An Exploratory Clinical Study on Autophagy and Multi-level Molecular Profiling During Spermidine Supplementation

Healthy Clinical Trial

Official title:

Autophagy Characterization and Multi-level Molecular Profiling of Spermidine Supplementation: a Clinical Study

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04823806
• Other study ID #: StressLess
• Status: Active, not recruiting
• Phase: N/A
• Start date: December 1, 2020
• Est. completion date: December 1, 2024

Study information

• Verified date: November 2022
• Source: University Hospital, Bonn
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 80
• Est. completion date: December 1, 2024
• Est. primary completion date: June 1, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Healthy

Intervention

Dietary Supplement:
• Spermidine (spermidineLIFE ®) OR Placebo
21 day of 6mg spermidine OR Placebo supplementation per day

Locations

Country	Name	City	State
Germany	University Hospital Bonn, Clinic for psychiatry and psychotherapy	Bonn

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Bonn

Country where clinical trial is conducted

Germany, 

References & Publications (5)

Eisenberg T, Knauer H, Schauer A, Büttner 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, H — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018 Jan 26;359(6374). pii: eaan2788. doi: 10.1126/science.aan2788. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proteomics and autophagy processes	Change in protein levels of autophagy biomarkers (LC3II & p62) of isolated PBMCs (peripheral blood mononuclear cells) by Western Blotting.	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Epigenetic patterns	Evaluate epigenetic methylation patterns through blood based epigenome analysis	change from baseline to day 21 of supplementation to 7 day follow up
Secondary	Proteome/phosphoproteome/ubiquitinome patterns	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 21 days of supplementation to 7 day follow up
Secondary	Metabolic processes	Targeted and quantitative analysis by mass spectrometry of change in metabolites of Plasma.	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Lipid profiling	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
Secondary	Exosomal protein patterns	Evaluate exosomal protein content through mass spectrometry based analysis	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Glomerular filtration rate	Estimated glomerular filtration rate (eGFR) in milliliter per minute (mL/min)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Cystatin C	Cystatin C in Milligram per Liter (mg/L)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Liver Enzymes	Alanine transaminase (ALT) and aspartate transaminase (AST) (U/L)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	White blood cell differential	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
Secondary	Saliva Cortisol Levels (dexamethasone suppression test)	Comparison of Saliva Cortisol Levels in nmol per Liter (nmol/L) after Dexamethason intake between spermidine and Placebo group	on day 19 and 20 of supplementation
Secondary	Sleep Efficiency	Assessment of Sleep Efficiency (total time in bed/time asleep during night) by GenActive Aktigraphs	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Overall sleep Quality	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	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Sleep Quality (PSQI)	Pittsburgh Sleep Quality Index (PSQI): self-report questionnaire to assess sleep quality over a 1-month time interval consisting of 19 individual items.	Change from baseline to day 7 day follow up visit
Secondary	Mental well-being (WEMWBS)	Warwick-Edinburgh Mental Well-being Scale (WEMWBS): self-reported 14-item scale to assess Overall mental well-being	Change from baseline to day 14 of supplementation to the 7 day follow up visit
Secondary	Resilience behavior (Wagnild &Young)	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
Secondary	Spermidine blood concentration	Assessment of spermidine blood Levels by HPLC (high pressure liquid chromatography) analysis	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	white cell count	Complete white cell count (per liter)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Hemoglobin	Hemoglobin (g/dL)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	Hematocrit	Hematocrit (%)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	red cell count	complete red cell count (per liter)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	MCV	mean corpuscular volume (fl)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	MCH	mean corpuscular hemoglobin (pg)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	thrombocytes	thrombocytes per Liter	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	MCHC	mean corpuscular hemoglobin concentration (g/dL)	change from baseline over 21 days of supplementation to 7 day follow up
Secondary	RDW	red cell distribution width (%)	change from baseline over 21 days of supplementation to 7 day follow up