Autophagy-Enhancers to Reduce Sleep Disturbances (SpSleep)

June 29, 2026 updated by: Nina Unger, University Medicine Greifswald

Autophagy-Enhancers to Reduce Sleep Disturbances: A Combined Approach

This clinical trial investigates the effects of spermidine supplementation on sleep quality and sleep-dependent memory consolidation in older adults with Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI), two populations at increased risk of future cognitive decline and dementia. Impaired sleep has been identified as a modifiable factor contributing to cognitive decline, and interventions targeting sleep architecture could offer therapeutic potential to prevent or slow down this decline.

Spermidine is a naturally occurring polyamine found in foods such as wheat germ and soybeans. It induces autophagy, a cellular degradation and recycling process essential for neuronal maintenance and function. In animal studies, spermidine has been shown to improve memory performance, reduce neuroinflammation, and support mitochondrial health. Preliminary findings from human trials in individuals with SCD or MCI suggest potential cognitive benefits of spermidine, but results are not unequivocal, and the impact on sleep has not been systematically evaluated.

In this randomized, double-blind, placebo-controlled trial, 76 participants aged 55 to 70 years with SCD or MCI will receive either spermidine (6 mg/day) or a placebo for 12 weeks. Sleep will be evaluated using overnight EEG in a controlled laboratory setting, focusing on measures such as slow-wave sleep and sleep spindle activity. Memory performance will be assessed before and after the intervention using standardized neuropsychological testing. Numerical skills will be tested at baseline only to compare SCD and MCI participants with healthy controls.

Blood samples will be collected to quantify metabolic indicators, neurodegeneration-related biomarkers, and autophagy-associated proteins. A control group of 38 cognitively healthy individuals will undergo comparable sleep and cognitive assessments without receiving any supplementation.

The primary objective of the study is to characterize the impact of spermidine on sleep-dependent memory consolidation and to identify associated biological changes relevant to aging and neurodegeneration. The results may inform the development of non-pharmacological strategies aimed at preserving cognitive function in individuals at risk for dementia.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) represent early stages along the continuum of cognitive decline preceding dementia. Individuals with SCD report persistent cognitive complaints despite normal performance on standardized cognitive testing, whereas MCI is characterized by objective cognitive impairment that does not yet interfere substantially with activities of daily living. Both conditions are associated with an elevated risk of progression to Alzheimer's disease and other dementias. Disruption of sleep architecture is increasingly implicated in the pathophysiology of neurodegenerative disorders, and early interventions targeting sleep-related mechanisms could help delay further cognitive decline. This clinical trial evaluates the effects of spermidine supplementation on sleep quality and sleep-dependent memory consolidation in older adults with SCD or MCI.

Following an adaptation night and an initial baseline sleep assessment with overnight electroencephalography (EEG), participants will be randomly assigned to either the spermidine or placebo group. The intervention consists of a daily oral dose of 6 mg spermidine (administered as three 2 mg sachets), continued over a 12-week period. The trial employs a randomized, double-blind, placebo-controlled design. Placebo sachets, identical in appearance and taste, contain only microcrystalline cellulose. After the 12-week supplementation period, participants will return for a second overnight EEG assessment.

A healthy control group (n=38), matched for age and sex, will undergo comparable baseline assessments but will not receive any intervention. These data will provide normative reference values for sleep and cognitive parameters.

The primary objective of the study is to assess the impact of spermidine on sleep architecture, measured via overnight polysomnography, with a specific focus on slow-wave sleep and sleep spindle activity, EEG markers associated with sleep-dependent memory consolidation and known to decline with age and neurodegeneration. Secondary outcomes include changes in memory consolidation (assessed using a battery of cognitive tasks that target declarative, procedural, and visuospatial memory domains), as well as numerical skills (tested via e.g., digit-letter-decision task, Berlin Numeracy Test). Testing occurs before and after each EEG night to evaluate overnight consolidation effects. All participants will wear actigraphs prior to both EEG nights to monitor sleep-wake cycles and physical activity.

