Targeting Autophagy in Depression: Fasting, Exercise, Diet
Targeting Autophagy in Depression: Fasting, Exercise, Diet
Depression is a common mental health condition that affects millions of people worldwide and is a leading cause of disability. Although current treatments can be effective, many patients do not fully recover or experience long-term improvement. This study aims to better understand how lifestyle factors such as physical activity and diet-related processes may influence biological mechanisms that could be linked to depression.
The study focuses on a natural cellular process called autophagy, which helps cells remove damaged components and maintain healthy function. Autophagy is influenced by energy availability in the body and may be affected by behaviors such as physical exercise and caloric restriction. Early evidence suggests that changes in autophagy may also be linked to mood regulation and depression, but this relationship is not yet well understood in humans.
In this exploratory study, we will investigate how physical activity influences autophagy and related metabolic and molecular processes in healthy adults. We will also examine whether these effects differ between individuals with different body weight and fitness levels, and between women and men.
A total of approximately 120 healthy adults aged 18 to 40 years will participate. Participants will be divided into four groups based on sex and body weight (normal weight or overweight). Each participant will attend study visits at the University Hospital Zurich and perform a standardized cycling exercise test under medical supervision.
During the exercise test, participants will perform a graded cycling protocol that gradually increases in intensity until exhaustion. We will collect small blood samples from a vein and from a fingertip at several time points before, during, and after exercise. Saliva samples will also be collected to measure stress-related hormones. Additional measurements include heart rate, breathing parameters, oxygen consumption, and physical performance.
Blood and saliva samples will be analyzed using advanced laboratory techniques to study changes in metabolism, immune signaling, hormones, gene activity, and markers related to autophagy. These analyses will help identify biological pathways that are activated by exercise and may be relevant to brain health and depression.
Participants will undergo medical screening before inclusion to ensure safety. Individuals with certain medical conditions or factors that could interfere with the study results will not be included. Participation is voluntary, and participants may withdraw at any time without consequences.
The study involves minimal risks associated with blood sampling and intense physical exercise, which will be performed under close medical supervision. The expected benefit is improved scientific understanding of how lifestyle-related biological processes may be linked to mental health, which could support the development of new preventive or therapeutic strategies for depression in the future.
Background and Rationale Depressive disorders are among the leading causes of disability worldwide and represent a major public health burden. Despite the availability of pharmacological and psychotherapeutic treatments, a substantial proportion of patients do not achieve full remission or experience relapse. Current antidepressant strategies primarily target monoaminergic systems and are often insufficient in addressing the biological heterogeneity of depression.
Emerging evidence suggests that metabolic regulation and cellular stress response pathways may play an important role in the pathophysiology of depression. In particular, associations between metabolic disorders (such as obesity and insulin resistance) and depressive symptoms indicate shared biological mechanisms. This has led to increasing interest in lifestyle-based interventions, including physical activity, dietary modification, and caloric restriction, as potential modulators of both metabolic and neuropsychiatric outcomes.
A central candidate mechanism linking metabolism and brain function is autophagy, a conserved cellular process responsible for the degradation and recycling of damaged proteins and organelles. Autophagy is tightly regulated by nutrient availability and energy status, primarily via the AMPK-mTOR signaling axis. It is activated under energy deprivation and suppressed under nutrient excess. Proper autophagic flux is essential for neuronal homeostasis, immune regulation, and cellular stress adaptation.
Preclinical and emerging clinical evidence suggests that impaired autophagy may be involved in psychiatric disorders, including depression. Furthermore, interventions such as physical exercise, caloric restriction, and certain pharmacological agents have been shown to modulate autophagy-related pathways. However, the direct measurement of autophagic flux in humans under physiological conditions remains methodologically challenging, and its relationship to exercise-induced metabolic and neurobiological changes is not fully understood.
This study aims to address this gap by investigating autophagy-related biological responses to acute physical exercise in humans using a multi-omics approach.
Objectives Primary Objective To investigate whether acute physical exercise induces measurable changes in autophagy-related pathways and associated metabolic, proteomic, transcriptomic, and hormonal markers in humans.
Secondary Objectives To characterize exercise-induced changes in systemic metabolism, inflammatory markers, and stress hormones.
To explore associations between fitness level, body mass index (BMI), and molecular responses to exercise.
To identify potential biomarkers of autophagy activation in peripheral blood and saliva.
To generate mechanistic hypotheses linking metabolic regulation, autophagy, and pathways relevant to mood disorders.
Study Design This is a single-center, exploratory human research study conducted at the University Hospital Zurich in collaboration with exercise physiology facilities.
The study uses a cross-sectional experimental design involving standardized acute exercise stimulation (cardiopulmonary exercise testing, CPET) combined with repeated biological sampling and multi-omics profiling.
Participants will be stratified into four groups based on sex and BMI:
Normal-weight women Normal-weight men Overweight women Overweight men All participants will perform a standardized incremental cycling exercise test under controlled laboratory conditions.
Study Population Approximately 120 healthy adults aged 18-40 years will be included. Participants will be selected based on predefined inclusion and exclusion criteria to ensure medical safety and reduce confounding variables such as chronic disease, medication use, psychiatric disorders, and hormonal influences (e.g., hormonal contraception or pregnancy in women).
Women will be tested during early follicular phase (cycle days 1-5) to minimize hormonal variability.
Study Procedures
Each participant will undergo:
The protocol includes:
15-minute warm-up phase at submaximal intensity Incremental ramp protocol until voluntary exhaustion
Continuous monitoring of:
Oxygen uptake (VO₂) Carbon dioxide production (VCO₂) Heart rate and ECG Blood pressure Respiratory exchange ratio
Key physiological thresholds will be determined:
Aerobic threshold Anaerobic threshold Respiratory compensation point 4. Biological Sampling
Repeated biological sampling will be performed at defined time points:
Rest (baseline) End of warm-up (aerobic phase) Peak exercise (maximal exertion) 10 minutes recovery 30 minutes recovery
Samples include:
Venous blood (PBMC isolation and plasma) Capillary blood microsamples (fingertip sampling devices) Saliva (cortisol analysis) Urine (pregnancy test in women) Total blood volume per participant will be approximately 320 mL across all time points.
Laboratory Analyses
Collected samples will be used for multi-layered molecular profiling:
Inclusion Criteria:
Exclusion Criteria: