Fasting-mimicking Diet Research Articles

Abstract 3719: Fasting-mimicking diet plus 2-DG drives antitumor immunity by targeting EDEM3-induced PD-L1 glycosylation

Abstract The PD-1/PD-L1 axis plays an essential role in immune escape and immunotherapy. Importantly, translated N-linked glycosylation of PD-L1 stabilizes protein, enters the cell membrane binding to PD-1, renders T cells anergic and leads to T-cell exhaustion and dysfunction. Targeting PD-L1 glycosylation as an attractive target by a rational combination of cancer immunotherapies. Cancer-associated fibroblasts (CAFs), a predominant cell component of the tumor microenvironment, exert crucial functions in promoting immune escape and immunotherapy resistance by increasing the tumor PD-L1 expression. However, whether and how CAFs upregulate the glycosylation of PD-L1 has never been reported. This study shows that CAFs can upregulate PD-L1 glycosylation and enhance PD-L1 cell surface expression via glycosyltransferase EDEM3, thus cancer immune evasion. Then, the study delves into the relationship between EDEM3 expression, prognosis and immunogenicity. We demonstrate that EDEM3 plays a role in tumor immunity during tumor progression, as evidenced by EDEM3 expression is only significantly correlated with poor prognosis in the CD8+ T cell-enriched population. In subcutaneous tumor models, we observed high cell-surface PD-L1 expression accompanied by decreased CD8+ T cell infiltration and increased M2 macrophage in immunocompetent mice transplanted with EDEM3 over-expressed CRC cells that promote resistance to PD-1/PD-L1 blockade cancer immunotherapy. By performing bioinformatic analysis, we found that the hexosamine biosynthesis pathway (HBP) is highly affected in EDEM3-upregulated CRC cancer. Subsequently, the production of the UDP-GlcNAc (the end product of HBP metabolic flow), a donor substrate for N-linked glycosylation, is significantly increased in EDEM3 over-expressed CRC cells by LC/MS. Meanwhile, glucose is confirmed to be the primary effector of PD-L1 glycosylation in CRC cells, and the glucose restriction attenuates EDEM3-modified PD-L1 glycosylation by reducing UDP-GlcNAc biosynthesis. Finally, we demonstrate that modulation of glucose metabolism through a fasting-mimicking diet (FMD) in combination with 2-deoxy glucose (2-DG) treatment enhances antitumor immunity, especially in tumors with high-EDEM3 expression that exhibit resistance to immunotherapy. We propose potential therapeutic targets for CRC that inhibit PD-L1 glycosylation through FMD+2-DG and could augment the efficacy of immune checkpoint blockers. Citation Format: Xiaoxia Liu, Shaoyong Peng, Xiaolin Wang, Huichuan Yu, Yanxin Luo. Fasting-mimicking diet plus 2-DG drives antitumor immunity by targeting EDEM3-induced PD-L1 glycosylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3719.

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Adipocyte p53 coordinates the response to intermittent fasting by regulating adipose tissue immune cell landscape

In obesity, sustained adipose tissue (AT) inflammation constitutes a cellular memory that limits the effectiveness of weight loss interventions. Yet, the impact of fasting regimens on the regulation of AT immune infiltration is still elusive. Here we show that intermittent fasting (IF) exacerbates the lipid-associated macrophage (LAM) inflammatory phenotype of visceral AT in obese mice. Importantly, this increase in LAM abundance is strongly p53 dependent and partly mediated by p53-driven adipocyte apoptosis. Adipocyte-specific deletion of p53 prevents LAM accumulation during IF, increases the catabolic state of adipocytes, and enhances systemic metabolic flexibility and insulin sensitivity. Finally, in cohorts of obese/diabetic patients, we describe a p53 polymorphism that links to efficacy of a fasting-mimicking diet and that the expression of p53 and TREM2 in AT negatively correlates with maintaining weight loss after bariatric surgery. Overall, our results demonstrate that p53 signalling in adipocytes dictates LAM accumulation in AT under IF and modulates fasting effectiveness in mice and humans.

Effects of the periodic fasting-mimicking diet on health, lifespan, and multiple diseases: a narrative review and clinical implications.

