Effects Of Caloric Restriction Research Articles

EXPLORING THE IMPACT OF CALORIC RESTRICTION ON MOLECULAR MECHANISMS OF LIVER DAMAGE INDUCED BY SUCROSE INTAKE IN THE DRINKING WATER.

A positive association has been demonstrated between consumption of sucrose-sweetened beverages and the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Since the administration of 30% sucrose in the drinking water (SRD) to rats has proven to be a good model of systemic insulin resistance, the aim of our study was to analyze the effect of caloric restriction applied on SRD-treated rats by switching back to a standard diet, on liver morphology, function, and metabolism.Consumption of a SRD causes a metabolic shift towards gluconeogenesis and fatty acid synthesis leading to an increase in triacilglyceride (TAG) levels in plasma and in the liver that were associated with a decrease in insulin sensitivity. Moreover, our results show that animals fed a SRD develop steatohepatitis characterized by the generation of oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis. Although no histological changes were observed after a two-week caloric restriction, key pathways associated with the progression of MASLD as inflammation, ER stress and apoptosis were slowed down. Notably, this two-week intervention also increased liver insulin sensitivity (evaluated by AKT activity in this tissue) and drove the lipid metabolic profile towards oxidation, thus lowering circulating TAG levels.In summary, the present study uncovers underlying mechanisms affected, and their metabolic consequences, during the first stages of the phenotypic reversal of steatohepatitis by switching back to a standard diet after receiving sucrose-sweetened water for several weeks.

Calcineurin inhibition enhances Caenorhabditis elegans lifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling.

Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance the lifespan of Caenorhabditis elegans through multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans. Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating caused by calcineurin inhibition mimics the effects of calorie restriction, resulting in enhanced lifespan. The TFEB ortholog, HLH-30, is required for lifespan extension mediated by calcineurin inhibition. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is necessary for the increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.

7943 In Obese C57Bl6 Male Mice, Weight Loss due to Caloric Restriction Reduced Bone Morphology but Improved Components of Systemic Metabolism

Abstract Disclosure: C. Chlebek: None. C. McAndrews: None. S.N. Costa: None. C.J. Rosen: None. Obesity and calorie restriction individually alter systemic cellular metabolism and affect musculoskeletal tissue health. Obesity reduces trabecular and cortical bone quality. Clinically, obese patients are advised to lose weight, despite the negative effects of calorie restriction on bone in nonobese preclinical models. Little is known about bone quality following weight loss in obese preclinical models. We hypothesized that in obese models, caloric restriction would further worsen bone quality. To induce obesity, male C57Bl6 mice (8 weeks old) received 60% high fat diet for 12 weeks (high fat feeding phase). Following obesity induction, the HFD-CR group was acclimated to control low fat diet for 2 wks and then underwent 30% caloric restriction for 8 wks (caloric restriction feeding phase). The HFD group received 60% kcal high fat diet from ages 8 to 30 wks. LFD mice received control low fat 10% kcal diet for the study duration. Mice were euthanized at 30 wks of age. Body weight, body composition, and bone mineral density were recorded at baseline and at the end of each diet. Glucose and insulin tolerance were recorded at the end of the high fat and caloric restriction feeding phases. At euthanasia, cortical and trabecular bone morphology (µCT) were assessed.Adverse metabolic parameters worsened with high fat feeding but improved by caloric restriction. Compared to LFD animals, HFD and HFD-CR mice gained body weight, fat mass, and lean mass during the high fat feeding phase. After the caloric restriction feeding phase, body weight, fat mass, and lean mass were reduced in HFD-CR compared to both HFD and LFD controls (p < 0.0001). After 12 weeks of high fat feeding, glucose and insulin tolerance were reduced in HFD and HFD-CR mice compared to LFD (p < 0.0001). Caloric restriction improved both glucose and insulin tolerance in HFD-CR mice compared to both HFD and LFD animals (p < 0.0001). Caloric restriction improved areal bone mineral density, but at euthanasia, HFD-CR mice had worse bone morphology compared to LFD or HFD animals. Although areal bone mineral density (aBMD) was reduced by the high fat feeding phase, HFD-CR and LFD aBMD was not different at the end of the study (p < 0.0001). At euthanasia, HFD-CR mice had reduced cortical area and cortical thickness (p < 0.05). Marrow area and moment of inertia were not different between diets. Compared to LFD, both HFD and HFD-CR mice had reduced tibial bone volume fraction (p < 0.05). HFD-CR animals had smaller trabecular thickness (p < 0.05) and greater trabecular number (p < 0.01) compared to HFD mice. Despite improvements in components of systemic metabolism, caloric restriction in obese preclinical models reduced bone morphology in both trabecular and cortical compartments. This work will improve our understanding of the musculoskeletal system following caloric restriction in obese models and will aid in nutritional counseling for obese patients. Presentation: 6/1/2024

