An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation
- Conditions
- HealthyDepression
- Interventions
- Dietary Supplement: Spermidine (spermidineLIFE ®) OR Placebo
- Registration Number
- NCT04823806
- Lead Sponsor
- University Hospital, Bonn
- Brief Summary
Recently, the autophagy inducing caloric restriction mimic spermidine became available. Autophagy is essential for energy and cellular homeostasis through protein catabolism and dysregulation results in compromised proteostasis, stress-coping behavior, and in excessive secretion of signaling molecules and inflammatory cytokines. Antidepressants for example effect autophagy dependent pathways to exert their beneficial effects. It can therefore be hypothesized that autophagy induction through spermidine supplementation also shows beneficial clinical effect, particularly in the field of psychiatric conditions. It would be safe, low cost and easy to implement in relay to psychotropic medication in the treatment of psychiatric patients.Therefore, the aim of the project is to analyze clinical effects of spermidine supplementation in correlation to the underlying, multi-level molecular profiling.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 80
- Present written declaration of consent
- Healty or diagnosed with depression
- BMI between 17 and 40
- Insufficient linguistic communication
- Pregnancy or lactation
- Gluten, histamine or wheat seedling intolerance
- Drug abuse or alcohol dependency
- Current spermidine substitution
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Healthy participants and participants with depressive disorder: dietary spermidine supplementation Spermidine (spermidineLIFE ®) OR Placebo Dietary Supplement: Polyamine 21 days of spermidine supplementation (3 sachets/day = 6mg spermidine/day) Healthy participants and participants with depressive disorder: dietary placebo supplementation Spermidine (spermidineLIFE ®) OR Placebo Dietary Supplement: Placebo 21 days of Placebo supplementation (3 sachets/day)
- Primary Outcome Measures
Name Time Method Proteomics and autophagy processes change from baseline over 21 days of supplementation to 7 day follow up Change in protein levels of autophagy biomarkers (LC3II \& p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting.
- Secondary Outcome Measures
Name Time Method Spermidine blood concentration 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
Metabolic processes 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.
Cystatin C change from baseline over 21 days of supplementation to 7 day follow up Cystatin C in Milligram per Liter (mg/L)
Overall sleep Quality 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
Proteome/phosphoproteome/ubiquitinome patterns 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).
Saliva Cortisol Levels (dexamethasone suppression test) on day 19 and 20 of supplementation Comparison of Saliva Cortisol Levels in nmol per Liter (nmol/L) after Dexamethason intake between spermidine and Placebo group
Sleep Quality (PSQI) Change from baseline to day 7 day follow up visit Pittsburgh Sleep Quality Index (PSQI): self-report questionnaire to assess sleep quality over a 1-month time interval consisting of 19 individual items.
Resilience behavior (Wagnild &Young) change from baseline over 21 days of supplementation to 7 day follow up Resilience scale (Wagnild \&Young): self-reported 25-item scale to assess overall resilience
Hematocrit change from baseline over 21 days of supplementation to 7 day follow up Hematocrit (%)
Glomerular filtration rate change from baseline over 21 days of supplementation to 7 day follow up Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)
Hemoglobin change from baseline over 21 days of supplementation to 7 day follow up Hemoglobin (g/dL)
Exosomal protein patterns change from baseline over 21 days of supplementation to 7 day follow up Evaluate exosomal protein content through mass spectrometry based analysis
White blood cell differential 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 %)
MCV change from baseline over 21 days of supplementation to 7 day follow up mean corpuscular volume (fl)
MCHC change from baseline over 21 days of supplementation to 7 day follow up mean corpuscular hemoglobin concentration (g/dL)
Epigenetic patterns change from baseline to day 21 of supplementation to 7 day follow up Evaluate epigenetic methylation patterns through blood based epigenome analysis
Lipid profiling 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.
Liver Enzymes change from baseline over 21 days of supplementation to 7 day follow up Alanine transaminase (ALT) and aspartate transaminase (AST) (U/L)
Sleep Efficiency change from baseline over 21 days of supplementation to 7 day follow up Assessment of Sleep Efficiency (total time in bed/time asleep during night) by GenActive Aktigraphs
Mental well-being (WEMWBS) Change from baseline to day 14 of supplementation to the 7 day follow up visit Warwick-Edinburgh Mental Well-being Scale (WEMWBS): self-reported 14-item scale to assess Overall mental well-being
white cell count change from baseline over 21 days of supplementation to 7 day follow up Complete white cell count (per liter)
red cell count change from baseline over 21 days of supplementation to 7 day follow up complete red cell count (per liter)
thrombocytes change from baseline over 21 days of supplementation to 7 day follow up thrombocytes per Liter
MCH change from baseline over 21 days of supplementation to 7 day follow up mean corpuscular hemoglobin (pg)
RDW change from baseline over 21 days of supplementation to 7 day follow up red cell distribution width (%)
Trial Locations
- Locations (1)
University Hospital Bonn, Clinic for psychiatry and psychotherapy
🇩🇪Bonn, Germany