Long-term Fasting: Multi-system Adaptations in Humans

The aim of this trial is to investigate the effects of long-term fasting on size, mass, composition and function of metabolic active tissues in several organs that reexpand possibly rejuvenated after 1-4 months. Additionally, the lipid metabolism is investigated in depth.

Study Overview

• Status: Completed
• Conditions: Fasting
• Intervention / Treatment: Other: Long-term fasting according to the Buchinger Wilhelmi fasting program

Detailed Description

Fasting displays numerous positive effects on metabolism, health and aging. Surprisingly, few considerations are given to long-term fasting periods.

The metabolic switch from food-derived glucose to adipose tissue-derived fatty acids and ketones as primary cellular fuel is the key to fasting metabolism. Fasting has been shown to improve cardiovascular risk factors and gut microbiota in humans. It provokes profound changes in lipid metabolism. However, many questions are still open concerning the mobilization, exchange, and function of lipids during long-term fasting. Furthermore, recent results show the ability of periodic restrictive nutritional strategies to trigger organ regeneration. This promising regenerative power has not been investigated comprehensively in humans. In addition, the knowledge about the role of human faecal microbiota in health and disease is increasing. Only little is known about its composition and function during fasting. We found indications that the gut microbiome could influence energy metabolism and consequently could influence the dynamic of the metabolic switch.

Long-term fasting under medical supervision according to the Buchinger Wilhelmi fasting program has been demonstrated to be safe and well-tolerated.

The current project investigates the effects of a 9±3 days fasting period by a multi-systemic approach focusing on lipid metabolism and the gut microbiome in 100 subjects. Additionally, the body composition in combination with muscle performance will be analyzed in-depth in a subgroup of 32 subjects.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Überlingen, Germany, 88662
    • Buchinger Wilhelmi Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• BMI between 22 - 35 kg/m2

Exclusion Criteria:

• intake of medication (cardiovascular diseases, lipid and glucose metabolism)
• chronic manifest psychical and psychiatric diseases
• participation in another study
• pregnancy or breastfeeding
• in the MRI/MRS sub-study, any MRI contraindication (claustrophobia, pacemakers, MR-incompatible prosthetic valves, metallic implants, foreign metallic body)
• active uncontrolled gastrointestinal disorders including ulcerative colitis, Crohn's disease, indeterminate colitis, severe irritable bowel syndrome, persistent infectious gastroenteritis, persistent or chronic diarrhea of unknown etiology, recurrent Clostridium difficile infection
• major surgery of the GI tract, in the past five years. Any major bowel resection at any time
• intake of antibiotics in the last 2 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Long-term fasting; The participants will undergo 6-12 fasting days according to the Buchinger Wilhelmi fasting program	Other: Long-term fasting according to the Buchinger Wilhelmi fasting program; the participants will undergo a fasting program that includes the daily intake of 250 kcal under medical supervision

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in whole body composition	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the heart	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the liver	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the kidney	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the spleen	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the quadriceps	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in the composition of the adipose tissue	Fat mass, lean mass, water content measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in HDL cholesterol efflux capacity	measured in serum by a standardized used radioisotopic technique	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in serum cholesterol loading capacity	measured in serum using radioactive cholesterol loaded macrophages	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in HS-Omega-3 Index	Determination of fatty acid (C 14:0; 16:0; 18:0; 20:0; 22:0; 24:0; 16:1 n-7; 18:1 n-9; 20:1 n-9; 24:1 n-9; 18:2 n-6; 18: 3 n-6; 20: 3 n-6; 22:2 n-6; 20:4 n-6; 22:4 n-6; 22:5 n-6; 18: 3 n-3; 20:5 n-3; 22:5 n-3; 22:6 n-3; 16:1 n-7t; 18:1 n-9t; 18:2 n-6tt; 18:2 n-6ct; 18:2 n-6tc) in erythrocyte membranes with highly standardized analytical procedure	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in faecal microbiota composition and function (carbohydrate metabolism)	Shotgun metagenomics, 5Gb of DNA sequencing data.	Baseline and changes after an average of 10 (+/-3) fasting days
Changes in metabolome	using an untargeted metabolomics approach to investigate changes in the metabolome, with a focus on the polyamine biosynthetic pathway at the cellular level in PBMCs and compare them with changes in the circulating plasma/serum metabolome	Baseline and changes after 3 fasting days, the end of fasting as well as one and four months afterwards
Changes in hydrogen sulfide production capacity	measured in serum and urine using the lead acetate assay	Baseline and changes at the end of fasting as well as one and four months afterwards

