Protocol · graded by use, two uses
Fasting-mimicking diet (FMD, 5-day cycles)
Blood pressure, HbA1c A blood test that reflects average blood sugar over the previous two to three months. and IGF-1 against an unrestricted diet, adults without diabetes.
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How this letter has changedLatest: October 2026 · Corrected.
The description called the human evidence pilot-scale; Wei 2017 (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 28202779) randomized 100 adults, Micarelli 2025 (PMID 39970875) 102 in crossover A trial design in which each participant receives both the treatment and the comparison, one after the other, and serves as their own control., van den Burg 2024 (PMID 38546821) 100 for 12 months, and Mohammadzadeh 2025 (PMID 40287774) pooled 11 trials; corrected. Wei 2017's randomized comparison showed weight, fat, blood pressure and IGF-1 only, with the glucose, lipid and CRP results post hoc in at-risk participants; the ref now says so. Espinoza (PMID 41372565) is dated 2026 as PubMed does, with 30 people, 8 days and differences not significant at all time points. Added: Mishra 2023 (PMID 40604264), no difference from a Mediterranean diet, and Sadeghian 2021 (PMID 33420673), no weight difference from continuous energy restriction, as the nulls; Brandhorst 2024 (PMID 38378685) as the inventor group's biological-age analysis. The type 2 diabetes trial (PMID 38546821), co-funded by the maker, is a separate C use rather than support for healthy adults. The kit's product name is no longer on the record. Headline letter unchanged; B versus C is on the decision sheet.PMID 28202779 PMID 39970875 PMID 38546821 PMID 40287774 PMID 41372565 PMID 40604264 PMID 33420673 PMID 38378685 PMID 38546821
The C rested on the view that the human evidence was pilot-scale. It is not: Wei et al. (Sci Transl Med, 2017; PMID 28202779) randomized 100 adults to three cycles, Micarelli et al. (Cell Rep Med, 2025; PMID 39970875) randomized 102 in crossover to six, and Mohammadzadeh et al. (Diabetol Metab Syndr, 2025; PMID 40287774) pooled 11 randomized trials, agreeing on lower blood pressure, HbA1c and IGF-1 and on no effect elsewhere. Replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. randomized evidence on validated surrogates is B under the written rule. The letter is scoped: against a Mediterranean diet, Mishra et al. (NPJ Metab Health Dis, 2023; PMID 40604264) found no between-group difference, and against continuous energy restriction Sadeghian et al. (Obes Surg, 2021; PMID 33420673) found no weight difference, so the B is for the comparison with an unrestricted diet only. Every positive trial used the maker's kit with the equity-holding inventor as coauthor; under the replication funding rule of September those trials count and are disclosed beside the letter. Moved October 2026 by editor adjudication (Arnold Sandlow, D.C.).PMID 28202779 PMID 39970875 PMID 40287774 PMID 40604264 PMID 33420673
Funding stated in the evidence. Wei 2017 (PMID 28202779) was publicly funded but used a diet provided by L-Nutra, which licenses it from USC, and two authors hold L-Nutra equity; Espinoza 2026 (PMID 41372565) was sponsored by L-Nutra, with two of its employees among the authors. Letter unchanged.PMID 28202779 PMID 41372565
Every change to a letter on this site is dated and published. The full evidence log →
This diet is a low-calorie eating plan followed for 5 days, once a month, meant to act like a fast. In trials of adults without diabetes, it lowered blood pressure, long-term blood sugar and a growth signal called IGF-1, compared with eating freely. Against a Mediterranean diet or plain calorie cutting, no gain was found. Nearly every good result used the maker's product, and most included the diet's inventor, who owns a stake in the firm. One trial in type 2 diabetes found better blood sugar control.
The B belongs to one of the two uses graded on this record. The other one carries its own letter.
This record carries a separate letter for each thing it has been measured on. The headline grade is the best of them, and it does not transfer to the others.
