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Modified7 human studies cited

Fasting-Mimicking Diet

5 days without food · Five consecutive days, once a month for three months in the trials

Written by Reviewed Sep 2026

Also called: FMD, 5-day fasting-mimicking cycle, ProLon-style protocol

Five days of engineered low-calorie, low-protein food designed to hold a fasting-like state while still eating. In the randomised comparison it moved weight, body fat, waist, systolic blood pressure and IGF-1, and did not move glucose, triglycerides, cholesterol, LDL, HDL or CRP.

Overview

The fasting-mimicking diet is a plant-based, low-protein, low-sugar formulation eaten for five consecutive days. It is not a fast and its results do not transfer from water fasting or to it. The prescription in the main trial was approximately 4,600 kJ on day 1 at 11% protein, 46% fat and 43% carbohydrate, and approximately 3,000 kJ per day on days 2 to 5 at 9% protein, 44% fat and 47% carbohydrate. Converted, that is roughly 1,100 kcal and roughly 717 kcal.

The headline trial randomised 100 people at a US university and ran three monthly cycles. What separated from control was weight, BMI, total and trunk body fat, waist circumference, systolic blood pressure and IGF-1. What did not separate was fasting glucose, triglycerides, total cholesterol, LDL, HDL and CRP. The frequently quoted glucose, CRP and lipid results come from post hoc analyses of at-risk subgroups within the pooled completers, and the paper labels them as post hoc.

The diet is a commercial product and the relationship is disclosed in the journals. That disclosure is set out below as fact rather than as an argument about the science.

How it works

Five consecutive days per cycle, repeated monthly. Day 1 is roughly 1,100 kcal and days 2 to 5 roughly 717 kcal, with the macronutrient split above. The oncology version used in the Dutch breast cancer trial was a 4-day plant-based low-amino-acid formulation at roughly 1,200 kcal on day 1 and roughly 200 kcal on days 2 to 4, given for the 3 days before and on the day of each chemotherapy cycle, with dexamethasone omitted in that arm.

Adherence is the practical story. In the 100-person trial, dropout in the randomised phase was 10% in the control arm and 25% in the FMD arm; after crossover, 11 of 43 control-arm participants who moved to the diet withdrew, another 26%. 71 of 100 completed all three cycles and 95 completed at least one. In the oncology trial the numbers were harder: 53 of 65 completed the first cycle, more than half completed two, only 22 of 65 used it for four or more cycles and 20.0% complied during all cycles, with dislike of the diet components given as the main reason for stopping.

Adverse events in the 100-person trial were graded with CTCAE v4.0. Depending on the event, 54% to 100% of participants reported none. The most common grade 1 to 2 events were fatigue, weakness and headaches, and there were no events of grade 3 or higher. The comprehensive metabolic panel showed no adverse liver or kidney effects.

What 5 days actually reaches

What the randomised comparison measured, as change from baseline against control: body weight -2.6 ± 2.5 against +0.1 ± 2.1 kg (p < 0.0001); BMI -0.9 ± 0.9 against 0.0 ± 0.7 (p < 0.0001); total body fat -1,393 ± 1,786 against -44 ± 1,365 (p = 0.0002); trunk fat -636 ± 1,198 against -33 ± 1,046 (p = 0.018); waist circumference -4.1 ± 5.2 against -0.8 ± 2.5 cm (p = 0.0035); systolic blood pressure -4.5 ± 6.0 against -0.7 ± 8.4 mmHg (p = 0.023); IGF-1 -21.7 ± 46.2 against +8.7 ± 36.9 ng/mL (p = 0.0017). What did not differ between groups: diastolic blood pressure (p = 0.053), fasting glucose (p = 0.27), triglycerides (p = 0.27), total cholesterol (p = 0.81), LDL (p = 0.50), HDL (p = 0.90) and CRP (p = 0.27). The IGF-1 result is the one that connects the diet to its stated rationale, and its timing fits the water fasting record: IGF-1 was unchanged at 56 hours of a true fast and fell about 41% by day 5, so a five-day protocol is the shortest duration at which this is a plausible target. On autophagy, the only measurement in a fasting-mimicking protocol is a pilot in 30 subjects using a chloroquine-based flux assay in peripheral blood mononuclear cells across an 8-day version. It found a between-group difference for the baseline to day 6 comparison, and states that differences were not significant across all time points. It was sponsored by the company that makes the diet. This page therefore does not list autophagy as a mechanism the fasting-mimicking diet reaches, and claims mitophagy at no duration, because no human trial has measured mitophagy in response to any fast.

Fig. 1 · what has been measured, hour by hour
  1. 0h to 4h

    Still absorbing

    Burning
    Glucose from the meal just eaten, with insulin high enough to hold fat release down
    • Insulin is at its post-meal peak, and while it is there, adipose tissue lipase stays suppressed and fat is being stored rather than released.
    • The hour count on most fasting charts starts at the last bite. Absorption of a mixed meal is still running here, so the clock and the physiology are not yet the same thing.

    Read the biologyInsulin and insulin sensitivity during a fast

    Measured in people
    The human hour-by-hour fasting series begin later than this. Klein 1993 took its first sample at 12 hours in 6 healthy men, and Rothman 1991 reports its first gluconeogenesis figure as an average across the first 22 hours. This row is the fed state those measurements are compared against, and no extended-fasting measurement exists inside it.

  2. 4h to 12h

    Post-absorptive

    Burning
    A mix of remaining glucose and fatty acids, with the liver covering the brain's glucose demand
    Blood glucose
    5.58 ± 0.08 mmol/L (100.5 mg/dL) at the 12 hour mark, in 6 healthy men
    Ketones (BHB)
    Total ketone bodies around 0.20 mmol/L in overnight-fasted subjects. That figure is acetoacetate plus beta-hydroxybutyrate, not BHB on its own.
    Insulin
    64.6 ± 12.9 pmol/L (9.3 microunits/mL) at 12 hours, in the same 6 men
    • Glycerol release runs at 2.08 ± 0.22 and palmitic acid release at 1.63 ± 0.20 micromol/kg/min at 12 hours. Those are the numbers everything later in the fast is measured against.
    • Gluconeogenesis is already the majority contributor to glucose production rather than a reserve waiting to be called on, which is the first place the popular switch model breaks.

    Read the biologyInsulin and insulin sensitivity during a fastGlycogen depletion and gluconeogenesis

    Measured in people
    Klein 1993 measured glucose, insulin and stable-isotope lipid kinetics at 12 hours in 6 healthy men. Féry 1983 measured total ketone body turnover in overnight-fasted subjects and put the baseline at 0.20 mmol/L. Rothman 1991 measured hepatic glycogen serially by 13C nuclear magnetic resonance through a 68 hour fast in healthy adults and calculated that gluconeogenesis supplied 64 ± 5% of total glucose production across the first 22 hours.

  3. 12h to 18h

    Ketones have not moved yet

    Burning
    Fatty acids rising, with glucose production increasingly made rather than released from store
    Ketones (BHB)
    Median change of 0% between 12 and 18 hours, sampled every 6 hours in 34 adults
    • Beta-hydroxybutyrate does not move in this window. In 34 adults sampled every 6 hours through the standard diagnostic 72 hour fast, the median change from 12 to 18 hours was zero.
    • Gluconeogenesis is supplying 64 ± 5% of glucose production across the first 22 hours, confirmed by an orthogonal method at about 47% by 14 hours. Glucose production does not switch from glycogen to fat at a threshold hour.
    • Whole blood LC3A messenger RNA was 22 ± 5% higher at 18 hours than in a 12 hour control arm in 11 overweight adults (p = 0.001). In the same subjects MTOR expression also rose, by 9 ± 3%.

    Read the biologyGlycogen depletion and gluconeogenesisKetogenesis and beta-hydroxybutyrateAutophagy

    Measured in people
    Service 2005 measured beta-hydroxybutyrate every 6 hours in 34 adults whose 72 hour fasts were negative for insulinoma. Rothman 1991 measured the gluconeogenic share by 13C NMR. Jamshed 2019 measured whole blood messenger RNA in an 11-person 4 day randomised crossover of an 08:00 to 14:00 eating window against 08:00 to 20:00. That is one gene's expression in blood cells, not autophagic flux and not muscle. No study in any species has tested a 16 hour timepoint for autophagy.

  4. 18h to 1d

    The steepest hours for fat release

    Burning
    Fatty acids and glycerol, with ketone production starting its climb
    Ketones (BHB)
    Climbing. The median rise from 18 to 36 hours was +333%, the steepest proportional stretch of a 72 hour fast.
    Insulin
    70% of the entire decline seen across a 72 hour fast has already happened by 24 hours
    • The largest single interval increase in lipolysis across a whole 72 hour fast falls between 18 and 24 hours, and 60% of the total rise in lipid kinetics happens between 12 and 24 hours. The authors attribute that to the falling insulin rather than to any change in glucose.
    • Growth hormone was significantly higher after a 24 hour water-only fast than after a fed day in a randomised crossover of 30 healthy adults (p = 1.1 x 10^-4). The size of that rise is not in the accessible record and is not published here.
    • Haemoglobin, red cell count and haematocrit all rose together at 24 hours in the same trial. That combination is the signature of plasma volume contraction, not of new red cells.
    • 24 hour energy expenditure measured in a whole-room calorimeter fell during 24 hour fasting in 20 volunteers, with the size of the fall varying between individuals.

    Read the biologyInsulin and insulin sensitivity during a fastThe growth hormone responseKetogenesis and beta-hydroxybutyrateAutophagy

    Measured in people
    Horne 2013 randomised 30 apparently healthy adults to a 24 hour water-only fast or a day of usual eating in crossover and measured growth hormone, blood counts, cholesterol, triglycerides, bicarbonate and weight. Klein 1993 measured the lipid kinetics by stable isotope tracer. Hollstein 2020 measured 24 hour energy expenditure by whole-room calorimetry in 20 volunteers; the exact percentage decrease is not in the accessible record and is not published here. On autophagy, a 24 hour fast raised p62/SQSTM1 in the vastus lateralis of 50 women, which is movement in the direction of less autophagic degradation rather than more.

