Fasting
Conditions
Keywords
long-term fasting, Buchinger Wilhelmi program, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), HDL efflux capacity, fatty acid profile in erythrocyte membrane, gut microbiota, metabolomics, hydrogen sulfide and transsulfuration pathway
Brief 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.
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.
Interventions
OTHERLong-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
Sponsors
Buchinger Wilhelmi Clinic
Claude Bernard University
University of Milan
Omegametrix GmbH
King's College London
MVZ Humangenetik Ulm
University of Graz
Leiden University Medical Center
MVZ Labor Ravensburg
ETH Zurich
Buchinger Wilhelmi Development & Holding GmbH
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention model description
single-arm interventional study
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in whole body composition | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in hydrogen sulfide production capacity | Baseline and changes at the end of fasting as well as one and four months afterwards | measured in serum and urine using the lead acetate assay |
| Changes in metabolome | Baseline and changes after 3 fasting days, the end of fasting as well as one and four months afterwards | 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 |
| Changes in faecal microbiota composition and function (carbohydrate metabolism) | Baseline and changes after an average of 10 (+/-3) fasting days | Shotgun metagenomics, 5Gb of DNA sequencing data. |
| Changes in HS-Omega-3 Index | Baseline and changes at the end of fasting as well as one and four months afterwards | 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 |
| Changes in serum cholesterol loading capacity | Baseline and changes at the end of fasting as well as one and four months afterwards | measured in serum using radioactive cholesterol loaded macrophages |
| Changes in HDL cholesterol efflux capacity | Baseline and changes at the end of fasting as well as one and four months afterwards | measured in serum by a standardized used radioisotopic technique |
| Changes in the composition of the adipose tissue | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in the composition of the quadriceps | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in the composition of the spleen | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in the composition of the kidney | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in the composition of the liver | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
| Changes in the composition of the heart | Baseline and changes at the end of fasting as well as one and four months afterwards | Fat mass, lean mass, water content measured by magnetic resonance imaging |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in muscle metabolism and mitochondrial oxidative capacity: PCr concentration | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in brain morphometry | Baseline and changes at the end of fasting as well as one and four months afterwards | measured by magnetic resonance imaging |
| Changes in cardiac mass | Baseline and changes at the end of fasting as well as one and four months afterwards | measured by magnetic resonance imaging |
| Changes in lower limbs (quadriceps, hamstrings, calves) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured by magnetic resonance imaging |
| Changes in lumbosacral muscle mass | Baseline and changes at the end of fasting as well as one and four months afterwards | measured by magnetic resonance imaging |
| Changes in systolic cardiac function | Baseline and changes at the end of fasting as well as one and four months afterwards | 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 |
| Changes in diastolic cardiac function | Baseline and changes at the end of fasting as well as one and four months afterwards | global and regional diastolic function (peak filling rate, torsion rate, diastolic strain rate) measured with magnetic resonance imaging |
| Changes in apparent diffusion coefficient (ADC) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in fiber strain (Eff) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in fractional anisotropy (FA) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in helix angle (HA) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in mean diffusivity (MD) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in cardiovascular fitness | Baseline and changes at the end of fasting as well as one and four months afterwards | using the maximal oxygen consumption (VO2max) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: TauPCr(s) | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: PCr hydrolysis (%) | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: Pi concentration | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: ATP concentration | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: pH at rest and post exercise in mM | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: T1 of metabolites at rest | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in muscle metabolism and mitochondrial oxidative capacity: PCr consumption | Baseline and changes at the end of fasting as well as one and four months afterwards | during ergometric effort in MRI at the level of the sural muscle (31P spectroscopy) |
| Changes in multiparametric muscle quantification: T2 | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with quantitative magnetic impedance imaging |
| Changes in multiparametric muscle quantification: T2 * relaxation time | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with quantitative magnetic impedance imaging |
| Changes in multiparametric muscle quantification: susceptibility (chi) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with quantitative magnetic impedance imaging |
| Changes in multiparametric muscle quantification: fat fraction (PDFF) | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with quantitative magnetic impedance imaging |
| Changes in quadricipital maximum voluntary contraction | Baseline and changes at the end of fasting as well as one and four months afterwards | measured with magnetic impedance imaging |
| Changes in DNA methylation | Baseline and changes at the end of fasting as well as one and four months afterwards | biomarker of biological aging using erythrocytes |
| Changes in serum amyloid A levels | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in paraoxonase (PON-1) activity | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in lipoprotein transfer enzymes | Baseline and changes at the end of fasting as well as one and four months afterwards | CETP activity, determined as U/ml using a commercially available assay |
| Changes in GlycA | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in proprotein convertase subtilisin/kexin type 9 (PCSK9) | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum by ELISA |
