Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote health from worms to humans. At the transcriptome and proteome levels, long-term CR and RM treatments have partially overlapping effects, while their impact on protein phosphorylation within cellular signaling pathways have not been compared. Here we measured the phosphoproteomes of soleus, tibialis anterior, triceps brachii and gastrocnemius muscles from adult (10 months) and 30-month-old (aged) mice receiving either a control, a calorie restricted or an RM containing diet from 15 months of age. We reproducibly detected and extensively analyzed a total of 6960 phosphosites, 1415 of which are not represented in standard repositories. We reveal the effect of these interventions on known mTORC1 pathway substrates, with CR displaying greater between-muscle variation than RM. Overall, CR and RM have largely consistent, but quantitatively distinct long-term effects on the phosphoproteome, mitigating age-related changes to different degrees. Our data expands the catalog of protein phosphorylation sites in the mouse, providing important information regarding their tissue-specificity, and revealing the impact of long-term nutrient-sensing pathway inhibition on mouse skeletal muscle.

The prevalence of overweight and obesity in women of reproductive age leads to significant health risks, including adverse metabolic and reproductive outcomes. Effective dietary interventions are critical to improving health outcomes in this population. This study investigates the impact of a 12-week diet intervention on metabolic markers of adipose tissue in overweight women of reproductive age, determining whether calorie restriction or low-starch diets are more effective, while also accounting for salivary amylase activity. A total of 67 overweight women of reproductive age were enrolled in a randomized controlled trial (RCT). Participants were divided into high-salivary-amylase (HSA) and low-salivary-amylase (LSA) groups based on baseline salivary amylase activity measured using a spectrophotometric method. Each group was further subdivided into two dietary intervention groups: calorie restriction (CR) and low starch (LS), resulting in four subgroups (HSA-CR, HSA-LS, LSA-CR, LSA-LS), along with a control group (CTR) of normal-weight individuals (no intervention). Participants were assigned to a calorie-restricted diet or a low-starch diet for 12 weeks. Key metabolic markers of adipose tissue, including insulin sensitivity, adipokines, cytokines, and lipid profiles, were measured at baseline (T0), 30 min after consuming starch-containing muesli (T1), and 12 weeks after intervention (T2). Active GLP-1, glucagon, and C-peptide levels were assessed to clarify the hormonal mechanisms underlying the dietary effects. Salivary amylase activity was also measured to examine its role in modulating glucose and GLP-1 responses. Both diet interventions led to significant improvements in metabolic markers of adipose tissue, though different ones. Calorie restriction improved insulin sensitivity by effectively reducing visceral fat mass and enhancing insulin signaling pathways. In contrast, the low-starch diet was linked to a reduction in the coefficient of glucose variation influenced partly by changes in GLP-1 levels. Our findings highlight the importance of personalized diet strategies to optimize metabolic health in this demographic.

Roux-en-Y gastric bypass (RYGB) is the most effective treatment for severe obesity. A very low-calorie diet (VLCD) is another effective dietary intervention to treat obesity. This study evaluated the effect of a VLCD versus RYGB on weight reduction, changes in body composition and the resolution of comorbidities during a 12-week period. Individuals with obesity at the obesity clinic, Ramathibodi Hospital, Mahidol University, Thailand with a body mass index (BMI) ≥ 37.5 kg/m2 or ≥32.5 kg/m2 with obesity-related complications were recruited. Treatment options, either RYGB or VLCD, were assigned depending on patients\' preferences and physicians\' judgment. The analysis included 16 participants in the RYGB group and 15 participants in the VLCD group. Baseline characteristics were similar between groups; nevertheless, the participants in the VLCD group were significantly younger than those in the RYGB group. The number of patients with type 2 diabetes (T2D) was slightly higher in the RYGB group (43.8% vs. 33.3%, p = 0.552). Additionally, patients in the RYGB group had a longer duration of T2D and were treated with anti-diabetic agents, while VLCD patients received only lifestyle modifications. At 12 weeks, total and percentage weight loss in the RYGB and VLCD groups, respectively, were as follows: -17.6 ± 6.0 kg vs. -15.6 ± 5.1 kg (p = 0.335) and -16.2% ± 4.3% vs. -14.1% ± 3.6% (p = 0.147). Changes in biochemical data and the resolution of comorbidities were similar between the groups at 12 weeks. A 12-week VLCD resulted in similar weight loss and metabolic improvement compared with RYGB. Large-scale studies with long follow-up periods are needed to elucidate whether VLCD is a viable alternative treatment to bariatric surgery.

Aging and obesity are intertwined in a vicious circle that leads to declining general and brain-specific functions. Kapogiannis and colleagues demonstrate that implementing just 8 weeks of two distinct low-calorie regimes can enhance cognition and biochemical markers of aging in older people with obesity.

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.