Additional biological endpoints will examine changes in circulating neuropeptides, insulin-glucose homeostasis, and autophagy-related biomarkers. Blood samples are collected at each EEG session and two weeks after the start of supplementation. Physiological assessments include measurements of inflammatory markers (e.g., interleukin (IL)-6, tumor necrosis factor (TNF-α), neuroprotective factors (e.g., Neuropeptide Y, eukaryotic translation initiation factor 5A (eIF5A) hypusination), and metabolic indicators (e.g., fasting insulin, glucose, and lipid profiles).

Participants will undergo structural brain imaging using a 3-Tesla MRI scanner to exclude individuals with comorbid neurological conditions (e.g., prior stroke, other neurodegenerative diseases) and to assess brain morphology. Eligibility is determined through standardized pre-screening procedures, including clinical interviews and neuropsychological assessments.

The study includes 76 participants with SCD or MCI, aged 55-70 years, randomly allocated to either the spermidine or placebo group (n=38 per group). The sample size provides adequate statistical power to detect medium-to-large effect sizes, based on previous pilot findings and anticipated attrition rates.

This study aims to investigate the effects of spermidine supplementation on neurophysiological and cognitive outcomes in individuals with early-stage cognitive decline. The results are expected to contribute to the growing body of evidence evaluating spermidine as a safe, nutrition-based strategy for maintaining brain health and cognitive function in the context of aging.

Study Type

Interventional

Enrollment (Estimated)

Phase

Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Agnes Flöel, Prof. Dr.
Phone Number: +49 (0)3834 86-6815
Email: agnes.floeel@med.uni-greifswald.de

Study Contact Backup

Name: Silke M Wortha, Dr.
Phone Number: +49 3834 86 - 6704
Email: SilkeMaria.Wortha@med.uni-greifswald.de

Study Locations

Germany
- Mecklenburg-Vorpommern
  - Greifswald, Mecklenburg-Vorpommern, Germany, 17475
    - Recruiting
    - Department of Neurology, University Medicine Greifswald
    - Contact:
      
      Agnes Flöel, Prof. Dr.
      
      Phone Number: +49 (0)3834 86-6815
      
      Email: agnes.floeel@med.uni-greifswald.de

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

Adult
Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria (SCD participants):

Men and women
Written consent to participate in the study
German at native speaker level
Age between 55 and 70 years
Subjective Cognitive Decline operationalized as:
1. Subjectively reported decline in cognitive function (particularly memory) despite objectively normal cognitive performance (e.g., WMS-LM)
2. Preservation of functional independence
3. No dementia

Inclusion Criteria (MCI patients):

Men and women
Written consent to participate in the study
German at native speaker level
Age between 55 and 70 years
Mild cognitive impairment (MCI) operationalized as:
1. A change in cognitive abilities reported by the patient, relatives or clinic staff (i.e. historical or observed evidence of deterioration over time)
2. Objective evidence of memory impairment (at least 1.0 Standard Deviation (SD) below the normal range on the Wechsler Logical Memory Scale (WMS-LM)); other cognitive domains may also be affected (i.e. amnestic MCI and amnestic + MCI)
3. Preservation of independence of functional abilities
4. No dementia

Exclusion Criteria (SCD and MCI participants):

Patients who are unable to give informed consent
Polyamine intake via dietary supplements and/or participation in corresponding intervention studies
Dementia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)
Any condition that impairs clinical or neuropsychological examination procedures
Diabetes mellitus
Polycystic ovary syndrome
Signs of epilepsy, focal brain lesion or head injury with loss of consciousness or immediate post-injury confusion
Previous stroke
Severe untreated medical problems or unstable medical condition
Current major depressive episode
Psychotic disorder
Bipolar disorder
Current or previous substance abuse
Other neurodegenerative disease, e.g. Parkinson's disease
Vascular dementia
Alcohol abuse
Participation in an interventional study in the last 3 months and during the entire study period
Sleep disorders
Taking medication that primarily affects the central nervous system (e.g. antipsychotics, antidepressants, benzodiazepines or any type of over-the-counter sleep-inducing medication such as valerian; anti-dementia medication)
Known intolerances or allergies to wheat germ, gluten or histamine