Dietary restriction and fasting have been recognized for their beneficial effects on health and lifespan and their potential application in managing chronic metabolic diseases. However, long-term adherence to strict dietary restrictions and prolonged fasting poses challenges for most individuals and may lead to unhealthy rebound eating habits, negatively affecting overall health. As a result, a periodic fasting-mimicking diet (PFMD), involving cycles of fasting for 2 or more days while ensuring basic nutritional needs are met within a restricted caloric intake, has gained widespread acceptance. Current research indicates that a PFMD can promote stem cell regeneration, suppress inflammation, extend the health span of rodents, and improve metabolic health, among other effects. In various disease populations such as patients with diabetes, cancer, multiple sclerosis, and Alzheimer's disease, a PFMD has shown efficacy in alleviating disease symptoms and improving relevant markers. After conducting an extensive analysis of available research on the PFMD, it is evident that its advantages and potential applications are comparable to other fasting methods. Consequently, it is proposed in this review that a PFMD has the potential to fully replace water-only or very-low-energy fasting regimens and holds promise for application across multiple diseases.

The effects of different intermittent fasting regimens in people with type 2 diabetes: a network meta-analysis

ObjectiveTo compare the effects of four intermittent fasting regimens on blood glucose and insulin sensitivity in people with type 2 diabetes.MethodsRandomized controlled trials of intermittent fasting in the treatment of patients with type 2 diabetes mellitus in PubMed, the Cochrane Library, Embase, ScienceDirect, Web of Science, CNKI, VIP Database, and WANFANG Database were searched for from the library to September 2023. 2 review authors independently screened studies and extracted data. RevMan 5.4 was used for direct comparison of meta-results. Network meta-analysis was performed using Stata16 software.Results13 studies with a total of 867 patients were included. The intervention effects of twice-per-week fasting, fasting-mimicking diet, time-restricted eating, and peridic fasting were better than that of conventional diet. The results of the network comparison showed that there was no significant difference in the intervention effect of the intermittent fasting regimens. SUCRA ranking results showed that the twice-per-week fasting was best for comprehensive interventions for improvement.ConclusionFrom the perspective of fasting blood glucose, glycated hemoglobin and insulin resistance, the twice-per-week fasting intervention has a good effect, which can be used as a reference for patients with inter-type 2 diabetes to choose intermittent fasting regimen. However, more clinical trials are needed to verify this at a later stage.

A bibliometric analysis of the Fasting-Mimicking Diet.

The Fasting-Mimicking Diet (FMD) is a nutritional strategy that involves significantly reducing calorie intake for a specific period to mimic the physiological effects of fasting while still providing the body with nutrition. Our study aimed to conduct a bibliometric study to explore the latest publishing trends and areas of intense activity within the sphere of FMD. We extracted data on FMD publications from the Web of Science Core Collection (WOSCC) database. The bibliometric analysis was conducted by WOSCC Online Analysis Platform and VOSviewer 1.6.16. In total, there were 169 publications by 945 authors from 342 organizations and 25 countries/regions, and published in 111 journals. The most productive country, organization, author, and journal were the United States, the University of Southern California, Valter D. Longo, and Nutrients, respectively. The first high-cited document was published in Ageing Research Reviews and authored by Mattson et al. In this study, they discuss the various health benefits of FMD including improved metabolic health, weight management, and even potential effects on delaying aging processes and reducing the risk of chronic diseases. In conclusion, our study is the first bibliometric analysis of the FMD. The main research hotspots and frontiers were FMD for cancer, FMD for metabolic-related diseases, and FMD for cognitive improvement. FMD may have some potential benefits for multiple diseases which should be further investigated.

Cyclic Fasting-Mimicking Diet Plus Bortezomib and Rituximab Is an Effective Treatment for Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia cells resist fasting-mimicking diet by inducing proteasome activation to escape starvation, which can be targeted using proteasome inhibition by bortezomib treatment to impede leukemia progression and prolong survival.

Fasting mimicking diet in diabetic mice partially preserves glomerular endothelial glycocalyx coverage, without changing the diabetic metabolic environment.