Wei et al. (Sci Transl Med, 2017; PMID 28202779): 100 adults, three monthly cycles against an unrestricted diet; weight, body fat, blood pressure and IGF-1 lower. Micarelli et al. (Cell Rep Med, 2025; PMID 39970875): 102 adults with overweight or obesity, randomized crossover, six cycles; cardiometabolic and inflammatory markers lower. Mohammadzadeh et al. (Diabetol Metab Syndr, 2025; PMID 40287774): 11 randomized trials pooled; systolic 4.1 and diastolic 2.3 mmHg lower, HbA1c and IGF-1 lower, no effect on other risk factors. Replicated randomized evidence on validated surrogates: B. Against active comparators the picture differs: Mishra et al. (NPJ Metab Health Dis, 2023; PMID 40604264) found no difference from a Mediterranean diet and Sadeghian et al. (Obes Surg, 2021; PMID 33420673) no weight difference from continuous energy restriction, so the B is for the comparison with an unrestricted diet only. Every positive trial used the maker's kit with the equity-holding inventor as coauthor; disclosed beside the letter.
van den Burg et al. (Diabetologia, 2024; PMID 38546821): the FIT trial, 100 adults with type 2 diabetes in Dutch primary care randomized to monthly 5-day FMD cycles added to usual care or usual care alone for 12 months, assessor-blinded; glucose-lowering medication score 0.3 lower, HbA1c 0.3 percentage points lower and weight 3.6 kg lower; glycemic management improved in 53 percent against 8 percent. Co-funded by Health~Holland, the Dutch Diabetes Foundation and L-Nutra, which contributed the formula diet and a small part of the funding and had no role in design or analysis. One trial, a clinical population, surrogate endpoints A lab value or measurement used in place of the outcome that matters, such as LDL cholesterol standing in for heart attacks. Moving a surrogate does not always move the outcome.: C, separate from the healthy-adult headline.
Funding: Both randomized trials replicating this Grade B for Blood pressure, HbA1c and IGF-1 against an unrestricted diet, adults without diabetes were funded by the maker of the studied product, who donated it, L-Nutra. Funder's role, as reported: University of Southern California, USA (PMID 28202779): the paper states the funding sources had no involvement in design, analysis or reporting and that the equity-holding authors did not take part in data collection or analysis. UNITER and CNR, Rome and Milan, Italy (PMID 39970875): the paper states L-Nutra had no influence on design, conduct, analysis or the article. The letter stands because each trial met the grading rules on its own; the funding is stated here so it can be weighed alongside it. Investigators: Both randomized trials replicating this Grade B for Blood pressure, HbA1c and IGF-1 against an unrestricted diet, adults without diabetes were run by investigators employed by, founded by, or belonging to the organization that developed, sells or teaches the intervention (the diet's inventors at USC, who hold L-Nutra equity under a USC license to L-Nutra; the diet's inventor, an equity-holding advisor to L-Nutra, is a coauthor). The funder may read non-commercial; the people who ran the trials are part of the organization whose intervention they tested, which is stated here so it can be weighed alongside the letter.
A low-calorie 5-day diet designed to reproduce the metabolic effects of fasting without full fasting, taken in monthly cycles. Human evidence in generally healthy or overweight adults: a 100-person randomized trial of three cycles in which weight, body fat, blood pressure and IGF-1 fell in the randomized comparison and the glucose, lipid and CRP changes were post hoc in at-risk participants; a 102-person randomized crossover of six cycles; a 30-person, 8-day pilot of autophagy The process cells use to break down and recycle their own worn-out parts. markers; a meta-analysis of 11 randomized trials finding lower blood pressure, HbA1c and IGF-1 and no effect on other risk factors; and two trials against active comparators, a Mediterranean diet and continuous energy restriction, that found no between-group difference. Nearly every positive trial used the maker's product and most include the diet's inventor, who holds equity in the maker. Grade B on blood pressure, HbA1c and IGF-1 against an unrestricted diet, replicated randomized evidence on validated surrogates; against a Mediterranean diet or ordinary calorie restriction no difference has been shown, and the B does not extend to those comparisons. A 12-month trial in type 2 diabetes is graded as a separate use below.
Why this gradeThe reasoning, and what the grade does not cover.
Grade B, scoped to blood pressure, HbA1c and IGF-1 against an unrestricted diet. Wei 2017 (PMID 28202779; 100 adults, three cycles) and Micarelli 2025 (PMID 39970875; 102 adults, six cycles) are randomized trials from different centers that agree on direction, and Mohammadzadeh 2025 (PMID 40287774) pools 11 randomized trials to the same three endpoints The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. with no effect on other risk factors. Blood pressure and HbA1c are validated surrogates, so replicated randomized evidence reaches B. Not A: no trial reports a clinical event. Every positive trial used the maker's kit and most include the diet's inventor, an equity holder, as a coauthor; under the replication funding rule those trials still count as replication and are disclosed beside the letter rather than discounted. Moved from C in October 2026 by editor adjudication.
