmal Environment are Attenuated by Lifelong Caloric Restriction and Voluntary Wheel Running

Sarcopenia is the age‐related reduction in skeletal muscle mass and strength. Previously we observed that lifelong mild caloric restriction (CR) and wheel running (WR) attenuated sarcopenia, in part by reducing the age‐induced disruptions of the sarcolemmal dystrophin‐glycoprotein complex (DGC) proteins. The purpose of this study was to determine if mild (8%) CR and lifelong CR + voluntary WR could maintain a phenotypically young sarcolemmal environment in plantaris muscle fibers. Fischer 344 rats were assigned into four groups: 6‐month‐old sedentary ad libitum (YAL), 24‐month‐old sedentary ad libitum group (OAL), 8% caloric restriction from 11 months – 24 months (OCR), and 8% CR plus voluntary wheel running from 11 months – 24 months (OCRWR). We observed significant age‐related increases in key membrane repair proteins (MG53, p &lt; 0.0001; dysferlin, p &lt; 0.0001; annexin A6, p &lt; 0.0001; and annexin A2, p = 0.004) in the OAL plantaris. Lifelong mild CR and CRWR interventions were effective at maintaining membrane repair proteins near YAL levels. Consistent with a perturbed sarcolemmal environment, we also found reduced protein content of NADPH oxidase isoform 2 (Nox2) subunits (p67phox, p = 0.03; p47phox, p = 0.01; and gp91phox, p = 0.096). Lifelong CR and CRWR protected against the age‐related reduction in gp91phox, p47phox, and p67phox proteins. Nox2 subunit abundance in OCR and OCRWR were not significantly different than YAL, while p67phox was significantly higher in OCR than YAL (p = 0.03). Novel data presented here are consistent with the hypothesis that lifelong CR and WR mitigate sarcopenia, in part, by ameliorating age‐induced alterations in the myofiber membrane environment.Support or Funding InformationNIH (AR054084), NASA (NNX12AR62G), the Sydney and J.L. Huffines Institute, and the College of Health and Education at Texas A&amp;M University

Caloric Restriction Diet (CR diet) or Mediterranean Diet (MD) - Which is the Best Choice for Former Athletes?

Overweight or obesity which often develop in athletes who end their careers is one of the most important issues of the world of sport. During aging, an increase in the amount of intra-abdominal fat is observed; this fat increases the risk of such metabolic disease as diabetes or hypertension. The participants of the study were 94 males. The people were randomly assigned to one of 2 groups: group 1 – people using the diet based on calorie restriction CRON (n = 32), and group 2 – those who followed the recommendations of the Mediterranean diet (n = 34). The patients who at the check-up declared not following any diet were assigned to the control group (n = 28). A change in parameters was observed in each of the sub-groups after the intervention. The most significant changes were observed in the sub-group which lost >2.6 kg. Both the diet based on mild calorie restriction and the Mediterranean diet had positive effect on the change of the former athlete’s body parameters after the 6-week long dietary intervention. Both diets which were being tested changed the body composition of the athletes who ended their careers in a similar way.