  5. 1d to 36h

    Thyroid drops before metabolic rate does

    Burning
    Fat, with the remaining glucose built from glycerol, lactate and amino acids
    Ketones (BHB)
    1.308 ± 1.053 mmol/L after day 1 in 13 men beginning a 10 day water fast, from a baseline of 0.177 ± 0.044. The spread on that mean is as wide as the mean.
    • Gluconeogenesis supplies 82 ± 5% of glucose production between 22 and 36 hours.
    • Serum T3 fell from 2.30 ± 0.06 to 1.84 ± 0.03 nmol/L by 30 hours in 8 healthy men (p < 0.01), TSH fell below 1 mU/L and the nocturnal TSH peak was abolished. Serum cortisol did not differ across conditions.
    • Thyroid suppression therefore begins inside the first 30 hours, well before any measurable fall in resting metabolic rate.
    • Sodium excretion has not turned yet. In 9 obese women fasting with pre-fast salt intake maintained, urinary sodium began to rise after roughly 48 hours and then exceeded intake.

    Read the biologyGlycogen depletion and gluconeogenesisKetogenesis and beta-hydroxybutyrateAutophagy

    Measured in people
    Rothman 1991 measured the gluconeogenic share by 13C NMR in healthy adults. Hugues 1984 fasted 8 healthy men for 30 hours with serial thyroid sampling. Dai 2022 measured blood beta-hydroxybutyrate daily in 13 men fasting in a controlled facility. Sigler 1975 collected urine in 3 hour blocks from 9 obese women on a metabolic ward. On autophagy, the only human study with several within-fast timepoints took vastus lateralis biopsies at 2, 12, 24 and 36 hours: LC3I, LC3II and p62 all fell, in untrained subjects only, which the authors summarise as skeletal muscle autophagy being only modestly affected by 36 hours of fasting.

  6. 36h to 2d

    Growth hormone multiplies, IGF-1 does not follow

    Burning
    Fat, with ketones now carrying a real share of the load and glucose production almost entirely gluconeogenic
    Ketones (BHB)
    Median +210% between 36 and 54 hours in 34 adults
    • 24 hour growth hormone production rose from 78 ± 12 to 371 ± 57 micrograms per litre of distribution volume on the second day of a fast in 9 normal men (p = 0.0001), a five-fold rise. Secretory bursts went from 14 ± 2.3 to 32 ± 2.4 per 24 hours and the mass per burst from 6.3 ± 1.2 to 11 ± 1.6 micrograms.
    • Growth hormone half-life was unchanged at 18 ± 2.2 against 20 ± 1.5 minutes (p = 0.47), so this is genuine secretion rather than slower clearance.
    • Serum IGF-1 was unchanged at 56 hours. It does not fall until around day 5, when it dropped from 1.31 ± 0.22 to 0.77 ± 0.18 U/mL in 6 men.
    • Gluconeogenesis supplies 96 ± 1% of glucose production from 36 hours onward.
    • Under an insulin clamp at 48 hours, whole-body glucose disposal fell from 39.8 ± 4.6 to 24.1 ± 2.1 micromol/kg/min (p < 0.01) and glucose oxidation collapsed from 21.8 ± 1.3 to 3.9 ± 1.4 (p < 0.001), while non-oxidative disposal was unchanged. That is a change in fuel selection, not glucose intolerance in the diabetic sense.
    • 24 hour energy expenditure in a respiration chamber was 10.9% lower on day 2 of a fast than in a fed condition at energy balance (9.8 ± 0.2 against 11.0 ± 0.4 MJ, p < 0.01).

    Read the biologyThe growth hormone responseGlycogen depletion and gluconeogenesisInsulin and insulin sensitivity during a fast

    Measured in people
    Hartman 1992 sampled serum growth hormone every 5 minutes for 24 hours in 9 normal men, on a fed day and on the second day of a fast, and applied multi-parameter deconvolution; IGF-1 was measured at 56 hours. Ho 1988 measured somatomedin C through a 5 day fast in 6 men. Mansell 1990 clamped 6 non-diabetic men at 48 hours of starvation. Andriessen 2023 put 12 healthy lean males in a respiration chamber for 60 continuous hours in a randomised crossover against a fed condition. No human study has measured autophagy in any tissue between 36 and 72 hours, which is why autophagy is not among the mechanisms linked from this row.

  7. 2d to 3d

    Ketones reach the brain

    Burning
    Fat and ketone bodies, with the brain now taking a measurable share of its fuel as beta-hydroxybutyrate
    Blood glucose
    4.14 ± 0.10 mmol/L (74.6 mg/dL) at 72 hours in 6 healthy men, about 25% below the 12 hour value
    Ketones (BHB)
    74% of people whose diagnostic fast was negative exceeded 2.7 mmol/L before the 72 hour mark. The median rise from 54 to 72 hours was +167%.
    Insulin
    30.1 ± 7.9 pmol/L (4.3 microunits/mL) at 72 hours, roughly half the 12 hour value (p < 0.001)
    • Brain beta-hydroxybutyrate, measured directly in the occipital lobe by 4-tesla magnetic resonance spectroscopy, rose from 0.05 ± 0.05 mmol/L non-fasted to 0.60 ± 0.26 after the second day and 0.98 ± 0.16 after the third. Brain lactate rose from 0.69 ± 0.17 to 1.47 ± 0.22 mmol/L.
    • Plasma and brain beta-hydroxybutyrate correlated at r = 0.86, with a brain-to-plasma slope of 0.26.
    • Across a 48 hour fast, triglyceride accumulated in the livers of men and in the muscles of women, while whole-body and hepatic glucose and oxidative responses were identical between the sexes.
    • The two energy expenditure measurements diverge here and both are real. Hood-measured resting expenditure rose 14.1% by day 3 in 11 lean subjects, while chamber-measured 24 hour expenditure was still 5.5% below the fed condition on day 3 (10.3 ± 0.3 against 10.9 ± 0.3 MJ, p < 0.01). The resting component can rise while the whole day falls.
    • The 72 hour supervised fast is a decades-old routine diagnostic procedure in endocrinology, which is the strongest available evidence that healthy people tolerate this duration under observation.

