- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04823806
An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation
Autophagy Characterization and Multi-level Molecular Profiling of Spermidine Supplementation: a Clinical Study
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Recently, the autophagy inducing caloric restriction mimic spermidine-rich wheat germ extract (spermidineLIFE ®, from here onwards: spermidine) was approved by the European Food Safety Authority (EFSA) and became commercially available for use. Spermidine is safe, well tolerated and as caloric restriction mimetic an easy alternative if fasting is too challenging, e.g. for psychiatric patients. Research on spermidine in animal models is limited, but a study with mice overexpressing spermidine/spermine N1-acetyltransferase (SSAT) an enzyme of spermidine catabolism, suggests that these mice may be more prone to stress. An association between spermidine supplementation and improved memory performance as well as reduced mortality has been shown in an epidemiological correlation. So far laboratory and molecular assessments are missing. It is therefore of great interest to perform broad multidisciplinary studies of behavioral changes with plasma spermidine levels, the quantification of autophagic flux, and protein acetylation levels as well as molecular signaling in a longitudinal fashion to establish an epidemiological triangulation between spermidine, autophagy and (mental) health.
This study is a monocentric, randomized, double-blind, placebo-controlled trial in which a 3-week spermidine-based nutritional supplementation (6 mg/d; target intervention) will be compared to 3-weeks of placebo administration (control intervention). Recruitment of 40 healthy individuals and 40 individuals with diagnosed depressive disorder is planned, who will be allocated to one of the two study arms (n = 20 per intervention). At different time points (baseline, intervention day 7, 14 and 21, as well as one week follow up after the last intervention day) serval psychometrical questionnaires will be gathered and blood will be collected. Sleep quality will be additionally assessed by actigraphy. At selected days blood will be collected. Following, autophagy activity will be assessed by Western Blot analysis, and mass spectrometry based proteomics, phosphoproteomics, metabolomics and lipidomics will be performed. Bioinformatic analysis, statistical evaluation, quality control, and in silico pathway analyses will then specifically identify factors and cascades of relevance. Furthermore it is of great interest, whether epigenetic changes take place during spermidine supplementation and whether these are stable throughout the follow up analysis.
The aim of the project is to analyze clinical effects of spermidine supplementation in correlation to the underlying, multi-level molecular profiling. Longitudinal multi-omic profiling including proteome, metabolome, lipidome, and epigenetic changes will reveal time-series analysis of thousands of molecular changes and an orchestrated composition of autophagy depended signaling. The resulting findings will advance the role of autophagy in the development of psychiatric disorders, investigate alternative treatment options on a molecular level, and finally contribute to a better clinical outcome.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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Bonn, Germany, 53111
- University Hospital Bonn, Clinic for psychiatry and psychotherapy
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Present written declaration of consent
- Healty or diagnosed with depression
- BMI between 17 and 40
Exclusion Criteria:
- Insufficient linguistic communication
- Pregnancy or lactation
- Gluten, histamine or wheat seedling intolerance
- Drug abuse or alcohol dependency
- Current spermidine substitution
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Healthy participants and participants with depressive disorder: dietary spermidine supplementation
Dietary Supplement: Polyamine 21 days of spermidine supplementation (3 sachets/day = 6mg spermidine/day)
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21 day of 6mg spermidine OR Placebo supplementation per day
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Placebo Comparator: Healthy participants and participants with depressive disorder: dietary placebo supplementation
Dietary Supplement: Placebo 21 days of Placebo supplementation (3 sachets/day)
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21 day of 6mg spermidine OR Placebo supplementation per day
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proteomics and autophagy processes
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Change in protein levels of autophagy biomarkers (LC3II & p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting.
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change from baseline over 21 days of supplementation to 7 day follow up
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Epigenetic patterns
Time Frame: change from baseline to day 21 of supplementation to 7 day follow up
|
Evaluate epigenetic methylation patterns through blood based epigenome analysis
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change from baseline to day 21 of supplementation to 7 day follow up
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Proteome/phosphoproteome/ubiquitinome patterns
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Change in protein levels and protein phosphorylation by untargeted mass spectrometry-based proteomics and phosphoproteomics of isolated PBMCs (peripheral blood mononuclear cells).
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change from baseline over 21 days of supplementation to 7 day follow up
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Metabolic processes
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Targeted and quantitative analysis by mass spectrometry of change in metabolites of Plasma.
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change from baseline over 21 days of supplementation to 7 day follow up
|
Lipid profiling
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Targeted and quantitative analysis by mass spectrometry of change in plasma Lipids.
|
change from baseline over 21 days of supplementation to 7 day follow up
|
Exosomal protein patterns
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Evaluate exosomal protein content through mass spectrometry based analysis
|
change from baseline over 21 days of supplementation to 7 day follow up
|
Glomerular filtration rate
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)
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change from baseline over 21 days of supplementation to 7 day follow up
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Cystatin C
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Cystatin C in Milligram per Liter (mg/L)
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change from baseline over 21 days of supplementation to 7 day follow up
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Liver Enzymes
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Alanine transaminase (ALT) and aspartate transaminase (AST) (U/L)
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change from baseline over 21 days of supplementation to 7 day follow up
|
White blood cell differential
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Absolute number (per Liter) and relative amounts of neutrophils, lymphocytes, monocytes, eosinophils, basophils, and immature granulocytes (in %)
|
change from baseline over 21 days of supplementation to 7 day follow up
|
Saliva Cortisol Levels (dexamethasone suppression test)
Time Frame: on day 19 and 20 of supplementation
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Comparison of Saliva Cortisol Levels in nmol per Liter (nmol/L) after Dexamethason intake between spermidine and Placebo group
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on day 19 and 20 of supplementation
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Sleep Efficiency
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Assessment of Sleep Efficiency (total time in bed/time asleep during night) by GenActive Aktigraphs
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change from baseline over 21 days of supplementation to 7 day follow up
|
Overall sleep Quality
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Sleep diary to assess overall sleep quality assessed as ratio of the total time spent asleep (in hours) to the total amount of time spent in bed (in hours) per night
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change from baseline over 21 days of supplementation to 7 day follow up
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Sleep Quality (PSQI)
Time Frame: Change from baseline to day 7 day follow up visit
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Pittsburgh Sleep Quality Index (PSQI): self-report questionnaire to assess sleep quality over a 1-month time interval consisting of 19 individual items.
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Change from baseline to day 7 day follow up visit
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Mental well-being (WEMWBS)
Time Frame: Change from baseline to day 14 of supplementation to the 7 day follow up visit
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Warwick-Edinburgh Mental Well-being Scale (WEMWBS): self-reported 14-item scale to assess Overall mental well-being
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Change from baseline to day 14 of supplementation to the 7 day follow up visit
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Resilience behavior (Wagnild &Young)
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Resilience scale (Wagnild &Young): self-reported 25-item scale to assess overall resilience
|
change from baseline over 21 days of supplementation to 7 day follow up
|
Spermidine blood concentration
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Assessment of spermidine blood Levels by HPLC (high pressure liquid chromatography) analysis
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change from baseline over 21 days of supplementation to 7 day follow up
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white cell count
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Complete white cell count (per liter)
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change from baseline over 21 days of supplementation to 7 day follow up
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Hemoglobin
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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Hemoglobin (g/dL)
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change from baseline over 21 days of supplementation to 7 day follow up
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Hematocrit
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
Hematocrit (%)
|
change from baseline over 21 days of supplementation to 7 day follow up
|
red cell count
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
complete red cell count (per liter)
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change from baseline over 21 days of supplementation to 7 day follow up
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MCV
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
|
mean corpuscular volume (fl)
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change from baseline over 21 days of supplementation to 7 day follow up
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MCH
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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mean corpuscular hemoglobin (pg)
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change from baseline over 21 days of supplementation to 7 day follow up
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thrombocytes
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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thrombocytes per Liter
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change from baseline over 21 days of supplementation to 7 day follow up
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MCHC
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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mean corpuscular hemoglobin concentration (g/dL)
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change from baseline over 21 days of supplementation to 7 day follow up
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RDW
Time Frame: change from baseline over 21 days of supplementation to 7 day follow up
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red cell distribution width (%)
|
change from baseline over 21 days of supplementation to 7 day follow up
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R, Schraml E, Criollo A, Megalou E, Weiskopf D, Laun P, Heeren G, Breitenbach M, Grubeck-Loebenstein B, Herker E, Fahrenkrog B, Frohlich KU, Sinner F, Tavernarakis N, Minois N, Kroemer G, Madeo F. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009 Nov;11(11):1305-14. doi: 10.1038/ncb1975. Epub 2009 Oct 4.
- Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374):eaan2788. doi: 10.1126/science.aan2788.
- Fond G, Macgregor A, Leboyer M, Michalsen A. Fasting in mood disorders: neurobiology and effectiveness. A review of the literature. Psychiatry Res. 2013 Oct 30;209(3):253-8. doi: 10.1016/j.psychres.2012.12.018. Epub 2013 Jan 15.
- Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017 Jul;16(7):487-511. doi: 10.1038/nrd.2017.22. Epub 2017 May 19.
- Jia J, Le W. Molecular network of neuronal autophagy in the pathophysiology and treatment of depression. Neurosci Bull. 2015 Aug;31(4):427-34. doi: 10.1007/s12264-015-1548-2. Epub 2015 Aug 8.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- StressLess
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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