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in brain morphometry	measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in cardiac mass	measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in lower limbs (quadriceps, hamstrings, calves)	measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in lumbosacral muscle mass	measured by magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in systolic cardiac function	global and regional function (right and left ejection fraction, right and left end-diastolic and end-systolic volumes, peak regional strains (circumferential, longitudinal strain) measured with magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in diastolic cardiac function	global and regional diastolic function (peak filling rate, torsion rate, diastolic strain rate) measured with magnetic resonance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in apparent diffusion coefficient (ADC)	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in fiber strain (Eff)	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in fractional anisotropy (FA)	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in helix angle (HA)	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in mean diffusivity (MD)	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in cardiovascular fitness	using the maximal oxygen consumption (VO2max)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: TauPCr(s)	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: PCr hydrolysis (%)	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: PCr concentration	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: Pi concentration	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: ATP concentration	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: pH at rest and post exercise in mM	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: T1 of metabolites at rest	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in muscle metabolism and mitochondrial oxidative capacity: PCr consumption	during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy)	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in multiparametric muscle quantification: T2	measured with quantitative magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in multiparametric muscle quantification: T2 * relaxation time	measured with quantitative magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in multiparametric muscle quantification: susceptibility (chi)	measured with quantitative magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in multiparametric muscle quantification: fat fraction (PDFF)	measured with quantitative magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in quadricipital maximum voluntary contraction	measured with magnetic impedance imaging	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in DNA methylation	biomarker of biological aging using erythrocytes	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in serum amyloid A levels	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in paraoxonase (PON-1) activity	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in lipoprotein transfer enzymes	CETP activity, determined as U/ml using a commercially available assay	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in GlycA	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in proprotein convertase subtilisin/kexin type 9 (PCSK9)	determined in serum by ELISA	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in chylomicrons	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in oxidized phospholipids	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in enzymes	immunoblotting of relevantly altered enzymes in PBMCs	Baseline and changes after 3 fasting days, the end of fasting as well as one and four months afterwards
Changes in persulfidation	persulfidation in serum and urine	Baseline, and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards
Changes in sulfur compounds	amino acids (using a targeted approach), thiosulfate (measured using the monobromobimane method using HPLC and LC-MS/MS), cysteine and cystine (use the S-sulfocysteine (SSC) method which is a HPLC-based method using automated precolumn derivatization with OPA and UV detection at 338 nm) in serum and urine	Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards
Changes in thiosulfate levels	measured using the monobromobimane method using HPLC and LC-MS/MS	Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards
Changes in cysteine and cystine levels	using the S-sulfocysteine (SSC) method which is a HPLC-based method using automated precolumn derivatization with OPA and UV detection at 338 nm in serum and urine	Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards
Changes in amino acids	using a targeted approach in serum and urine	Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in body weight	in kg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in body mass index	in kg/m²	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in abdominal circumference	in cm	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in resting systolic blood pressure	in mmHg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in resting diastolic blood pressure	in mmHg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in resting heart frequency	in beats/min	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in bio-electrical multifrequency impedance analysis	Global and segmental body composition (water, fat and lean mass), liquid distribution (total, extracellular and intracellular water), metabolic indexes (metabolic activity index (MAI), protein content (total and active cell mass fraction) as determined by bioimpedance analysis	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in liver stiffness	measured by FibroScan	Baseline, during and after fasting
Changes in physical activity	intensity, duration, frequency measured by triaxial actigraphy	Before, daily during fasting as well as one and four months afterwards
Changes in circadian rhythm and sleep	measured by triaxial actigraphy	Before, daily during fasting as well as one and four months afterwards