    Read the biologyKetogenesis and beta-hydroxybutyrateInsulin and insulin sensitivity during a fast

    Measured in people
    Klein 1993 sampled 6 healthy men at 12, 18, 24, 30, 42, 54 and 72 hours with stable isotope tracers and indirect calorimetry. Service 2005 measured beta-hydroxybutyrate every 6 hours in 34 adults. Pan 2000 measured brain beta-hydroxybutyrate and lactate by magnetic resonance spectroscopy in healthy adults. Browning 2012 measured liver and muscle triglyceride by spectroscopy across 48 hours in healthy men and women. Zauner 2000 measured resting expenditure by hood in 11 lean subjects and Andriessen 2023 measured 24 hour expenditure in a chamber in 12 lean men, and the two are measuring different quantities rather than contradicting each other.

  8. 3d onward

    Adapted, and the risk moves to the refeed

    Burning
    Fat and ketones, with glucose production splitting between liver and kidney as the fast lengthens
    Blood glucose
    3.5 ± 0.5 mmol/L (63.1 mg/dL) on day 4 in 11 lean adults, and 3.2 ± 0.2 mmol/L (57.7 mg/dL) on day 5 in 6 men
    Ketones (BHB)
    Production begins to plateau after about 5 days. Across a 21 day fast in 13 volunteers, blood ketones went from 0.1 ± 0.04 to 6.61 ± 1.25 mmol/L.
    Insulin
    Reaches its plateau by day 3 in obese subjects fasting for weeks, while plasma glucagon rises about two-fold to its own peak on the same day
    • In 8 healthy men at 72 hours, skeletal muscle mTOR Ser2448 phosphorylation fell about 50% and LC3B-II rose about 30%. p62 rose about 10% in the same biopsies, and the authors state that this makes autophagic flux impossible to read from these markers alone.
    • Continuous glucose monitors on 12 healthy adults through a 7 day water-only fast recorded time below 70 mg/dL rising from 3.0 ± 7.1% to 66.0 ± 25.7% by day 5, with minimum daily glucose falling from 76 ± 14 to 50 ± 7 mg/dL, and no symptoms of hypoglycaemia reported. Symptom-based self-monitoring stops working at this point.
    • Serum uric acid roughly doubled by day 7, from 5.9 ± 0.4 to 12.5 ± 1.0 mg/dL in 15 obese patients, then fell back to 7.7 ± 1.3 by day 28 while ketosis continued. Urate clearance fell proportionally more than creatinine clearance, so this is a specific tubular handling change.
    • Resting energy expenditure fell 20.3 ± 11.13% across a 21 day complete fast in 13 volunteers, which is where the eventual metabolic decline shows up.
    • Urinary nitrogen excretion decreases progressively for about 4 weeks and then holds at roughly 3 to 6 g per day. Nitrogen loss per kilogram of weight lost is inversely related to body fat, roughly 20 g of nitrogen per kg in non-obese people against roughly 10 g per kg in those carrying 50 kg or more of fat.
    • Mineral balance runs hundreds of milligrams per day negative while serum phosphorus and magnesium stay unchanged. That dissociation is why the deaths in the case literature cluster in the refeeding period rather than in the fast.

    Read the biologyKetogenesis and beta-hydroxybutyrateAutophagyRefeeding, the leucine threshold and refeeding syndrome

    Measured in people
    Vendelbo 2014 took muscle biopsies from 8 healthy men after 72 hours with forearm tracer kinetics. Kolnes 2026 monitored 12 healthy adults continuously through a 7 day water-only fast. Fox 1976 measured serum urate and urate clearance through 28 days in 15 obese patients. Dai 2024 measured resting energy expenditure and blood ketones across a 21 day fast in 13 volunteers. Owen 1969 measured urinary nitrogen fractions in 11 obese subjects through 5 to 6 weeks, and Forbes 1979 established the scaling of nitrogen loss with body fat. Licata 1981 measured mineral balance directly over 40 days on a metabolic ward and found mean daily balances of -104 mg calcium, -48 mg magnesium and -363 mg phosphorus while serum phosphorus and magnesium did not change at all.

Human evidence

One randomised crossover in 100 people with three monthly cycles, one exploratory secondary analysis pooling two trials, one multicentre randomised phase 2 trial in breast cancer that missed both primary endpoints, one 101-patient phase Ib safety and immunology study, and one sponsored autophagy pilot.

