Fasting, Exercise, and Diet to Activate Autophagy in Depression

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.

Inclusion Criteria: * age: 18-40 years * BMI: between 18.5 and 24.9 kg/m2 (SG1/2) or BMI between 25.0 and 39.9 kg/m2 (SG3/4) * ability to understand the study procedure and give consent * Written informed consent * SG1 women: any fitness level * SG2 men: VO2max \< 45 ml/kg/KG29,30 * Available to conduct CPET on menstrual cycle days 1-5 (SG1/3) * No infection with HIV or Hepatitis B/C Exclusion Criteria: * No infectious illness for at least two weeks prior to the test * No vitamin supplementation during the week prior to the performance test * SG3 and SG4: More than 1 hour moderate exercise per week * No use of hormonal contraceptives in the last 6 months before the onset of the study (SG1/3) * a clinically diagnosed menstrual disorder (e.g., polycystic ovarian syndrome or amenorrhea) (SG1/3) * having given birth within the 12 months before inclusion in the study (SG1/3) * pregnancy or breastfeeding (SG1/3) * premenstrual dysphoric disorder (PMDD) (SG1/3) * history of epileptic seizure * history of depression * history of manic or psychotic episode * existing/current eating disorders (bulimia nervosa, anorexia nervosa) within the past 5 years * inability to communicate adequately in speech * inability to follow instructions * regular use of medication other than thyroxine * alcohol consumption as equivalent doses of more than 12 g of pure alcohol per day on average for women and 24 g of pure alcohol per day for men * vegan diet * daily nicotine consumption * currently or history of (regular) consumption of illegal drugs within the last year * known diseases of the cardiovascular system * arterial hypertension above 160/90 mmHg at rest * known pulmonary diseases * arthritis and rheumatic diseases and conditions * hematologic diseases * bronchial asthma * surgery less than 4-6 months ago * orthopedic or other diseases (e.g. neurological) that preclude maximum load on the bicycle ergometer * anemia (\