Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease.

Adherence to a periodic fast-mimicking diet improves health and promotes longevity.

Prolonged fasting promotes stress resistance, but its effects on longevity are poorly understood. Calorie restriction or major dietary composition changes can have profound effects on healthy aging but the inability of many subjects to adhere to chronic and extreme diets together with the potential of adverse effects limit their application. Fasting-mimicking diets (FMDs) are effective in increasing health and lifespan, possibly by inducing stem cell-based regeneration, or as therapies in mouse models of a variety of diseases. FMDs reduce cancer incidence/progression, modulate the immune response, reduce immuno-senescence, ameliorate or reverse disease progression of multiple sclerosis, Type I and Type II diabetes, and reverse inflammatory bowel disease pathology. In a randomized clinical trial, markers/risk factors for metabolic syndrome and other age-related diseases were favorably impacted after completion of 3 FMD cycles. These effects were larger in participants at risk for age-related diseases. Conclusions: We conclude that the FMD was safe and feasible in rodent and human studies. Larger studies on patients with diagnosed diseases are necessary to determine its impact on diabetes and cardiovascular disease treatment.

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.

Elevated plasma levels of trimethylamine N-oxide (TMAO) have been proposed as a diet-derived biomarker of cardiometabolic disease risk. Caloric restriction is the most common dietary intervention used to improve cardiometabolic health; however, novel trends suggest a fasting-mimicking diet (FMD) as a more feasible alternative. FMD is a variation of intermittent fasting, based on caloric restriction and limitation of protein sources of animal origin, applied in daily cycles during a 5-day period. As TMAO is intensively produced by gut microbiota after the consumption of animal-derived products, we aim to investigate whether a 5-day FMD affects plasma TMAO levels and markers of metabolic health. To investigate whether an increase in vegetable intake possesses similar effects on TMAO levels and metabolic parameters, healthy volunteers (n = 24) were subjected to a 5-day FMD and 19 volunteers served as a reference group (VEG). This group of volunteers consumed an additional four servings of vegetables per day, but otherwise stayed on their usual diet. FMD resulted in a twofold decrease in plasma TMAO levels, which was not evident in the volunteers from the VEG group. Moreover, FMD led to a weight loss of 2.8 ± 0.2 kg and a subsequent reduction in BMI compared to baseline. The FMD group exhibited a significant elevation in plasma ketone bodies (14-fold compared to baseline) and a decrease in IGF-1 levels by 37 ± 8 ng/mL. Since fasting glucose and C-peptide levels decreased, all volunteers in the FMD group showed improved insulin sensitivity and a decreased HOMA-IR index. In contrast, in the VEG group, only a slight reduction in plasma levels of fasting glucose and triglycerides was noted. In conclusion, we show that FMD is a viable strategy to reduce plasma levels of TMAO by limiting caloric intake and animal-derived protein consumption. The reduction in the level of TMAO could be an additional benefit of FMD, leading to a reduced risk of cardiometabolic diseases.

We investigated the effect of weight loss, independent of change in diet composition, on HDL and apoAI metabolism in men with metabolic syndrome (MetS). Subjects (19 men with MetS [NCEP-ATPIII]) were fed an isoenergetic Mediterranean-style diet for 5 weeks (all foods provided). Participants then underwent a 20-week free-living period during which they were counseled to restrict energy intake, after which they were again fed an isoenergetic Mediterranean-style diet for 5 weeks. At the end of the two controlled diets, participants received a single bolus of [5,5,5-(2)H(3)] (L)-leucine, and fasting blood samples were collected over a 96 h period. ApoAI kinetic was assessed using multicompartmental modeling of the tracer enrichment data. Participants achieved a 9.1 ± 2.8% reduction in body weight (P < 0.001). Weight loss resulted in an increase in plasma HDL-cholesterol (HDL-C) concentrations of 6.0% (P = 0.059) and HDL(3)-C of 7.9% (P = 0.045), attributable to a reduction in apoAI fractional catabolic rate (-7.8%; P = 0.046) with no change in apoAI production rate (2.2%; P = 0.58). These data indicate that weight loss, independent of variation in diet composition, increases plasma HDL primarily by delaying the catabolism of apoAI.

Simple SummaryInsulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD) targets insulin signaling pathway downregulation to hamper tumor growth. Genes encoding for the insulin receptors on the cell’s surface contain genetic variation between patients, which can affect insulin receptor function and cellular response. Therefore, a group of 113 patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy with or without a fasting mimicking diet were investigated. We found that two IGF1 receptor variants were associated with worse pathological response compared to the reference alleles, out of the 17 interrogated common variants. Additionally, two IGF1 receptor variants could interact negatively within the FMD group regarding radiological response. These results emphasize that genetic variation harbors predictive clinical relevance to optimize and personalize cancer therapy.Aim: 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. Methods: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. Results: 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). Conclusions: 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.