| Changes in chylomicrons | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in oxidized phospholipids | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in enzymes | Baseline and changes after 3 fasting days, the end of fasting as well as one and four months afterwards | immunoblotting of relevantly altered enzymes in PBMCs |
| Changes in persulfidation | Baseline, and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards | persulfidation in serum and urine |
| Changes in sulfur compounds | Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards | 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 |
| Changes in thiosulfate levels | Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards | measured using the monobromobimane method using HPLC and LC-MS/MS |
| Changes in cysteine and cystine levels | Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards | 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 |
| Changes in amino acids | Baseline and changes after 3 fasting days, at the end of fasting as well as one and four months afterwards | using a targeted approach in serum and urine |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in resting heart frequency | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | in beats/min |
| Changes in resting diastolic blood pressure | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | in mmHg |
| Changes in resting systolic blood pressure | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | in mmHg |
| Changes in abdominal circumference | Baseline and changes at the end of fasting as well as one and four months afterwards | in cm |
| Changes in body mass index | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | in kg/m² |
| Changes in body weight | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | in kg |
| Changes in energy level | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in circadian rhythm and sleep | Before, daily during fasting as well as one and four months afterwards | measured by triaxial actigraphy |
| Changes in physical activity | Before, daily during fasting as well as one and four months afterwards | intensity, duration, frequency measured by triaxial actigraphy |
| Changes in mental well-being | Baseline and at the end of fasting as well as one and four months afterwards | questionnaires: Warwick-Edinburgh Mental Well-Being Scale |
| Changes in global health | Baseline and at the end of fasting as well as one and four months afterwards | questionnaires: PROMIS Scale |
| Changes in sleep quality | Baseline and at the end of fasting as well as one and four months afterwards | questionnaires: Pittsburgh Sleep Quality Index |
| Changes in ketonuria | during the fasting period and food reintroduction | Ketone bodies in urine measured by urine dip sticks |
| Changes in ketonemia | during the fasting period and food reintroduction | Ketone bodies in capillary blood |
| Changes in glycemia | during the fasting period and food reintroduction | Glucose in capillary blood |
| Changes in dietary behaviour | Baseline and after fasting as well as one and four months afterwards | questionnaire: short healthy eating index survey |
| Changes in smoking behaviour | Baseline and after fasting as well as one and four months afterwards | questionnaire |
| Changes in alcohol consumption | Baseline and after fasting as well as one and four months afterwards | questionnaire |
| Changes in symptoms: muscle weakness | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in symptoms: back pain | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in symptoms: hunger | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in symptoms: anxiety | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in symptoms: headache | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in symptoms: sleep disturbances | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Adverse events | through study completion, an average of 4.5 months | Documentation of side effects |
| Changes in blood count | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: leucocytes, erythrocytes, haemoglobin, haematocrit, MCV, MCH, MCHC, thrombocytes, bilirubin |
| Changes in differential blood count | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: basophiles, neutrophils, eosinophiles, monocytes, reticulocytes |
| Changes in coagulation | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: INR, PTT in sec |
| Changes in liver enzymes | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: GOT, GPT, GGT, AP in U/l |
| Changes in kidney parameters | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: uric acid, urea, creatinine in mg/dl |
| Changes in inflammatory parameters | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: hs-CRP, ESR in mm/h, inflammasome, cortisol in µg/dl |
| Changes in glucose metabolism | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: glucose in mmol/l, HbA1c in %, insulin in mU/l |
| Changes in lipid parameters | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: total cholesterol, HDL-C, LDL-C, triglycerides in mmol/l |
| Changes in electrolytes | Baseline and at the end of fasting as well as one and four months afterwards | blood parameters: sodium, potassium, calcium, magnesium in mmol/l |
| Changes in the immune response to fasting | Baseline, after 3 fasting days, and at the end of fasting as well as one and four months afterwards | using single cell nucleus sequencing |
| Changes in cell populations (natural killer and T cells) | Baseline, after 3 fasting days, and at the end of fasting as well as one and four months afterwards | using single cell nucleus sequencing |
| Changes in lipoprotein subclasses | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum by high-density ultracentrifugation reflecting cholesterol and triglyceride composition |
| Changes in apolipoproteins | Baseline and changes at the end of fasting as well as one and four months afterwards | ApoA-I and ApoB determined in serum |
| Changes in lipoprotein(a) | Baseline and changes at the end of fasting as well as one and four months afterwards | determined in serum |
| Changes in methylation based clocks | Baseline and changes at the end of fasting as well as one and four months afterwards | biomarker of biological aging using PBMCs |
| Sociodemographic Measurements | Baseline | Age, gender, language, complete family history, current and previous illness and co-morbidities, and current medications |
| Changes in nitrogen balance | Baseline, daily during fasting as well as food reintroduction | nitrogen in 24-hours-urine |
| Changes in symptoms: fatigue | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in liver stiffness | Baseline, during and after fasting | measured by FibroScan |
| Changes in physical well-being | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in emotional well-being | Baseline, daily during fasting and food reintroduction as well as one and four months afterwards | measured by visual scale (0-10) |
| Changes in bio-electrical multifrequency impedance analysis | Baseline and changes at the end of fasting as well as one and four months afterwards | 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 |
Countries
Germany
Outcome results
None listed