An Exploratory Clinical Study on Autophagy During Fasting

The Kinetics of Autophagy During Periodic Fasting in Healthy People and Patients With Rheumatoid Arthritis or Metabolic Syndrome - an Exploratory Clinical Study

Autophagy is considered one of the key molecular mechanisms for the broad preventive and therapeutic effects of periodic fasting. While it is generally known that fasting induces autophagy, there are no human studies that focus on the size and temporal kinetics of autophagy and its association with fasting specific signaling pathways. The kinetics of autophagy in patients with chronic diseases will now be compared with the kinetics of autophagy in healthy subjects, who both fast according to the same scheme; and further changes in metabolic and inflammatory parameters will be investigated.

Study Overview

• Status: Recruiting
• Conditions: Healthy; Arthritis, Rheumatoid; Syndrome, Metabolic
• Intervention / Treatment: Other: Fasting

Detailed Description

Therapeutic fasting has been used for many decades in naturopathy and integrative medicine clinically successfully in the treatment of chronic diseases and pain syndromes. In particular, fasting therapy is used for chronic rheumatic, inflammatory, and metabolic diseases with increasing patient demand in specialized clinical facilities (fasting clinics).

Within the various historically developed forms of fasting, the fasting program according to the Buchinger Wilhelmi method has established itself worldwide as the most frequently applied method. This involves a subtotal caloric restriction with a daily caloric intake (200-400kcal/day) in the form of liquid components over a defined period of at least 10 days, accompanied by supporting measures of a health-promoting lifestyle program with elements such as exercise therapy, manual procedures, stress reduction and hydro-balneotherapy.

In early randomized studies and a systematic review, the effectiveness of inpatient fasting therapy for patients with rheumatoid arthritis was proven with 1a evidence. For the other indications, there is mainly empirical evidence or data from observation or prospective uncontrolled studies. In recent years, extensive basic science research activity has developed in the area of caloric restriction and intermittent fasting. In this context, a large number of favorable animal experimental findings have been demonstrated by defined fasting periods, including reductions in insulin, IGF-1, increases in adiponectins, insulin sensitivity, neurotrophic factors, and, over longer observation periods, a decrease in the incidence of cardiovascular, inflammatory, and metabolic, and more recently oncological diseases in a wide variety of animal species.

Numerous experimental studies have demonstrated that fasting or total or subtotal caloric restriction is a potent inducer of cellular autophagy. For autophagy, numerous beneficial effects on chronic diseases or disease defense functions have now been experimentally documented and also hypothesized for humans, including neurodegenerative and metabolic diseases, but also acute infections and inflammatory diseases. Unclear to date is the kinetics of the autophagy enhancing effect of fasting. In theoretical transfer from animal experimental data, an increase is postulated between 12 and 36h of fasting and possibly a decrease after several days.

Against this background, autophagy will now be investigated for the first time in blood samples from fasting healthy and diseased individuals in an exploratory clinical study.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nadine Sylvester; Phone Number: +4930 80505 734; Email: nadine.sylvester@immanuelalbertinen.de

Study Locations

• Germany
  • Berlin, Germany, 14109
    • Recruiting
    • Hochschulambulanz für Naturheilkunde der Charité-Universitätsmedizin Berlin am Immanuel-Krankenhaus
    • Principal Investigator: Andreas Michalsen, Prof. Dr.
    • Contact: Miriam Rösner, Study nurse; Phone Number: 00493080505682; Email: miriam.roesner@immanuel.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• One of the following diagnoses: rheumatoid arthritis, metabolic syndrome OR healthy volunteer
• Beginning (first 24h) inpatient treatment or hospital stay at Immanuel Hospital Berlin, Department of Naturopathy OR healthy volunteer
• Present written declaration of consent

Exclusion Criteria:

• Insufficient linguistic communication
• Dementia or other cognitive disorder
• Pregnancy or lactation
• Simultaneous participation in another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Healthy Participants; Healthy participants	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.
Active Comparator: Metabolic Syndrome; Participants with diagnosed metabolic syndrome	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.
Active Comparator: Rheumatoid Arthritis; Participants with diagnosed rheumatoid arthritis	Other: Fasting; Patients undergo a 5-10 day fasting period with a dietary energy supply 350-400kcal per day with fruit and vegetable juices or, if not feasible, an established fasting-mimicking diet of 600-800 kcal according to Longo et al.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Proteomics of Autophagy Processes I	- Change in protein levels of autophagy biomarkers (LC3II & p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Exploratory Proteomics of Autophagy Processes II	- Change in protein levels and protein phosphorylation by untargeted mass spectrometry-based proteomics and phosphoproteomics of isolated PBMCs (peripheral blood mononuclear cells), change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle mass	Estimation of the body composition via bio-electrical impedance analysis (muscle mass in kg)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Body fat	Estimation of the body composition via bio-electrical impedance analysis (body fat and visceral fat in %)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Resting blood pressure		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Cutaneous carotenoid level (CCL)	Cutaneous carotenoid level (CCL), correlating with the overall antioxidant status, measured with a noninvasive skin carotenoid sensor (Biozoom®)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Heart rate		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Waist to Hip Ratio		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Body Mass Index (kg/m2)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Disease Activity Score 28 (DAS-28-CRP)	Change from Baseline in the DAS-28-CRP, range from 2.0 to 10.0 while higher values meaning a higher disease activity and below of 2.6 meaning remission	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Health Assessement Questionnaire (HAQ)	Change from Baseline in the HAQ, range from 0 to 3 while higher values meaning a higher grade of disability	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Simplified Disease Activity Index Score (SDAI)	Change from Baseline in the SDAI, range from 0 to 86 with assumed range from 0.1 to 10mg/dL for CRP. Higher values mean a higher disease activity and below of 34 meaning remission.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Stress questionnaire (Cohen Perceived Stress Scale, CPSS)	Change from Baseline in the CPSS, range from 0 to 4 in each item. Scores are obtained by reversing responses (e.g., 0 = 4, 1 = 3, 2 = 2, 3 = 1 & 4 = 0) to the positively stated items and then summing across all scale items, higher values meaning a higher grade of perceived stress.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Mindful Attention Awareness Scale (MAAS)	Assessing full scale, range from 15 to 90, higher score values meaning a better outcome.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Numerical Analog Scales	Assessing stress, back pain, headache, shoulder/neck tension, sleep quality and duration, exhaustion, nervousness, digestive complaints, mood on 0-10 points each.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Quality of Life questionnaire (WHO-5)	Change from Baseline in the WHO-5, range from 0 to 100 %, higher values meaning a higher grade of well-being	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Hospital Anxiety and Depression Scale (HADS)	Assessing full scale, range 0-42, lower score meaning a better outcome	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
General Self-efficacy Short Scale (ASKU)	Assessing full scale, range 3-15, higher score meaning a better outcome	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Mood questionnaire (Profile of Mood States, POMS)	Change from Baseline in Emotional Distress will be measured using the German Version of the Profile of Mood States (ASTS) short version (19 items, 7-point Likert scale; 0=not at all, 6=extremely). Lower scores indicate more stable mood profiles.	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Sociodemographic Measurements	Age, gender, education level, household income, employment status, marital status, language spoken, complete family history, current and previous illness and co-morbidities, and current medications	Day 1 (baseline)
Behavioral Factors	Physical inactivity, coffee, health promoting activities via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Behavioral Factors: alcohol consumption	Number of alcoholic beverages on average per week in the last month	Day 1 (baseline), after 2 and 6 weeks
Behavioral Factors: smoking	Number of cigarettes on average per week in the last month	Day 1 (baseline), after 2 and 6 weeks
Behavioral Factors: fasting experience	Type, definition, duration and date of previous fasting experiences	Day 1 (baseline)
Expectation questions	For fasting on a 5-point likert scale from 1 (nothing at all) to 5 (very strong)	Day 1 (baseline)
Creatinine in µmol per liter (µmol/L)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Electrolytes	potassium (mmol/L) sodium (mmol/L)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Blood lipids and fasting glucose	triglycerides (mmol/L) total cholesterol (mmol/L) LDL (mmol/L) HDL (mmol/L) fasting glucose (mmol/L)	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Insulin (mU/L)		change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
ß-Hydroxybutyrate	Evaluate change in ketone body production by POCT	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
CrP (mg/L)	Evaluate change in CrP levels in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Erythrocyte sedimentation rate (ESR) in millimeters per hour (mm/h)	Evaluate change in ESR in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Rheumatoid factor (RF, IgM) (U/mL)	Evaluate RF status in participants with RA	Day 1 (baseline)
Anti-cyclic citrullinated peptide (ACPA) (U/mL)	Evaluate change in ACPA levels in participants with RA	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Metabolic processes	Targeted and quantitative analysis by mass spectrometry of change in metabolites of plasma, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Lipid profiling	Targeted and quantitative analysis by mass spectrometry of change in plasma lipids, change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Transcription expression patterns	Change of the gene expression profile by RNA sequencing of isolated PBMCs (peripheral blood mononuclear cells), change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Proteome/phosphoproteome/ubiquitinome patterns	Evaluate proteome expression patterns through blood based proteome, phosphoproteome, and ubiquitinome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Epigentic patterns	Evaluate epigentic methylation patterns through blood based epigenome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up
Exosomal protein patterns	Evaluate exosomal protein content through blood based metabolome analysis assessed prior to intervention (pre) vs. after 5-day fasting, day 2 of refeeding and 7 days post intervention	change from baseline over 5 fasting days, to day 3 refeeding and to 7 days follow up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Final questionnaire to record tolerability of fasting and nutrition, adverse effects	Measurement of tolerability of fasting and nutrition as well as adverse effects via Likert Scales, range from 0 to 5 while higher values meaning a higher grade of agreement	After 6 weeks

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Universitätsklinikum Bonn AöR
• Investigators: Study Director: Nils Gassen, Dr., Department of Psychiatry and Psychotherapy University Bonn, Clinical Centre; Principal Investigator: Andreas Michalsen, Prof. Dr., Charité - Universitätsmedizin Berlin

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2021
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: January 5, 2021
• First Submitted That Met QC Criteria: February 1, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Estimated): January 1, 2024
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Fasting; Autophagy
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Insulin Resistance; Hyperinsulinism; Syndrome; Arthritis; Arthritis, Rheumatoid; Metabolic Syndrome
• Other Study ID Numbers: Autophagy Fasting

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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