Effect of caloric restriction and probiotic supplementation on preservation of muscle quality of men living with obesity: Preliminary data from a randomized, double-blind, clinical trial

Effect of caloric restriction and probiotic supplementation on preservation of muscle quality of men living with obesity: Preliminary data from a randomized, double-blind, clinical trial

Influence of equation selection on adaptive thermogenesis in obese men: Effects of caloric restriction and probiotic supplementation

Influence of equation selection on adaptive thermogenesis in obese men: Effects of caloric restriction and probiotic supplementation

Effects of caloric restriction with different doses of exercise on fat loss in people living with type 2 diabetes: A secondary analysis of the DOSE-EX randomized clinical trial

BackgroundFat loss mainly conveys the benefits of caloric restriction for people living with type 2 diabetes. The literature is equivocal regarding whether exercise facilitates fat loss during caloric restriction. This analysis aimed to assess the dose–response effects of exercise in combination with a caloric restriction on fat mass (FM) and FM percentage (FM%) in persons with diagnosed type 2 diabetes. MethodsIn this secondary analysis of a 4-armed randomized trial, 82 persons living with type 2 diabetes were randomly allocated to the control group (CON) (n = 21), diet control (DCON) (25% caloric restriction; n = 20), diet control and exercise 3 times per week (MED) (n = 20), or diet control and exercise 6 times per week (HED) (n = 21) for 16 weeks. The primary analysis was the change in FM% points. Secondary analyses included fat-free mass and visceral adipose tissue (VAT) volume (cm3). ResultsFM% decreased compared to CON by a mean difference of –3.5% (95% confidence interval (95%CI): –5.6% to –1.4%), –6.3% (95%CI: –8.4% to –4.1%), and –8.0% (95%CI: –10.2% to –5.8%) for DCON, MED, and HED, respectively. Compared to DCON, MED and HED decreased FM% by –2.8% (95%CI: –4.9% to –0.7%) and –4.5% (95%CI: –6.6% to –2.4%), respectively. The difference in FM% between HED and MED was –1.8% (95%CI: –3.9% to 0.4%). DCON and MED decreased fat-free mass compared to CON, whereas HED preserved fat-free mass (–0.2% (95%CI: –2.0% to 1.7%)). Compared to CON, VAT volume decreased by –666.0 cm3 (95%CI: –912.8 cm3 to –385.1 cm3), –1264.0 (95%CI: –1679.6 cm3 to –655.9 cm3), and –1786.4 cm3 (95%CI: –2264.6 cm3 to –1321.2 cm3) more for DCON, MED, and HED, respectively. HED decreased VAT volume more than DCON (–1120.4 cm3 (95%CI: –1746.6 cm3 to –639.4 cm3)) while the remaining comparisons did not reveal any differences. ConclusionAll interventions were superior in reducing FM% compared to standard care. Adding exercise to a caloric restriction was superior in reducing FM% compared to a caloric restriction alone.

Less Is More: Protective Effects of Caloric Restriction on Acute and Chronic Kidney Injury

Less Is More: Protective Effects of Caloric Restriction on Acute and Chronic Kidney Injury

A Systematic Review and Meta-Analysis of the Effect of Caloric Restriction on Skeletal Muscle Mass in Individuals with, and without, Type 2 Diabetes.

Severe caloric restriction interventions (such as very-low-calorie diets) are effective for inducing significant weight loss and remission of type 2 diabetes (T2DM). However, suggestions of associated significant muscle mass (MM) loss create apprehension regarding their widespread use. We conducted a systematic review and meta-analysis to provide a quantitative assessment of their effect on measures of MM in individuals with, or without, T2DM. EMBASE, Medline, Pubmed, CINAHL, CENTRAL and Google Scholar were systematically searched for studies involving caloric restriction interventions up to 900 kilocalories per day reporting any measure of MM, in addition to fat mass (FM) or body weight (BW). Forty-nine studies were eligible for inclusion, involving 4785 participants. Individuals with T2DM experienced significant reductions in MM (WMD -2.88 kg, 95% CI: -3.54, -2.22; p < 0.0001), although this was significantly less than the reduction in FM (WMD -7.62 kg, 95% CI: -10.87, -4.37; p < 0.0001). A similar pattern was observed across studies involving individuals without T2DM. MM constituted approximately 25.5% of overall weight loss in individuals with T2DM, and 27.5% in individuals without T2DM. Subgroup analysis paradoxically revealed greater BW and FM reductions with less restrictive interventions. Our review suggests that caloric restriction interventions up to 900 kilocalories per day are associated with a significant reduction in MM, albeit in the context of a significantly greater reduction in FM. Furthermore, MM constituted approximately a quarter of the total weight loss. Finally, our data support the use of less restrictive interventions, which appear to be more beneficial for BW and FM loss.

Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels

BackgroundCalorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR. MethodsMice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications. ResultsIn the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number. ConclusionThis study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.

Fueling the Heart: What Are the Optimal Dietary Strategies in Heart Failure?

Heart failure (HF) is a global health concern with rising incidence and poor prognosis. While the essential role of nutritional and dietary strategies in HF patients is acknowledged in the existing scientific guidelines and clinical practice, there are no comprehensive nutritional recommendations for optimal dietary management of HF. In this review, we discuss results from recent studies on the obesity paradox and the effects of calorie restriction and weight loss, intermittent fasting, the Western diet, the Mediterranean diet, the ketogenic diet, and the DASH diet on HF progression. Many of these strategies remain under clinical and basic investigation for their safety and efficacy, and there is considerable heterogeneity in the observed response, presumably because of heterogeneity in the pathogenesis of different types of HF. In addition, while specific aspects of cardiac metabolism, such as changes in ketone body utilization, might underlie the effects of certain dietary strategies on the heart, there is a critical divide between supplement strategies (i.e., with ketones) and dietary strategies that impact ketogenesis. This review aims to highlight this gap by exploring emerging evidence supporting the importance of personalized dietary strategies in preventing progression and improving outcomes in the context of HF.

Effects of intermittent fasting and caloric restriction on inflammatory biomarkers in individuals with obesity/overweight: A systematic review and meta-analysis of randomized controlled trials.

Obesity is characterized by chronic low-grade inflammation. This study presents an updated systematic review and meta-analysis on the effect of caloric restriction (CR) and intermittent fasting (IF) on plasma inflammatory biomarkers (C-reactive protein [CRP], tumor necrosis factor [TNF]-alpha, and interleukin [IL]-6) in individuals with obesity/overweight compared with unrestricted or ad libitum feeding. PubMed, Web of Science, and SCOPUS databases were searched for randomized controlled trials (RCTs) reporting inflammatory biomarkers after at least 8 weeks of intervention. Standardized mean differences (SMDs) were calculated using a fixed effect model. Heterogeneity was determined using I2 statistics. Sensitivity analysis was conducted using the "leave-one-out" approach. Relatively few RCTs have investigated the effect of IF on inflammatory biomarkers than with CR (6 vs. 15). Analysis of pooled data showed that CR was associated with a significant reduction in CRP with low heterogeneity (SMD -0.15 mg/L [95% CI -0.30 to -0.00], p = 0.04; I2= 0%, p = 0.69) and IL-6 with high heterogeneity (SMD -0.31 pg/mL [95% CI -0.51 to -0.10], p = 0.004; I2= 73%, p = 0.001). IF was associated with a significant decrease in TNF-alpha with moderate heterogeneity (SMD -0.32 pg/mL [95% CI -0.63 to -0.02], p = 0.04; I2= 44%, p = 0.13). No associations were detected between IF and CRP or IL-6 and CR and TNF-alpha. CR may be more effective in reducing chronic low-grade inflammation than IF. However, there were some concerns regarding the included studies' randomization and allocation sequence concealment process.

Prediction of individual weight loss using supervised learning: findings from the CALERIETM 2 study