Intermittent fasting has become of interest for its possible metabolic benefits and reduction of inflammation and oxidative damage, all of which play a role in the pathophysiology of diabetic nephropathy. We tested in a streptozotocin (60 mg/kg)-induced diabetic apolipoprotein E knockout mouse model whether repeated fasting mimicking diet (FMD) prevents glomerular damage. Diabetic mice received 5 FMD cycles in 10 wk, and during cycles 1 and 5 caloric measurements were performed. After 10 wk, glomerular endothelial morphology was determined together with albuminuria, urinary heparanase-1 activity, and spatial mass spectrometry imaging to identify specific glomerular metabolic dysregulation. During FMD cycles, blood glucose levels dropped while a temporal metabolic switch was observed to increase fatty acid oxidation. Overall body weight at the end of the study was reduced together with albuminuria, although urine production was dramatically increased without affecting urinary heparanase-1 activity. Weight loss was found to be due to lean mass and water, not fat mass. Although capillary loop morphology and endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced together with the presence of UDP-glucuronic acid. Mass spectrometry imaging further revealed reduced protein catabolic breakdown products and increased oxidative stress, not different from diabetic mice. In conclusion, although FMD preserves partially glomerular endothelial glycocalyx, loss of lean mass and increased glomerular oxidative stress argue whether such diet regimes are safe in patients with diabetes.NEW & NOTEWORTHY Repeated fasting mimicking diet (FMD) partially prevents glomerular damage in a diabetic mouse model; however, although endothelial glycocalyx heparan sulfate contents were preserved, hyaluronan surface expression was reduced in the presence of UDP-glucuronic acid. The weight loss observed was of lean mass, not fat mass, and increased glomerular oxidative stress argue whether such a diet is safe in patients with diabetes.

Ketone bodies in cell physiology and cancer.

Ketogenic diets (KDs), fasting, or prolonged physical activity elevate serum ketone bodies (KBs) levels, providing an alternative fuel source for the brain and other organs. However, KBs play pleiotropic roles that go beyond their role in energy production. KBs can act as signaling metabolites, influence gene expression, proteins' posttranslational modifications (PTMs), inflammation, and oxidative stress. Here, we explore the impact of KBs on mammalian cell physiology, including aging and tissue regeneration. We also concentrate on KBs and cancer, given the extensive evidence that dietary approaches inducing ketosis, including fasting-mimicking diets (FMDs) and KDs, can prevent cancer and affect tumor progression.

Fasting mimicking diet extends lifespan and improves intestinal and cognitive health.

Caloric restriction is an effective means of extending a healthy lifespan. Fasting mimicking diet (FMD) is a growing pattern of caloric restriction. We found that FMD significantly prolonged the lifespan of prematurely aging mice. In naturally aging mice, FMD improved cognitive and intestinal health. Through a series of behavioral experiments, we found that FMD relieved anxiety and enhanced cognition in aged mice. In the intestine, the FMD cycles enhanced the barrier function, reduced senescence markers, and maintained T cell naïve-memory balance in the lamina propria mucosa. To further explore the causes of immune alterations, we examined changes in the stool microbiota using 16S rRNA sequencing. We found that FMD remodeled gut bacterial composition and significantly expanded the abundance of Lactobacillus johnsonii. Our research revealed that FMD has in-depth investigative value as an anti-aging intervention for extending longevity and improving cognition, intestinal function, and gut microbiota composition.

Impact of daily cyclic enteral nutrition versus standard continuous enteral nutrition in critically ill patients: a study protocol for a randomised controlled trial in three intensive care units in France (DC-SCENIC)

IntroductionCurrent guidelines on clinical nutrition of ventilated patients in the intensive care unit (ICU) recommend initiating continuous enteral nutrition within 48 hours of ICU admission when feasible. However, discontinuous feeding...

Targeted Degradation of Signal Transduction and Activator of Transcription 3 by Chaperone-Mediated Autophagy Targeting Chimeric Nanoplatform.

Chaperone-mediated autophagy (CMA) is a lysosomal-dependent proteolysis pathway for the degradation of cytosolic proteins. However, exploiting CMA-mediated proteolysis to degrade proteins of interest in cancer therapy has not been widely applied. In this study, we develop a CMA-targeting chimera (CMATAC) to efficiently and specifically degrade signal transduction and activator of transcription 3 (STAT3) in tumor cells. CMATAC consists of STAT3 and heat shock cognate 70 kDa protein (HSC70) targeting peptides connected by a linker. To efficiently deliver CMATACs into tumor cells, lipid nanoparticles (LNPs) are used to encapsulate CMATACs (nCMATACs) and decorated with an insulin-like growth factor 2 receptor (IGF2R) targeting peptide (InCMATACs) to achieve tumor targeting and precise delivery. The CMA pathway is activated in tumor cells by a fasting-mimicking diet (FMD). Furthermore, FMD treatment strongly enhances the cellular uptake and tumor accumulation of InCMATACs by upregulating the IGF2R expression. As a result, InCMATACs efficiently degrade STAT3 protein in both A549 and HCC827 tumor cells and inhibit tumor growths in vivo. This study demonstrates that InCMATACs can be used for selective proteolysis in cancer therapy.