WHAT THIS GRADE DOES NOT COVERcomparison with an active diet, where Mishra 2023 (PMID 40604264) found no difference from a Mediterranean diet and Sadeghian 2021 (PMID 33420673) no weight difference from continuous energy restriction; lipids, glucose, CRP and weight, which the pooled analysis did not find changed; biological-age measures, which rest on the inventor group's exploratory analysis; and type 2 diabetes, graded as its own use.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
The evidence, in fullSeven papers, each linked to its PubMed record.
Wei et al. (Science Translational Medicine, 2017; PMID 28202779): 100 generally healthy adults randomized to three monthly FMD cycles or an unrestricted diet; in the randomized comparison, body weight, trunk and total fat, blood pressure and IGF-1 fell; the reported improvements in fasting glucose, triglycerides, LDL Low-density lipoprotein cholesterol, the cholesterol fraction most closely tied to plaque in the arteries. and CRP come from a post hoc analysis of participants at risk for disease, after the control arm had crossed over. Brandhorst et al. (Nat Commun, 2024; PMID 38378685): secondary and exploratory analysis of blood samples from the Wei trial and a second trial, reporting lower insulin resistance, lower hepatic fat and a 2.5-year drop in median biological age on a blood-marker measure; same inventor group, NIH-funded, maker-supplied diet. Micarelli et al. (Cell Rep Med, 2025; PMID 39970875): 102 adults with overweight or obesity, randomized crossover, six monthly cycles; taste and smell function and cardiometabolic markers improved; no external funding, diet provided by the maker, the inventor an equity-holding advisor and coauthor. Espinoza et al. (GeroScience, 2026; PMID 41372565): 30 healthy adults randomized to one of two FMD formulations or control for 8 days; body weight, fasting glucose, beta-hydroxybutyrate, HOMA-IR and autophagic flux in blood cells differed between groups at the end of the 6-day diet but not across all time points; sponsored by the maker, two authors its employees. Mohammadzadeh et al. (Diabetol Metab Syndr, 2025; PMID 40287774): meta-analysis of 11 randomized trials; HbA1c, IGF-1, systolic and diastolic pressure lower, no significant effect on other cardiovascular risk factors. Against active comparators: Mishra et al. (NPJ Metab Health Dis, 2023; PMID 40604264): four FMD cycles against a continuous Mediterranean diet in hypertensive adults with excess weight; no parameter differed between groups at the end of the intervention; inventor coauthor with equity, maker-supplied diet. Sadeghian et al. (Obes Surg, 2021; PMID 33420673): independent trial in 60 women with obesity, FMD against continuous energy restriction for 2 months; no difference in weight loss. Grade B on blood pressure, HbA1c and IGF-1 against an unrestricted diet: replicated randomized evidence on validated surrogates, with every positive trial disclosed as maker-supplied and inventor-affiliated. Not against active comparators, where no difference has been shown. Funding: Wei 2017 was funded by a University of Southern California chair fund and the NIH, the diet was provided by L-Nutra Inc., USC licenses the diet to L-Nutra with potential royalties, and two authors hold L-Nutra equity (the paper states they did not take part in data collection or analysis). Espinoza 2026 states it was sponsored and supported by L-Nutra, which provided the diet kits and did not take part in conduct, data collection or analysis; two authors are L-Nutra employees. Micarelli 2025, Mishra 2023 and Brandhorst 2024 used L-Nutra's diet with the equity-holding inventor as coauthor. Sadeghian 2021 is the one cited trial run without the maker's product or the inventor.
IGF-1, fasting glucose, CRP, and body weight at baseline, after each 5-day cycle, and at the 3-month mark. Biological age markers (epigenetic clock A test that estimates biological age from chemical marks on DNA (DNA methylation). at baseline and 6 months) if the Brandhorst 2024 analysis (PMID 38378685) is the benchmark. The published evidence uses the maker's commercial 5-day kit; home-assembled FMD diets have not been validated against the same endpoints.
Evidence notes: randomized trial, meta-analysis
Endpoint graded: Blood pressure, HbA1c and IGF-1 against an unrestricted diet (surrogate)
Last reviewed: July 2026
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