  • Wei 2017, randomised crossover, 100 randomised at a US university between 2013 and 2015, three monthly 5-day cycles. Against control: weight -2.6 ± 2.5 kg (p < 0.0001), total body fat -1,393 ± 1,786 (p = 0.0002), trunk fat -636 ± 1,198 (p = 0.018), waist -4.1 ± 5.2 cm (p = 0.0035), systolic blood pressure -4.5 ± 6.0 mmHg (p = 0.023) and IGF-1 -21.7 ± 46.2 ng/mL (p = 0.0017). Fasting glucose, triglycerides, total cholesterol, LDL, HDL and CRP did not differ. 71 of 100 completed all three cycles. No adverse event above grade 2 (Science Translational Medicine, 2017).
  • The post hoc subgroup analyses in the same paper, in the pooled 71 completers and labelled post hoc by the authors: systolic blood pressure fell 6.7 ± 6.9 mmHg if baseline was above 120 against 2.4 ± 6.3 if at or below (p = 0.013); fasting glucose fell 11.8 ± 6.9 mg/dL if baseline was above 99 mg/dL and did not change otherwise (p < 0.0001); IGF-1 fell 55.1 ± 45.6 ng/mL if baseline was above 225 against 14.1 ± 39.9 (p < 0.001); LDL fell 14.9 ± 21.7 mg/dL if baseline total cholesterol was above 199 with no reduction in the normal-range group (p = 0.013); CRP fell 1.6 ± 1.3 mg/L if baseline was above 1 mg/L with no reduction below it (p = 0.0003).
  • Brandhorst 2024, a secondary and exploratory analysis of the same trial plus an independent second trial, not a new randomised trial. Biological age by a clinical-chemistry estimate built from seven biomarkers fell a median of about 2.5 years after three cycles (n = 52, p = 0.0007) against a non-significant increase of 0.78 years in controls (n = 19, p = 0.76), with a pooled median of -2.6 years (n = 86) and significance surviving weight adjustment (p = 0.029). 16 of 52 and 8 of 34 participants had an increase in biological age rather than a decrease (Nature Communications, 2024).
  • DIRECT, de Groot 2020, a multicentre observer-blind randomised phase 2 trial across 11 Dutch centres, 129 analysed with HER2-negative stage II/III breast cancer. Both primary endpoints were missed: grade III/IV toxicity was 75.4% against 65.6%, not significantly different, and pathological complete response was 10.8% against 12.7%, odds ratio 0.830 (95% CI 0.282 to 2.442, p = 0.735). The planned phase III component was abandoned on data safety monitoring board advice (Nature Communications, 2020).
  • DIRECT's secondary endpoints, which is where its positive results are: radiological complete or partial response in the intention-to-treat population, multivariate odds ratio 3.168 (95% CI 1.062 to 9.446, p = 0.039), and Miller and Payne 4/5 tumour cell loss per protocol, multivariate odds ratio 4.109 (95% CI 1.297 to 13.02, p = 0.016). Per-protocol pathological complete response remained null at 13.6% against 12.1%. Only 22 of 65 in the diet arm used it for four or more cycles.
  • Vernieri 2022, 101 patients with mixed tumour types on cyclic 5-day cycles alongside standard therapy. Phase Ib: safe and feasible, with consistent falls in blood glucose and growth factors, contraction of immunosuppressive myeloid and regulatory T cell compartments, and enhanced intratumour Th1 and cytotoxic responses. There was no efficacy endpoint (Cancer Discovery, 2022).
  • Espinoza 2025, a pilot in 30 subjects measuring autophagic flux in peripheral blood mononuclear cells with chloroquine across an 8-day fasting-mimicking diet. A between-group difference was found for baseline to day 6, and the paper states that differences were not significant across all time points. Sponsored by L-Nutra Inc (GeroScience, 2025).

What this does not tell you: The 100-person trial is 5 days a month for 3 months with biomarkers as endpoints and no clinical outcome, and its most quoted results are post hoc subgroup analyses in pooled completers rather than randomised comparisons. The biological age paper is a secondary exploratory analysis whose most quotable numbers rest on very small samples: HOMA-IR in 11 people, HbA1c in 3, hepatic steatosis in 5, magnetic resonance imaging in 15. Its life expectancy and mortality projections are model simulations on population data assuming annual cycles to age 70, and the paper says so. DIRECT missed both primary endpoints with two thirds of its diet arm not completing four cycles. No trial has run the diet for longer than a few monthly cycles or measured a hard clinical outcome.

Reading the research record

Three things are consistently misreported about this protocol and all three are checkable.

The first is what the randomised comparison showed. Reporting the trial as showing that the diet lowers glucose, CRP and LDL misstates it: in the randomised comparison those three did not differ from control. The results people quote are from post hoc subgroups of the pooled completers, restricted to participants whose baseline value was already outside the normal range, and the paper labels them as post hoc. That does not make them meaningless. It makes them hypothesis-generating rather than the trial's finding.

The second is the oncology evidence. DIRECT is the multicentre randomised phase 2 trial and it missed both of its primary endpoints. Pathological complete response was 10.8% in the diet arm and 12.7% in the control arm, odds ratio 0.830 (95% CI 0.282 to 2.442). A commentary from another fasting-mimicking research group, whose authors disclose that three of them are inventors of a competing regimen, describes DIRECT as having overall negative study results because the primary endpoints were not met. The positive findings are secondary: a radiological response endpoint in the intention-to-treat population and a pathological endpoint in the per-protocol population, in a trial where only 22 of 65 patients in that arm completed four or more cycles.

The third is a paper that does not exist. There is no New England Journal of Medicine paper by Valter Longo on the fasting-mimicking diet or on prolonged fasting. Searches for him as an author in that journal return nothing, as do searches of the journal for fasting mimicking and for prolonged fasting. The New England Journal of Medicine fasting paper commonly misattributed to him is a 2019 review by de Cabo and Mattson, on which he is not an author and which is a review rather than a trial.