BackgroundPredicting individual weight loss (WL) responses to lifestyle interventions is challenging but might help practitioners and clinicians select the most promising approach for each individual. ObjectiveThe primary aim of this study was to develop machine learning (ML) models to predict individual WL responses using only variables known before starting the intervention. In addition, we used ML to identify pre-intervention variables influencing the individual WL response. MethodsWe used 12-mo data from the comprehensive assessment of long-term effects of reducing intake of energy (CALERIETM) phase 2 study, which aimed to analyze the long-term effects of caloric restriction on human longevity. On the basis of the data from 130 subjects in the intervention group, we developed classification models to predict binary (“Success” and “No/low success”) or multiclass (“High success,” “Medium success,” and “Low/no success”) WL outcomes. Additionally, regression models were developed to predict individual weight change (percent). Models were evaluated on the basis of accuracy, sensitivity, specificity (classification models), and root mean squared error (RMSE; regression models). ResultsBest classification models used 20–40 predictors and achieved 89%–97% accuracy, 91%–100% sensitivity, and 56%–86% specificity for binary classification. For multiclass classification, accuracy (69%) and sensitivity (50%) tended to be lower. The best regression performance was obtained with 36 variables with an RMSE of 2.84%. Among the 21 variables predicting individual weight change most consistently, we identified 2 novel predictors, namely orgasm satisfaction and sexual behavior/experience. Other common predictors have previously been associated with WL (16) or are already used in traditional prediction models (3). ConclusionsThe prediction models could be implemented by practitioners and clinicians to support the decision of whether lifestyle interventions are sufficient or more aggressive interventions are needed for a given individual, thereby supporting better, faster, data-driven, and unbiased decisions.The CALERIETM phase 2 study was registered at clinicaltrials.gov as NCT00427193.

Non-canonical metabolic and molecular effects of calorie restriction are revealed by varying temporal conditions

Calorie restriction (CR) extends lifespan and healthspan in diverse species. Comparing ad libitum- and CR-fed mice is challenging due to their significantly different feeding patterns, with CR-fed mice consuming their daily meal in 2h and then subjecting themselves to a prolonged daily fast. Here, we examine how ad libitum- and CR-fed mice respond to tests performed at various times and fasting durations and find that the effects of CR-insulin sensitivity, circulating metabolite levels, and mechanistic target of rapamycin 1 (mTORC1) activity-result from the specific temporal conditions chosen, with CR-induced improvements in insulin sensitivity observed only after a prolonged fast, and the observed differences in mTORC1 activity between ad libitum- and CR-fed mice dependent upon both fasting duration and the specific tissue examined. Our results demonstrate that much of our understanding of the effects of CR are related to when, relative to feeding, we choose to examine the mice.

The Effects of Caloric Restriction and Clinical Psychological Intervention on the Interplay of Gut Microbial Composition and Stress in Women.

Both mental and metabolic disorders are steadily becoming more prevalent, increasing interest in non-pharmacological lifestyle interventions targeting both types of disorders. However, the combined effect of diet and psychological interventions on the gut microbiome and mental health outcomes remains underexplored. Thus, in this study, we randomized 41 women into two caloric restriction (CR) dietary groups, namely very-low-calorie diet (VLCD) and F.X. Mayr diet (FXM). The patients were then further randomized to either receive clinical psychological intervention (CPI) or no CPI. Blood and fecal samples were collected before and after two weeks of CR. Psychometric outcomes were assessed using the Perceived Stress Scale (PSS), Brief Symptom Index (BSI), and Burnout Dimension Inventory (BODI). Stool samples underwent 16S-rRNA sequencing. Upon two weeks of CR, α-diversity decreased overall and longitudinal PERMANOVA models revealed significant shifts in β-diversity according to diet, CPI, age, and body-mass-index. Furthermore, Agathobacter, Fusicatenibacter, and Subdoligranulum decreased in abundance. However, the Oscillibacter genus was enriched solely in FXM. CPI had a negligible effect on the microbiome. Dimension reduction models revealed clusters of taxa which distinctly associated with psychometric outcomes. Members of the Oscillospiraceae family were linked to favorable psychometric outcomes after two weeks of CR. Despite α-diversity reductions after CR, enrichment of Oscillospiraceae spp., solely seen in FXM, correlated with improved psychometric outcomes. This study suggests a promising direction for future interventions targeting mental health through gut microbial modulation.

Distinct effect of calorie restriction between congenic mating types of Cryptococcus neoformans

Cryptococcus neoformans (Cn) is an opportunistic yeast that causes meningoencephalitis in immunocompromised individuals. Calorie restriction (CR) prolongs Cn replicative lifespan (RLS) and mimics low-glucose environments in which Cn resides during infection. The effects of CR-mediated stress can differ among strains and have only been studied in MATα cells. Cn replicates sexually, generating two mating types, MATα and MATa. MATα strains are more dominant in clinical and environmental isolates. We sought to compare the effects of CR stress and longevity regulation between congenic MATα and MATa. Although MATα and MATa cells extended their RLS in response to CR, they engaged different pathways. The sirtuins were upregulated in MATα cells under CR, but not in MATa cells. RLS extension was SIR2-dependent in KN99α, but not in KN99a. The TOR nutrient-sensing pathway was downregulated in MATa strains under CR, while MATα strains demonstrated no difference. Lower oxidative stress and higher ATP production were observed in KN99α cells, possibly due to higher SOD expression. SIR2 was important for mitochondrial morphology and function in both mating types. Increased ATP production during CR powered the upregulated ABC transporters, increasing efflux in MATα cells. This led to enhanced fluconazole tolerance, while MATa cells remained sensitive to fluconazole. Our investigation highlights differences in the response of the mating types to CR.

