Clinical trial NCT04823806: An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation
Official title: Autophagy Characterization and Multi-level Molecular Profiling of Spermidine Supplementation: a Clinical Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Depression
Healthy
Keywords: Spermidine
Autophagy
Depression
Lead sponsor: University Hospital, Bonn
Sponsor class: OTHER
First posted: 2021-04-01
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2 groups of different inclusion criteria (healthy or depressive disorder) each group undergoing one out of two conditions (spermidine vs. placebo Supplementation) (randomized)
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proteomics and autophagy processes
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
Secondary outcomes:
measure: Epigenetic patterns
timeFrame: change from baseline to day 21 of supplementation to 7 day follow up
measure: Proteome/phosphoproteome/ubiquitinome patterns
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Metabolic processes
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Lipid profiling
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Exosomal protein patterns
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Glomerular filtration rate
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Cystatin C
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Liver Enzymes
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: White blood cell differential
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Saliva Cortisol Levels (dexamethasone suppression test)
timeFrame: on day 19 and 20 of supplementation
measure: Sleep Efficiency
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Overall sleep Quality
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Sleep Quality (PSQI)
timeFrame: Change from baseline to day 7 day follow up visit
measure: Mental well-being (WEMWBS)
timeFrame: Change from baseline to day 14 of supplementation to the 7 day follow up visit
measure: Resilience behavior (Wagnild &Young)
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Spermidine blood concentration
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: white cell count
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Hemoglobin
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: Hematocrit
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: red cell count
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: MCV
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: MCH
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: thrombocytes
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: MCHC
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
measure: RDW
timeFrame: change from baseline over 21 days of supplementation to 7 day follow up
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: University Hospital Bonn, Clinic for psychiatry and psychotherapy
Study officials:
References:
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