The commercial relationship, stated as documented fact from the journals' own conflict-of-interest sections. The experimental diet was provided by L-Nutra Inc. The University of Southern California has licensed intellectual property to L-Nutra that is under study in this research and has the potential to receive royalty payments. Two of the authors, including Valter Longo, have equity interest in L-Nutra and did not participate in the collection and analysis of the data, and 100% of Longo's equity is assigned to a nonprofit foundation. Longo is the founder of L-Nutra, which sells the commercial version of the diet. The size of the equity stake is not published in any journal disclosure, regulatory filing or university statement, so no percentage appears here. The same relationship is disclosed in the DIRECT trial and its quality-of-life companion, where one further author holds shares in a company that invested in L-Nutra.

What happens to muscle

This is one of the few protocols on this page where body composition was a randomised outcome rather than an afterthought, and the diet separated from control on fat rather than on total weight alone. Total body fat fell 1,393 ± 1,786 against 44 ± 1,365 in controls (p = 0.0002) and trunk fat 636 ± 1,198 against 33 ± 1,046 (p = 0.018), alongside a 4.1 ± 5.2 cm reduction in waist circumference.

A discrete lean mass figure from that randomised comparison is not in the accessible record and is not published here. That absence matters, because the direction of the total fat result cannot tell you what happened to the lean compartment.

The closest thing to a lean mass answer for a five-day low-protein protocol comes from adjacent work rather than from this trial. In 16 men on a 10 day modified fast at 200 to 250 kcal a day, lean soft tissue fell 3.53 ± 0.13 kg but decomposed into 44% extracellular water, 14% glycogen with its bound water and only 42% metabolically active lean tissue. In 20 middle-aged volunteers fasting a mean of 9.8 ± 3.1 days followed by refeeding, proteomics indicated preservation of skeletal muscle and bone. Neither is this diet, and both are longer.

The protein arithmetic is worth stating plainly, because it is the one part of the design that is deliberately low. At 9% to 11% of roughly 720 to 1,100 kcal, the diet supplies far less protein than the 1.6 to 2.2 g/kg/day that every compressed-window trial preserving lean mass ran, and the one compressed-window trial run at 1.0 g/kg/day lost more lean mass than its control while daily myofibrillar protein synthesis was identical between arms. Low protein is the mechanism the diet is built around, and it is also the variable most associated with lean mass loss elsewhere in this literature.

Doing it

It is not a fast and its data do not transfer
Roughly 1,100 kcal on day 1 and roughly 717 kcal on days 2 to 5, with 43% to 47% of energy as carbohydrate. Nothing measured on this protocol can be read across to a water fast, and nothing measured on a water fast can be read across to it. The two produce different ketosis, different glucose and different sodium handling.
What the randomised trial actually moved
Weight, BMI, total and trunk fat, waist, systolic blood pressure and IGF-1. Fasting glucose, triglycerides, total cholesterol, LDL, HDL and CRP did not differ from control. Anyone choosing this protocol for a lipid or inflammation result is choosing it on a post hoc subgroup rather than on the trial's finding.
Expect the dropout rate to apply to you too
25% withdrew from the diet arm in the randomised phase and another 26% withdrew after crossing over to it. In the oncology trial only 22 of 65 used it for four or more cycles, with dislike of the components as the main reason. This is the least-completed protocol on this page.
Protein is deliberately low, and that is the trade
9% to 11% of a small energy intake for five days. The trials that preserved lean mass anywhere in this literature ran 1.6 to 2.2 g/kg/day with resistance training. If maintaining lean mass is the priority, this protocol is designed against it.
Medication review still applies
A carbohydrate-containing 700 kcal a day is not a fast, but it is a large reduction in intake and the same drug classes behave differently against it: insulin, sulfonylureas, meglitinides, SGLT2 inhibitors, ACE inhibitors, ARBs and diuretics. The published adjustment table for intermittent fasting is the starting point for that conversation with a prescriber.
The commercial relationship is disclosed, and it is a fact rather than a verdict
The diet in the trials was provided by L-Nutra Inc. The university has licensed intellectual property to the company with the potential to receive royalties, and two authors hold equity and did not participate in data collection or analysis. The size of the stake is not published anywhere verifiable, so no figure is given here.

Breaking the fast

The five-day protocol ends by returning to normal eating, and the trials did not prescribe a reintroduction schedule beyond that. That is a real gap in the published record rather than evidence that no schedule is needed. What the risk framework says is that this protocol sits below every formal refeeding threshold in a well-nourished person: ASPEN treats none or negligible intake for 5 to 6 days as one of two criteria for moderate risk and more than 7 days as a single significant-risk criterion, and 700 kcal a day with carbohydrate present is not negligible intake. NICE's equivalent lines are little or no nutritional intake for more than 5 days as one of two criteria and more than 10 days as a single sufficient one. The mechanism behind those thresholds still applies in miniature and is worth knowing. Phosphate, potassium and magnesium fall in the body during energy restriction while serum values look normal, and reintroducing carbohydrate raises insulin, which drives all three into cells at once. In the cleanest human demonstration, mean daily balances during a 40 day protein-supplemented fast were -104 mg calcium, -48 mg magnesium and -363 mg phosphorus while serum phosphorus and magnesium did not change at all. The practical failure mode after five days at 700 kcal is behavioural rather than biochemical: reactive over-eating on the first normal day, which is the most consistently described way people erase the deficit they built.