IGF1 and Insulin Receptor Single Nucleotide Variants Associated with Response in HER2-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without a Fasting Mimicking Diet (BOOG 2013-04 DIRECT Trial).

We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD.

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival.

Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.

Fasting regulates mitochondrial function through lncRNA PRKCQ-AS1-mediated IGF2BPs in papillary thyroid carcinoma

Recurring evidence suggests that fasting has extensive antitumor effects in various cancers, including papillary thyroid carcinoma (PTC). However, the underlying mechanism of this relationship with PTC is unknown. In this study, we study the effect of fasting on glycolysis and mitochondrial function in PTC. We find that fasting impairs glycolysis and reduces mitochondrial dysfunction in vitro and in vivo and also fasting in vitro and fasting mimicking diets (FMD) in vivo significantly increase the expression of lncRNA-protein kinase C theta antisense RNA 1 (PRKCQ-AS1), during the inhibition of TPC cell glycolysis and mitochondrial function. Moreover, lncRNA PRKCQ-AS1 was significantly lower in PTC tissues and cells. In addition, PRKCQ-AS1 overexpression increased PTC cell glycolysis and mitochondrial function; PRKCQ-AS1 knockdown has the opposite effect. On further mechanistic analysis, we identified that PRKCQ-AS1 physically interacts with IGF2BPs and enhances protein arginine methyltransferases 7 (PRMT7) mRNA, which is the key player in regulating glycolysis and mitochondrial function in PTC. Hence, PRKCQ-AS1 inhibits tumor growth while regulating glycolysis and mitochondrial functions via IGF2BPs/PRMT7 signaling. These results indicate that lncRNA PRKCQ-AS1 is a key downstream target of fasting and is involved in PTC metabolic reprogramming. Further, the PRKCQ-AS1/IGF2BPs/PRMT7 axis is an ideal therapeutic target for PTC diagnosis and treatment.

Fasting mimicking diet cycles versus a Mediterranean diet and cardiometabolic risk in overweight and obese hypertensive subjects: a randomized clinical trial

Abnormalities in the vascular endothelium such as impaired vasodilation can contribute to atherosclerosis and hypertension. Here we have performed a single-center randomized clinical trial to evaluate the efficacy of 4 months of a continuous Mediterranean diet (MD) regimen as compared to 4 cycles of fasting mimicking diet (FMD) administered for only 5 days/month on endothelial function, measured as reactive hyperemia index (RHI) and large/small-resistance artery compliance (AC1/AC2), and on other cardiometabolic risk factors, in hypertensive patients with obesity/excess weight [both sexes, body mass index (BMI) ≥ 28, RHI ≤ 2.0, and/or small-resistance artery compliance (AC2) ≤ 5.0]. At the end of the intervention period, FMD but not MD decreased RHI (p = 0.0023) compared to baseline with no increase in the portion of patients with abnormal RHI. Both FMD and MD improved PULS cardiac test score; evaluating the risk of cardiovascular events. FMD and MD did not show any significant change in either AC1 or AC2 compared to baseline. Both FMD and MD led to comparable decreases in weight, waist circumference, BMI, body fat mass and % body fat, total cholesterol, and leptin. FMD decreased HbA1c (p = 0.0059) and IGF-1 (p = 0.0427), while MD decreased glucose (p = 0.0488), HOMA-IR (p = 0.0476), and HDL-C (p = 0.0419). None of the parameters were significantly different between the FMD vs. MD group at the end of the intervention period. During the 3-month follow-up period, the FMD and MD groups continued to display weight and BMI reduction; however, the MD group also lost fat free mass (FMD vs. MD, p = 0.0498). In summary, both MD and FMD reduced a range of cardiometabolic risk factors, but FMD also decreased RHI, a change associated with either impaired functional integrity of vascular endothelial cells but also with vascular rejuvenation, with the latter being more likely considering the improved cardiometabolic profile, reduced PULS cardiac score and calculated heart age, and unaltered arterial compliance in the FMD group. MD but not FMD cycles caused loss of lean body mass.

Restrictive diets have a beneficial impact on dextran sodium sulfate-induced colitis in male mice

BackgroundPreviously, we assessed the impact of restrictive diets, including caloric restriction (CR), intermittent fasting (IF), or fasting-mimicking diet (FMD), on a healthy gastrointestinal tract. We revealed that each of the diets shows anti-inflammatory outcomes. ObjectiveThe current study aimed to verify the diets' applicability in treating colitis. MethodsWe exposed a mouse model with mild chronic dextran sodium sulfate (DSS)-induced colitis to ad libitum control feeding, CR, IF, or FMD. The collected samples were analyzed for markers of inflammation. ResultsThe diets reduced DSS-triggered increases in spleen weight and myeloperoxidase (MPO) activity. Diet intervention also influenced occludin levels, small intestine morphology, as well as cytokine and inflammatory gene expression, mainly in the mucosa of the proximal colon. The diets did not reverse DSS-enhanced gut permeability and thickening of the colon muscularis externa. Concerning inflammatory gene expression, the impact of DSS and the dietary intervention was limited to the colon as we did not measure major changes in the jejunum mucosa, Peyer's patches, and mesenteric lymph nodes. Further, rather modest changes in the concentration of intestinal bile acids were observed in response to the diets, whereas taurine and its conjugates levels were strongly affected. ConclusionsDespite the differences in the dietary protocol, the tested diets showed very similar impacts and, therefore, may be interchangeable when aiming to reduce inflammation in the colon. However, FMD showed the most consistent beneficial impact.

Energy and macronutrient restriction regulate bile acid homeostasis

As we reported previously, caloric restriction (CR) results in an increased concentration of bile acids (BA) in the intestinal mucosa. We now investigated the background of this phenotype, trying to identify nutrition-related factors modulating BA levels. Male mice were submitted to various types of restrictive diets and BA levels and expression of associated factors were measured. We found that BA concentration is increased in the liver of CR mice, which corresponds to reduced expression of the Shp gene and elevated mRNA levels of Cyp27a1, Bal, and Ntcp, as well as CYP7A1 protein and gene expression. Correlation between decreased concentration of BAs in the feces, increased BAs levels in plasma, and elevated gene expression of BAs transporters in the ileum mucosa suggests enhanced BA uptake in the intestine of CR mice. Corresponding to CR upregulation of liver and ileum mucosa, BA concentration was found in animals submitted to other types of prolonged energy-restricting dietary protocols, including intermittent fasting and fasting-mimicking diet. While over-night fasting had negligible impact on BAs levels. Manipulation of macronutrient levels partly affected BA balance. Low-carbohydrate and ketogenic diet increased BAs in the liver but not in the intestine. Carbohydrate restriction stimulates BA synthesis in the liver, but energy restriction is required for the increase in BA levels in the intestine and its uptake.

Molecular Mechanism of Fasting-Mimicking Diet in Inhibiting Colorectal Cancer Progression: Implications for Immune Therapy and Metabolic Regulation.

Recently, fasting-mimicking diet and caloric restriction have been shown to improve antitumor immunity. In this issue of Cancer Research, Zhong and colleagues provide insights into the molecular mechanism of fasting-mimicking diet-mediated metabolic reprogramming in colorectal cancer progression. The authors performed comprehensive mechanistic experiments in mouse models to show that fasting-mimicking diet prevents colorectal cancer progression by lowering intratumoral IgA+ B cells by accelerating fatty acid oxidation to inhibit B-cell IgA class switching. In addition, they found that fatty acid oxidation-dependent acetylation prevents IgA class switching and that IgA+ B cells interfere with the anticancer effects of fasting-mimicking diet in colorectal cancer. Overall, their study establishes that fasting-mimicking diet has the potential to activate anticancer immunity and to induce tumor regression in colorectal cancer. See related article by Zhong et al., p. 3529.

Fasting-Mimicking Diet and Podocyte Protection

Fasting-Mimicking Diet and Podocyte Protection