Changes in mental well-being	questionnaires: Warwick-Edinburgh Mental Well-Being Scale	Baseline and at the end of fasting as well as one and four months afterwards
Changes in global health	questionnaires: PROMIS Scale	Baseline and at the end of fasting as well as one and four months afterwards
Changes in physical activity	questionnaires: Godin Leisure-Time Exercise Questionnaire	Baseline and at the end of fasting as well as one and four months afterwards
Changes in sleep quality	questionnaires: Pittsburgh Sleep Quality Index	Baseline and at the end of fasting as well as one and four months afterwards
Changes in ketonuria	Ketone bodies in urine measured by urine dip sticks	during the fasting period and food reintroduction
Changes in ketonemia	Ketone bodies in capillary blood	during the fasting period and food reintroduction
Changes in glycemia	Glucose in capillary blood	during the fasting period and food reintroduction
Changes in dietary behaviour	questionnaire: short healthy eating index survey	Baseline and after fasting as well as one and four months afterwards
Changes in smoking behaviour	questionnaire	Baseline and after fasting as well as one and four months afterwards
Changes in alcohol consumption	questionnaire	Baseline and after fasting as well as one and four months afterwards
Changes in physical activity	in hours/week	Baseline and after fasting as well as one and four months afterwards
Changes in energy level	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in emotional well-being	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in physical well-being	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: fatigue	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: muscle weakness	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: back pain	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: hunger	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: anxiety	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: headache	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Changes in symptoms: sleep disturbances	measured by visual scale (0-10)	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Adverse events	Documentation of side effects	through study completion, an average of 4.5 months
Changes in blood count	blood parameters: leucocytes, erythrocytes, haemoglobin, haematocrit, MCV, MCH, MCHC, thrombocytes, bilirubin	Baseline and at the end of fasting as well as one and four months afterwards
Changes in differential blood count	blood parameters: basophiles, neutrophils, eosinophiles, monocytes, reticulocytes	Baseline and at the end of fasting as well as one and four months afterwards
Changes in coagulation	blood parameters: INR, PTT in sec	Baseline and at the end of fasting as well as one and four months afterwards
Changes in liver enzymes	blood parameters: GOT, GPT, GGT, AP in U/l	Baseline and at the end of fasting as well as one and four months afterwards
Changes in kidney parameters	blood parameters: uric acid, urea, creatinine in mg/dl	Baseline and at the end of fasting as well as one and four months afterwards
Changes in inflammatory parameters	blood parameters: hs-CRP, ESR in mm/h, inflammasome, cortisol in µg/dl	Baseline and at the end of fasting as well as one and four months afterwards
Changes in glucose metabolism	blood parameters: glucose in mmol/l, HbA1c in %, insulin in mU/l	Baseline and at the end of fasting as well as one and four months afterwards
Changes in lipid parameters	blood parameters: total cholesterol, HDL-C, LDL-C, triglycerides in mmol/l	Baseline and at the end of fasting as well as one and four months afterwards
Changes in electrolytes	blood parameters: sodium, potassium, calcium, magnesium in mmol/l	Baseline and at the end of fasting as well as one and four months afterwards
Changes in the immune response to fasting	using single cell nucleus sequencing	Baseline, after 3 fasting days, and at the end of fasting as well as one and four months afterwards
Changes in cell populations (natural killer and T cells)	using single cell nucleus sequencing	Baseline, after 3 fasting days, and at the end of fasting as well as one and four months afterwards
Changes in lipoprotein subclasses	determined in serum by high-density ultracentrifugation reflecting cholesterol and triglyceride composition	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in apolipoproteins	ApoA-I and ApoB determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in lipoprotein(a)	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Changes in methylation based clocks	biomarker of biological aging using PBMCs	Baseline and changes at the end of fasting as well as one and four months afterwards
Sociodemographic Measurements	Age, gender, language, complete family history, current and previous illness and co-morbidities, and current medications	Baseline
Changes in nitrogen balance	nitrogen in 24-hours-urine	Baseline, daily during fasting as well as food reintroduction

Collaborators and Investigators

• Sponsor: Buchinger Wilhelmi Development & Holding GmbH
• Collaborators: King's College London; Leiden University Medical Center; ETH Zurich; Claude Bernard University; University of Milan; University of Graz; Buchinger Wilhelmi Clinic; Omegametrix GmbH; MVZ Humangenetik Ulm; MVZ Labor Ravensburg

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 10, 2021
• Primary Completion (ACTUAL): August 30, 2022
• Study Completion (ACTUAL): December 31, 2022

Study Registration Dates

• First Submitted: August 11, 2021
• First Submitted That Met QC Criteria: August 26, 2021
• First Posted (ACTUAL): September 2, 2021

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: gut microbiota; metabolomics; magnetic resonance imaging (MRI); magnetic resonance spectroscopy (MRS); long-term fasting; Buchinger Wilhelmi program; HDL efflux capacity; fatty acid profile in erythrocyte membrane; hydrogen sulfide and transsulfuration pathway
• Other Study ID Numbers: F-2021-075

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No