Citations

  1. Human2017
    Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease

    Science Translational Medicine

    100 randomised at a US university, three monthly 5-day cycles of approximately 1,100 kcal on day 1 and approximately 717 kcal on days 2 to 5. Randomised comparison against control: weight -2.6 ± 2.5 against +0.1 ± 2.1 kg (p < 0.0001), total body fat -1,393 ± 1,786 against -44 ± 1,365 (p = 0.0002), trunk fat -636 ± 1,198 (p = 0.018), waist -4.1 ± 5.2 cm (p = 0.0035), systolic blood pressure -4.5 ± 6.0 mmHg (p = 0.023) and IGF-1 -21.7 ± 46.2 ng/mL (p = 0.0017). Fasting glucose (p = 0.27), triglycerides (p = 0.27), total cholesterol (p = 0.81), LDL (p = 0.50), HDL (p = 0.90) and CRP (p = 0.27) did not differ. Dropout 25% in the diet arm against 10% in control; 71 of 100 completed all three cycles. No adverse event above grade 2. The diet was provided by L-Nutra Inc, the university has licensed intellectual property to the company with royalty potential, and two authors hold equity and did not participate in data collection or analysis.

  2. Human2024
    Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk

    Nature Communications

    A secondary and exploratory analysis of the 2017 trial plus an independent second trial, not a new randomised trial. Biological age, estimated from seven clinical-chemistry biomarkers, fell a median of about 2.5 years after three cycles (n = 52, p = 0.0007) while controls showed a non-significant increase of 0.78 years (n = 19, p = 0.76); pooled median -2.6 years (n = 86), still significant after weight adjustment (p = 0.029). 16 of 52 and 8 of 34 diet participants had an increase in biological age. The most quotable secondary results rest on very small samples: HOMA-IR n = 11, HbA1c n = 3, hepatic steatosis n = 5, imaging n = 15. The life expectancy and mortality figures are model simulations assuming annual cycles to age 70, which the paper states.

  3. Human2020
    Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial

    Nature Communications

    129 analysed across 11 Dutch centres, HER2-negative stage II/III breast cancer, a 4-day plant-based low-amino-acid diet before each chemotherapy cycle. Both primary endpoints were missed: grade III/IV toxicity 75.4% against 65.6%, not significantly different, and pathological complete response 10.8% against 12.7%, odds ratio 0.830 (95% CI 0.282 to 2.442, p = 0.735). Secondary endpoints were positive: radiological complete or partial response in the intention-to-treat population, multivariate odds ratio 3.168 (95% CI 1.062 to 9.446, p = 0.039), and Miller and Payne 4/5 per protocol, multivariate odds ratio 4.109 (95% CI 1.297 to 13.02, p = 0.016). Only 22 of 65 (33.8%) used the diet for four or more cycles and 20.0% complied during all cycles, with dislike of the components the main reason for stopping. The phase III component was abandoned on data safety monitoring board advice.

  4. Review2020
    Fasting-mimicking diet plus chemotherapy in breast cancer treatment

    Nature Communications

    A commentary on DIRECT from a separate fasting-mimicking research group, describing the trial as having overall negative study results because the primary endpoints were not met, and calling for better trial design. Three of its authors disclose that they are themselves inventors of a fasting-mimicking regimen.

  5. Human2022
    Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer

    Cancer Discovery

    101 patients with mixed tumour types on cyclic 5-day fasting-mimicking cycles alongside standard therapy. Phase Ib: safe and feasible, with consistent falls in blood glucose and growth factors, contraction of immunosuppressive myeloid and regulatory T cell compartments, and enhanced intratumour Th1 and cytotoxic responses. There is no efficacy endpoint in this trial.

  6. Human2025
    Effect of fasting-mimicking diet on markers of autophagy and metabolic health in human subjects

    GeroScience

    A pilot in 30 subjects measuring autophagic flux in peripheral blood mononuclear cells with chloroquine across an 8-day fasting-mimicking diet. A between-group difference was found for the baseline to day 6 comparison, and the paper states that differences were not significant across all time points. Sponsored by L-Nutra Inc.

  7. Review2019
    Effects of Intermittent Fasting on Health, Aging, and Disease

    New England Journal of Medicine

    The actual New England Journal of Medicine fasting paper, and a review rather than a trial. It is included here because the fasting-mimicking literature is frequently credited with a paper in this journal that does not exist: searches for Valter Longo as an author in the journal, and of the journal for fasting mimicking and for prolonged fasting, return nothing. This paper is by de Cabo and Mattson, and Longo is not an author.

  8. Human1988
    Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man

    Journal of Clinical Investigation

    6 normal adult men across a control fed day and days 1 and 5 of a 5 day fast. Somatomedin C, which is IGF-1, fell from 1.31 ± 0.22 to 0.77 ± 0.18 U/mL by day 5, roughly 41%, against no change at 56 hours in a separate 2 day fasting study. Glucose fell from 4.9 ± 0.2 to 3.2 ± 0.2 mmol/L (88.3 to 57.7 mg/dL) and free fatty acids rose from 0.43 ± 0.12 to 1.55 ± 0.35 mmol/L. Included here because it establishes that IGF-1 suppression is a multi-day effect, which is the timescale this protocol targets.