Caloric and time restriction diets improve acute kidney injury in experimental menopausal rats: role of silent information regulator 2 homolog 1 and transforming growth factor beta 1.

Estrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-β1), and other indicators in the presence and absence of ovaries in AKI female rats. The female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI. After AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-β1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-β1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-β1, SIRT1, urea, creatinine, and albumin. The present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-β1 in ovary-intact animals.

Intermittent fasting, calorie restriction, and a ketogenic diet improve mitochondrial function by reducing lipopolysaccharide signaling in monocytes during obesity: A randomized clinical trial

BackgroundMitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota. Methods and findingsA randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p=0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p=0.0001), enriched the abundance of Phascolarctobacterium faecium (p=0.019) in the CR group and Ruminococcus bromii (p=0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman’s correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p=0.002; IF, p=0.001; and KD, p=0.001) compared to those in the AL group at the end of the study. ConclusionsWe conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials. Trial registrationThis trial was registered with ClinicalTrials.gov (NCT05200468)

Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.

Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation.

Long-term intermittent caloric restriction remodels the gut microbiota in mice genetically prone to breast cancer

ObjectivesGut microbiota dysbiosis is among the risk factors for breast cancer development, together with genetic background and dietary habits. However, caloric restriction has been shown to remodel the gut microbiota and slow tumor growth. Here, we investigated whether the gut microbiota mediates the preventive effects of long-term chronic or intermittent caloric restriction on breast cancer predisposition. Methods10-week-old transgenic breast cancer-prone mice were randomly assigned to dietary groups (ad libitum, chronic caloric restriction, and intermittent caloric restriction groups) and fed up to week 81. Stool samples were collected at weeks 10 (baseline), 17 (young), 49 (adult), and 81 (old). 16S rRNA gene sequencing was performed to identify the gut microbiota profile of the different groups. In order to investigate the breast cancer gut microbiota profile within genetically predisposed individuals regardless of diet, mammary tumor-bearing mice and mammary tumor-free but genetically prone mice were selected from the ad libitum group (n = 6). ResultsIntermittent caloric restriction increased the microbial diversity of adult mice and modified age-related compositional changes. A total of 13 genera were differentially abundant over time. Pathogenic Mycoplasma was enriched in the re-feeding period of the old intermittent caloric restriction group compared with baseline. Furthermore, mammary tumor-free mice showed shared gut microbiota characteristics with mammary tumor-bearing mice, suggesting an early link between genetic predisposition, gut microbiota, and breast cancer development. ConclusionsOur study revealed the role of gut microbes in the preventive effects of caloric restriction against breast cancer development, implying the significance of diet and microbiome interplay.

Levels of Oxidative Stress in Rats Treated with Calorie Restrictive Treatment and 50% Sucrose Solution

This study aims to analyze the level of stress oxidative with treatment calorie restrictions and administration of sucrose solution. This study was a laboratory experimental study with 12 male white rats (Wistar strain) as subjects for caloric restrictive treatment and 12 rats for 50% sucrose solution. Where each group of rats is determined by the dependent and independent variables. Using the pre-posttest control design, the dependent variable of caloric restriction, and the independent variable malondialdehyde. The dependent variables used were body weight using a scale, fasting blood glucose using a glucometer, and MDA using a UV-Vis spectrophotometer. The independent variable used was the administration of 50% sucrose solution. The data were statistically analyzed by T-test analysis. There was no significant decrease in MDA levels in the caloric restriction treatment rats (p = 0.060), besides that there was a significant difference in body weight in both the control and sucrose groups (p &lt;0.05). There was no significant difference in fasting blood sugar in the control group (p &gt; 0.05) and there was a significant difference in the sucrose group (p &lt; 0.05). There was no significant difference in serum MDA levels in either the control or sucrose groups (p &gt; 0.05). There is an effect of calorie restriction on MDA levels. Also, administration of 50% sucrose solution for 4 weeks had a significant effect on the rats' body weight and blood glucose but did not have a significant effect on serum MDA levels.