Long-term Fasting: Multi-system Adaptations in Humans

Fasting Clinical Trial

Official title:

Long-term Fasting: Multi-system Adaptations in Humans

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05031598
• Other study ID #: F-2021-075
• Status: Completed
• Phase: N/A
• Start date: September 10, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: February 2023
• Source: Buchinger Wilhelmi Development & Holding GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: December 31, 2022
• Est. primary completion date: August 30, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 20 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Fasting

Intervention

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

Locations

Country	Name	City	State
Germany	Buchinger Wilhelmi clinic	Überlingen

Sponsors (11)

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

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in body weight	in kg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Other	Changes in body mass index	in kg/m²	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Other	Changes in abdominal circumference	in cm	Baseline and changes at the end of fasting as well as one and four months afterwards
Other	Changes in resting systolic blood pressure	in mmHg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Other	Changes in resting diastolic blood pressure	in mmHg	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Other	Changes in resting heart frequency	in beats/min	Baseline, daily during fasting and food reintroduction as well as one and four months afterwards
Other	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
Other	Changes in liver stiffness	measured by FibroScan	Baseline, during and after fasting
Other	Changes in physical activity	intensity, duration, frequency measured by triaxial actigraphy	Before, daily during fasting as well as one and four months afterwards
Other	Changes in circadian rhythm and sleep	measured by triaxial actigraphy	Before, daily during fasting as well as one and four months afterwards
Other	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
Other	Changes in global health	questionnaires: PROMIS Scale	Baseline and at the end of fasting as well as one and four months afterwards
Other	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
Other	Changes in sleep quality	questionnaires: Pittsburgh Sleep Quality Index	Baseline and at the end of fasting as well as one and four months afterwards
Other	Changes in ketonuria	Ketone bodies in urine measured by urine dip sticks	during the fasting period and food reintroduction
Other	Changes in ketonemia	Ketone bodies in capillary blood	during the fasting period and food reintroduction
Other	Changes in glycemia	Glucose in capillary blood	during the fasting period and food reintroduction
Other	Changes in dietary behaviour	questionnaire: short healthy eating index survey	Baseline and after fasting as well as one and four months afterwards
Other	Changes in smoking behaviour	questionnaire	Baseline and after fasting as well as one and four months afterwards
Other	Changes in alcohol consumption	questionnaire	Baseline and after fasting as well as one and four months afterwards
Other	Changes in physical activity	in hours/week	Baseline and after fasting as well as one and four months afterwards
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	Adverse events	Documentation of side effects	through study completion, an average of 4.5 months
Other	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
Other	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
Other	Changes in coagulation	blood parameters: INR, PTT in sec	Baseline and at the end of fasting as well as one and four months afterwards
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	Changes in lipoprotein(a)	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Other	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
Other	Sociodemographic Measurements	Age, gender, language, complete family history, current and previous illness and co-morbidities, and current medications	Baseline
Other	Changes in nitrogen balance	nitrogen in 24-hours-urine	Baseline, daily during fasting as well as food reintroduction
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Changes in GlycA	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Secondary	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
Secondary	Changes in chylomicrons	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Secondary	Changes in oxidized phospholipids	determined in serum	Baseline and changes at the end of fasting as well as one and four months afterwards
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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