Inclusion criteria (healthy controls):

Men and women
Written consent to participate in the study
German at native speaker level
Age between 55 and 70 years
Subjective cognitive disorders are denied

Exclusion criteria (healthy controls):

Subjects who are not able to give informed consent
Polyamine intake via dietary supplements and/or participation in corresponding intervention studies
Dementia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV)
Mild cognitive impairment (MCI), defined as described above in the patient inclusion criteria
Any condition that interferes with clinical or neuropsychological examination procedures
Diabetes mellitus
Polycystic ovary syndrome
Signs of epilepsy, focal brain lesion or head injury with loss of consciousness or immediate post-injury confusion
Previous stroke
Severe untreated medical problems or unstable medical condition
Current major depressive episode
Psychotic disorder
Bipolar disorder
Current or past substance abuse
Other neurodegenerative disease, e.g. Parkinson's disease
Vascular dementia
Alcohol abuse
Participation in an interventional study in the last 3 months and during the entire study period
Sleep disorders
Taking medication that primarily affects the central nervous system (e.g. antipsychotics, antidepressants, benzodiazepines or any type of over-the-counter sleep-inducing medication such as valerian; anti-dementia medication)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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 Participant Group / Arm A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.	Intervention / Treatment Intervention / Treatment A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Dietary Supplement	Dietary supplement: Spermidine Supplementation supplementation of 6 mg Spermidine per day across 3 doses
No Intervention: Healthy elderly controls baseline comparison, healthy controls are not part of the intervention
Placebo Comparator: Dietary Placebo	Dietary supplement: Dietary Placebo supplementation of 6 mg Placebo per day across 3 doses (placebo consists of maltodextrin, rice extract microcrystalline cellulose mixture, citric acid (anhydrous), silicon oxide (precipitated, E551))