Accurate weight predictions are essential for weight management program patients. The freely available National Institutes of Health Body Weight Planner (NIH-BWP) returns expected weights over time but overestimates weight when patients consume a low-calorie diet. This study sought to increase the accuracy of NIH-BWP predicted weights for people on low-calorie diets. People enrolled in a weight management program were included if they received meal replacements with defined caloric content for the 3 months of the weight loss phase of the program. The Ottawa Weight Loss Prediction Model (OWL-PM) modelled the relative difference between observed and NIH-BWP predicted weights using longitudinal analysis methods based on patient factors. OWL-PM was externally validated. 1761 people were included (mean age 46 years, 73.3% women) with a mean (SD) baseline weight in pounds and body mass index of 271.9 (55.6) and 43.9 (7.4), respectively. At the end of the program\'s weight loss phase, people lost a median (IQR) of 17.1% (14.8-19.5) of their baseline weight. Observed weight relative to NIH-BWP predicted weights had a median value of - 4.9% but ranged from - 32.1% to + 28.5%. After adjustment, weight overestimation by NIH-BWP was most pronounced in male patients, people without diabetes and with increased observation time. OWL-PM returned expected weights at 3 months that were significantly more accurate than those from NIH-BWP alone (mean difference observed vs. expected [95% CI] 6.7lbs [6.4-7.0] vs. 12.6lbs [12.1-13.0]). In the external validation cohort (n = 106), OWL-PM was significantly more accurate than NIH-BWP (mean squared error 24.3 vs. 40.0, p = 0.0018). OWL-PM incorporated patient-level covariates to significantly increase weight prediction accuracy of NIH-BWP in patients consuming a low-calorie diet.

OBJECTIVE: Previously, we demonstrated that caloric restriction (CR) stimulates the synthesis, conjugation, secretion, and deconjugation of taurine and bile acids in the intestine, as well as their reuptake. Given taurine\'s potent anti-obesogenic properties, this study aimed to assess whether the CR-induced shift in taurine homeostasis contributes to adipose tissue loss.
METHODS: Male C57Bl/6 mice were subjected to 20% CR or ad libitum feeding, with variations in cage bedding and gut microbiota conditions. Additional groups received taurine supplementation or were fed a low-taurine diet (LTD).
RESULTS: In CR animals, taurine derived from the intestine was preferentially trafficked to epididymal white adipose tissue (eWAT) over other tested organs. Besides increased levels of taurine transporter TauT, gene expression of Cysteine dioxygenase (Cdo) involved in taurine synthesis was upregulated in CR eWAT. Taurine concentration in adipocytes was inversely correlated with fat pad weight of CR mice. Different types of cage bedding did not impact eWAT taurine levels; however, the lack of bedding and consumption of a diet high in soluble fiber did. Depleting gut microbiota with antibiotics or inhibiting bile salt hydrolase (BSH) activity reduced WAT taurine concentration in CR mice. Taurine supplementation increased taurine levels in WAT and brown adipose tissue (BAT), promoting fat loss in CR animals. LTD consumption blunted WAT loss in CR animals, with negligible impact on BAT.
CONCLUSIONS: This study provides multiple insights into taurine\'s role in CR-triggered fat loss and describes a novel communication path between the liver, gut, microbiota, and WAT, with taurine acting as a messenger.

Conventional chemotherapies can stimulate the immune system by increasing tumour antigenicity (e.g., neoantigen exposure to immune cells) and altering adjuvanticity in the tumour (e.g., danger associated molecular patterns and cytokines). These molecules promote the recruitment, activation, and maturation of dendritic cells, which in turn, prime and activate cytotoxic T cells against tumour cells. However, several factors can decrease the immunostimulatory efficacy of chemotherapeutic agents. These include reduced tumour cell antigenicity and adjuvanticity and compromised immune function at a local and systemic level. Findings from preclinical studies show that dietary restriction and exercise promote systemic changes that may help to restore immune system function through several mechanisms, including an enhanced infiltration and function of antitumoral immune cells and a decrease in immunosuppressive cells, leading to a reduction in tumour volume. In addition, dietary restriction and exercise training in mice have been shown to enhance the efficacy of chemotherapy. In human studies there is also emerging evidence that dietary restriction and exercise can impact the immune system towards a more antitumoral profile. In this review, we discuss the immunostimulatory effects of dietary restriction (caloric restriction and fasting) and exercise training in preclinical cancer models, and potential synergies with chemotherapy. We then review clinical studies assessing the effects of these interventions on immune-related endpoints and tumour responses. Finally, we propose that combining dietary restriction with exercise could be a promising strategy to increase chemotherapy efficacy.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after ≥5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors, the RAVE complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1Δ mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1Δ mutation extends lifespan. Importantly, the level of Rav2, a key subunit of the RAVE complex, declines in aged cells. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosome acidification with age, which affects replicative lifespan.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common ovarian dysfunction. Recent studies showed the effectiveness of licorice on metabolic profiles with inconsistent findings. So, we investigated the effect of licorice on obesity indices, glycemic indices, and lipid profiles in women with PCOS.
METHODS: This randomized, double-blind, placebo-controlled trial was performed on 66 overweight/obese women with PCOS. The participants were randomly assigned to receive either 1.5 gr/day licorice extract plus a low-calorie diet (n = 33) or placebo plus a low-calorie diet (n = 33) for 8 weeks. Participants\' anthropometric indices and body composition were assessed using standard protocols. Fasting blood sugar (FBS), insulin levels, low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) were measured using enzymatic kits. The homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-B) were calculated using valid formulas.
RESULTS: Between-group comparisons demonstrated significant differences between the groups in terms of obesity indices (body weight, BMI, and body fat), lipid profiles (TG, TC, LDL-C, and HDL-C), FBS and insulin levels, HOMA-IR, and HOMA-B at the end of the study (P < 0.05). Supplementation with licorice plus a low-calorie diet was also more effective in improving all parameters than a low-calorie diet alone after adjusting for confounders (baseline values, age, weight changes, and physical activity changes) (P < 0.05).
CONCLUSIONS: The findings showed that licorice consumption leads to improvements in obesity indices, glucose homeostasis, and lipid profiles compared to placebo. Due to possible limitations of the study, further research is needed to confirm these findings.