IntroductionThe Fasting Mimicking Diet (FMD) has gained significant attention as a potential intervention for reducing cardiovascular risk factors. While studies have investigated its effectiveness, findings have been inconsistent. Therefore, this systematic review and meta-analysis aimed to clarify evidence on the impact of FMD on cardiovascular risk factors.MethodPubMed, Web of Science, Scopus, and Google Scholar were searched for eligible Randomized controlled trials (RCTs) published up to July 2024. Weighted mean differences (WMD) were calculated for the net changes in risk factors using random-effects models.ResultsEleven RCTs (with twelve treatment arms) were included. FMD significantly reduced glycated hemoglobin (HbA1c) (WMD = -8.589 mmol/mol, 95% CI: −12.389, -4.769), insulin-like growth factor 1 (IGF-1) (WMD= -19.211 ng/ml, 95% CI: −32.986, -5.437), systolic blood pressure (SBP) (WMD = -4.148 mmHg, 95% CI: −7.584, -0.711), and diastolic blood pressure (DBP) (WMD = -2.263 mmHg, 95% CI: −4.162, -0.364) levels. No significant effects were observed on other cardiovascular risk factors.ConclusionThis meta-analysis suggests that FMD can significantly reduce HbA1c, IGF-1, SBP, and DBP levels. Further research is warranted to investigate the long-term and potential clinical implications of FMD on cardiovascular health.Prospero registrationThe protocol of the study was registered in the International Prospective Register of Systematic Reviews (PROSPERO registration no: CRD42024569426).

Background Prolonged fasting in which only water is consumed for 2 days or more has been shown to reduce pro‐growth signaling, activate cellular protection mechanisms and promote protection against cancer, diabetes, heart disease and neurodegenerative diseases. Since prolonged fasting is difficult for most human subjects, we developed a Fasting Mimicking Diet (FMD) which is a low calorie, low protein, plant‐based meal plan for 5 continuous days. During periods of low calorie intake, the body enters a protected mode, removes damaged cells and tissues, and undergoes self‐repair. Methods 100 participants without a diagnosed medical condition in the preceding six months were enrolled based on Inclusion criteria (generally healthy adult volunteers, 18–70 years of age, body mass index: 18.5 and up). This study is designed as a randomized cross‐over trial, includes two arms: Control and multi‐cycle special 5‐day dietary regimen (Diet, 3 cycles). We evaluated the effects of the FMD on risk factors and markers for aging, cancer, metabolic syndrome and cardiovascular diseases. Results For all subjects who completed 3 FMD cycles (combining both FMD arms), body weight, BMI, total body fat, trunk fat, absolute lean body mass, waist circumference, IGF‐1, systolic and diastolic blood pressure, total cholesterol and LDL were significantly reduced (P&lt;0.05) and relative lean body mass (p=0.0002) was increased. Conclusions FMD cycles are effective in improving an array of metabolic markers/risk factors associated with poor health and aging and in contributing to the treatment and prevention of multiple age‐related diseases. Support or Funding Information Funding was provided by the USC Edna Jones chair fund. Dr. Mack's contributions were provided through the Southern California Clinical and Translational Science Institute (SCCTSI) supported by NIH ULTR001855

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.

Brief Report: A Pilot Study Evaluating the Feasibility, Safety, and Compliance With a Fasting-Mimicking Diet in Patients With Metastatic Non-Small Cell Lung Cancer.

Chronic dietary interventions have been known for decades to help prevent disease and extend longevity, yet most are difficult to adopt especially long-term. Brief periods of a diet that mimics fasting by regulating key starvation response genes including IGF-1, TOR-S6K and PKA lasting between 4 and 7 days and followed by long periods on a normal diet, are emerging as potentially effective pro-longevity interventions. These periodic fasting mimicking diets (FMD) provide low calories, sugars, and proteins and high levels of unsaturated fats. In mice, 4 day bi-monthly cycles of the FMD started at middle age extend longevity, reduce tumors by nearly 50%, reduce inflammatory diseases and increase cognitive performance at old ages. In humans, 3 monthly cycles of a 5 day FMD reduce markers or risk factors for aging, diabetes, cancer and cardiovascular disease including cholesterol, blood pressure, CRP, IGF-1, and fasting glucose, particularly in subjects with elevated levels of these markers at baseline. Here I will present our most recent mouse and clinical studies indicating that FMDs can help reverse insulin resistance, reduce risk factors/markers of aging and age-related diseases, and lower biological age.

Intermittent Administration of a Modified Fasting-Mimicking Diet Reduces Intestinal Inflammation and Promotes Repair to Ameliorate Inflammatory Bowel Disease in Mice

Intermittent administration of a fasting-mimicking diet reduces intestinal inflammation and promotes repair to ameliorate inflammatory bowel disease in mice

模拟禁食饮食（fasting-mimicking diet, FMD）作为一种新兴的周期性低热量膳食干预策略，通过重塑机体代谢与免疫微环境，在肿瘤治疗领域引起了广泛关注。研究表明，FMD不仅能够延长健康个体的寿命，降低癌症及其他疾病的发病率，还能增强对正常细胞的保护作用，同时提高肿瘤细胞对多种治疗手段的敏感性。FMD通过降低血糖、胰岛素及胰岛素样生长因子-1水平，激活正常细胞的保护性通路，同时诱导肿瘤细胞的差异应激敏化，从而增强癌细胞对肿瘤治疗的敏感性，为个体化治疗提供新靶点。本文系统综述了FMD的基本概念、作用机制及其在肿瘤治疗中的潜在应用，重点探讨了FMD与化疗、免疫治疗等传统疗法的协同效应。此外，本文还分析了FMD在临床转化中的挑战，并展望了其未来的应用前景。

Metabolic Flexibility: Interplay of Diet Composition and Intermittent Fasting on Healthspan (P08-053-19)