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of spermidine supplementation on sleep quality as measured by electroencephalography (EEG) mean power spectra Time Frame: baseline, 12-week follow-up	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow oscillations (0.5-1 Hz), low delta (1-1.5 Hz), delta (1-4 Hz), theta (4-8 Hz), and beta (15-25 Hz). For the spermidine effect, baseline and follow-up EEG data are compared with each other.	baseline, 12-week follow-up
Effects of spermidine supplementation on sleep quality as measured by sleep spindle count assessed from EEG Time Frame: baseline, 12-week follow-up	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz), and the number of slow frontal and fast parietal discrete spindles are counted. Spindle detection is performed based on an algorithm adopted from previous studies. For the spermidine effect, baseline and follow-up EEG data are compared with each other.	baseline, 12-week follow-up
Effects of spermidine supplementation on sleep quality as measured by sleep spindle power assessed from EEG Time Frame: baseline, 12-week follow-up	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz). Spindle power is analyzed as a further measure of spindle activity. Spindle detection is performed based on an algorithm adopted from previous studies. For the spermidine effect, baseline and follow-up EEG data are compared with each other.	baseline, 12-week follow-up
Effects of spermidine supplementation on sleep-related alertness as measured by computer-based task Time Frame: baseline, 12-week follow-up	The alertness task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. It comprises two runs without and two runs with a prior warning tone. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other. Task performance is measured by speed (in ms) and hit/false or miss.	baseline, 12-week follow-up
Effects of spermidine supplementation on sleep-related visual-spatial memory as measured by computer-based task Time Frame: baseline, 12-week follow-up	The visual-spatial memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 60 objects (e.g., photo of a band-aid) placed in front of a background (e.g., photo of a treatment room in a doctor's office), a retrieval phase follows directly after encoding in the evening before bedtime, in which 30 randomly selected images from the total of 60 are tested. Participants should memorize the position of the object placed in front of the background and select the correct position by pressing a button. In the next morning, the remaining 30 images are tested in a recall phase. Task performance is measured by speed (in ms) and hit/false or miss. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other.	baseline, 12-week follow-up
Effects of spermidine supplementation on sleep-related verbal memory as measured by computer-based task Time Frame: baseline, 12-week follow-up	The verbal memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 44 word pairs, a retrieval phase follows directly after encoding in the evening before bedtime, in which all word pairs are tested in randomized order. The next morning, all word pairs are tested in a recall phase. Task performance is measured by hit/false or miss. For the spermidine effect, baseline and follow-up task performances of SCD and MCI participants are compared with each other.	baseline, 12-week follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in autophagy-related blood markers pre and post spermidine intervention in SCD and MCI as measured by polyamine concentration Time Frame: baseline, 2 weeks after baseline, 12-week follow-up	concentration in nmol / mg Protein assessed via Peripheral Blood Mononuclear Cells (PBMCs)	baseline, 2 weeks after baseline, 12-week follow-up
Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by electroencephalography (EEG) mean power spectra Time Frame: baseline data	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow oscillations (0.5-1 Hz), low delta (1-1.5 Hz), delta (1-4 Hz), theta (4-8 Hz), and beta (15-25 Hz). The differences between SCD / MCI and healthy controls are assessed from baseline EEG data.	baseline data
Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by sleep spindle count assessed from EEG Time Frame: baseline data	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz), and the number of slow frontal and fast parietal discrete spindles are counted. Spindle detection is performed based on an algorithm adopted from previous studies. The differences between SCD / MCI and healthy controls are assessed from baseline EEG data.	baseline data
Differences in sleep quality between SCD or MCI and healthy controls (HC) as measured by sleep spindle power assessed from EEG Time Frame: baseline data	Individual mean power spectra are calculated. Subsequently, the mean power is calculated in the following EEG bands: slow frontal spindle (8-12 Hz), fast parietal spindle (12-15 Hz). Spindle power is analyzed as a further measure of spindle activity. Spindle detection is performed based on an algorithm adopted from previous studies. The differences between SCD / MCI and healthy controls are assessed from baseline EEG data.	baseline data
Differences in autophagy-related blood markers pre and post spermidine intervention in SCD or MCI as measured by eIF5A hypusination Time Frame: baseline, 2 weeks after baseline, 12-week follow-up	assessed via Hypusinated eIF5A levels (Western Blot) from Peripheral Blood Mononuclear Cells (PBMCs)	baseline, 2 weeks after baseline, 12-week follow-up
Differences in neuropeptide Y blood levels pre and post spermidine intervention in SCD or MCI Time Frame: baseline, 12-week follow-up	Neuropeptide Y blood levels in pg/ml analyzed from serum blood sample	baseline, 12-week follow-up
Differences in sleep-related alertness between SCD or MCI participants and healthy controls as measured by computer-based task Time Frame: baseline	The alertness task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. It comprises two runs without and two runs with a prior warning tone. The differences between SCD / MCI and healthy controls are assessed from baseline task data. Task performance is measured by speed (in ms) and hit/false or miss.	baseline
Differences in sleep-related visual-spatial memory between SCD or MCI participants and healthy controls as measured by computer-based task Time Frame: baseline	The visual-spatial memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 60 objects (e.g., photo of a band-aid) placed in front of a background (e.g., photo of a treatment room in a doctor's office), a retrieval phase follows directly after encoding in the evening before bedtime, in which 30 randomly selected images from the total of 60 are tested. Participants should memorize the position of the object placed in front of the background and select the correct position by pressing a button. In the next morning, the remaining 30 images are tested in a recall phase. Task performance is measured by speed (in ms) and hit/false or miss. The differences between SCD / MCI and healthy controls are assessed from baseline task data.	baseline
Differences in sleep-related verbal memory between SCD or MCI participants and healthy controls as measured by computer-based task Time Frame: baseline	The verbal memory task is trained at adaptation night and assessed at baseline and follow-up before and after sleep. After an encoding phase consisting of 44 word pairs, a retrieval phase follows directly after encoding in the evening before bedtime, in which all word pairs are tested in randomized order. The next morning, all word pairs are tested in a recall phase. Task performance is measured by hit/false or miss. The differences between SCD / MCI and healthy controls are assessed from baseline task data.	baseline
Differences in neuropeptide Y blood levels between SCD or MCI and healthy controls Time Frame: baseline data	blood levels in pg/ml analyzed from serum blood sample	baseline data
Differences in autophagy-related blood markers between SCD or MCI and healthy controls as measured by polyamine concentration Time Frame: baseline data	concentration in nmol / mg Protein assessed via Peripheral Blood Mononuclear Cells (PBMCs)	baseline data
Differences in autophagy-related blood markers between SCD or MCI and healthy controls as measured by eIF5A hypusination Time Frame: baseline data	assessed via Hypusinated eIF5A levels (Western Blot) from Peripheral Blood Mononuclear Cells (PBMCs)	baseline data
Differences in numerical skills between SCD or MCI patients and healthy controls as measured by lexical decision task Time Frame: assessed at baseline only	Participants complete a computer-based lexical decision task, in which a row of six symbols is presented after a fixation cross. Depending on the condition, the test subjects must decide by pressing a key on the keyboard whether the row presented contains a letter (e.g., condition 1) or a digit (e.g., condition 2). Each condition consists of two blocks. After the first block, there is a short pause before the second block starts. The condition (digit or letter) with which the trial starts is randomized for each test subject.	assessed at baseline only
Differences in numerical skills between SCD or MCI participants and healthy controls as measured by Berlin Numeracy Test Time Frame: assessed at baseline only	The Berlin Numeracy Test contains 4 short, text-based questions testing statistical numeracy and risk literacy, requiring Bayesian inference for problems like understanding probabilities in health concerns (e.g., poisonous mushrooms) or lotteries, often presenting data in relative/absolute numbers and asking for probability estimates. Correct answers scored for a total of 0-4 points.	assessed at baseline only