  9. Human2021
    Quality of life and illness perceptions in patients with breast cancer using a fasting mimicking diet as an adjunct to neoadjuvant chemotherapy in the phase 2 DIRECT (BOOG 2013-14) trial

    Breast Cancer Research and Treatment

    The quality-of-life and illness-perception secondary paper from the DIRECT trial, in the same patients. In the per-protocol analysis, diet-adherent patients reported better emotional, physical, role, cognitive and social functioning and less fatigue, nausea and insomnia. The same L-Nutra equity disclosure applies, with one further author holding shares in a company that invested in L-Nutra.

What people report

These are uncontrolled self-reports, not evidence. They are here because they tell you what to expect and what to watch for, which the trial literature does not. They cannot tell you whether anything works.

  • Fatigue, weakness and headaches, which were also the most common graded adverse events in the trial
  • Dislike of the specific food components, which was the main reason given for stopping in the oncology trial
  • Finding a partial-calorie protocol harder to keep than a total fast, because eating a small amount keeps appetite engaged
  • Hunger through the first two days easing afterwards, which is the same shape people describe on water fasts

Sources: Uncontrolled self-report, except where noted. The fatigue, weakness and headache items were graded adverse events in the randomised trial, where 54% to 100% of participants reported none depending on the event and nothing above grade 2 occurred. The dislike-of-components item is the reason recorded in the oncology trial's own compliance analysis, where only 22 of 65 patients used the diet for four or more cycles.

Who this is wrong for

  • Anyone taking an SGLT2 inhibitor without a prescriber managing it first. Carbohydrate restriction plus continuous urinary glucose loss is the same mechanism that produces euglycaemic ketoacidosis during a true fast, and the first published case of it during Ramadan-style caloric restriction is on record.
  • Anyone on insulin, a sulfonylurea or a meglitinide without a prescriber adjusting the dose against a 700 kcal day.
  • Anyone with type 1 diabetes outside a structured programme with glucose monitoring.
  • Pregnancy and breastfeeding. Neither has been studied on this protocol, and lactation alone draws roughly 30 to 50 g of glucose a day out of the mother.
  • Anyone with a history of an eating disorder or current loss-of-control eating. A five-day prescribed-food protocol repeated monthly is a restriction rule with a score attached.
  • Children and adolescents, where no long-term growth or development follow-up exists for any fasting protocol.
  • Anyone with a BMI under 18.5 or meeting the NICE refeeding risk criteria on the way in.
  • Anyone with cancer who is considering this alongside treatment outside a trial. The randomised phase 2 trial missed both primary endpoints, its positive results are secondary endpoints in a trial where two thirds of the diet arm did not complete four cycles, and the phase III component was abandoned on data safety monitoring board advice.
  • Anyone whose priority is maintaining lean mass, given that the protocol supplies 9% to 11% of a small energy intake as protein for five consecutive days.
  • Anyone with chronic kidney disease on an ACE inhibitor, ARB or diuretic, or with primary adrenal insufficiency, for the same reasons that apply to a true fast.

Questions

Did the trial show the diet lowers glucose, cholesterol and inflammation?
Not in the randomised comparison. Fasting glucose (p = 0.27), triglycerides (p = 0.27), total cholesterol (p = 0.81), LDL (p = 0.50), HDL (p = 0.90) and CRP (p = 0.27) did not differ from control. The widely quoted numbers for glucose, CRP and LDL come from post hoc analyses of pooled completers whose baseline values were already outside the normal range, and the paper labels them post hoc. What did separate from control was weight, BMI, body fat, trunk fat, waist, systolic blood pressure and IGF-1.
Is there a New England Journal of Medicine paper behind this diet?
No. There is no paper by Valter Longo in that journal on the fasting-mimicking diet or on prolonged fasting. The New England Journal of Medicine fasting paper usually misattributed to him is a 2019 review by de Cabo and Mattson, on which he is not an author.
What is the commercial relationship?
Stated as the journals state it: the experimental diet was provided by L-Nutra Inc, the University of Southern California has licensed intellectual property to L-Nutra that is under study in this research and has the potential to receive royalty payments, and two of the authors, including Valter Longo, hold equity in L-Nutra and did not participate in the collection and analysis of the data, with 100% of Longo's equity assigned to a nonprofit foundation. Longo founded L-Nutra, which sells the commercial version. The size of the equity stake is not published in any journal disclosure, regulatory filing or university statement, so no figure appears here.
Did it work alongside chemotherapy?
The multicentre randomised phase 2 trial missed both primary endpoints. Grade III/IV toxicity was 75.4% against 65.6%, not significantly different, and pathological complete response was 10.8% against 12.7%, odds ratio 0.830 (95% CI 0.282 to 2.442). Its positive results are secondary endpoints, a radiological response measure in the intention-to-treat population and a pathological measure per protocol, in a trial where only 22 of 65 patients in that arm completed four or more cycles. The phase III component was abandoned on data safety monitoring board advice.
Does it trigger autophagy?
The only measurement is a 30-person pilot using a chloroquine flux assay in blood mononuclear cells across an 8-day version, which found a between-group difference for baseline to day 6 and states that differences were not significant across all time points. It was sponsored by the company that makes the diet. That is not enough for this page to list autophagy as a mechanism the protocol reaches.