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Medicine Greifswald

Collaborators

Department of Experimental Neuroimmunology, University Medicine

Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald

Institute of Biology, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 28, 2025

Primary Completion (Estimated)

December 1, 2028

Study Completion (Estimated)

May 1, 2029

Study Registration Dates

First Submitted

September 17, 2025

First Submitted That Met QC Criteria

January 28, 2026

First Posted (Actual)

February 3, 2026

Study Record Updates

Last Update Posted (Actual)

July 2, 2026

Last Update Submitted That Met QC Criteria

June 29, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Autophagy and Sleep
508402643 (Other Grant/Funding Number: Deutsche Forschungsgemeinschaft (DFG))

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Autophagy-Enhancers to Reduce Sleep Disturbances (SpSleep)

Autophagy-Enhancers to Reduce Sleep Disturbances: A Combined Approach

Study Overview

Status

Conditions

Intervention / Treatment

Detailed Description

Study Type

Enrollment (Estimated)

Phase

Contacts and Locations

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Eligibility Criteria

Ages Eligible for Study

Accepts Healthy Volunteers

Description

Study Plan

How is the study designed?

Design Details

Number of Arms

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure

Measure Description

Time Frame

Secondary Outcome Measures

Outcome Measure

Measure Description

Time Frame

Collaborators and Investigators

Sponsor

Collaborators

Publications and helpful links

General Publications

Study record dates

Study Major Dates

Study Start (Actual)

Primary Completion (Estimated)

Study Completion (Estimated)

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

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