Long-term fasting: Multi-system adaptations in humans (GENESIS) study-A single-arm interventional trial

Abstract

Fasting provokes fundamental changes in the activation of metabolic and signaling pathways leading to longer and healthier lifespans in animal models. Although the involvement of different metabolites in fueling human fasting metabolism is well known, the contribution of tissues and organs to their supply remains partly unclear. Also, changes in organ volume and composition remain relatively unexplored. Thus, processes involved in remodeling tissues during fasting and food reintroduction need to be better understood. Therefore, this study will apply state-of-the-art techniques to investigate the effects of long-term fasting (LF) and food reintroduction in humans by a multi-systemic approach focusing on changes in body composition, organ and tissue volume, lipid transport and storage, sources of protein utilization, blood metabolites, and gut microbiome profiles in a single cohort. This is a prospective, single-arm, monocentric trial. One hundred subjects will be recruited and undergo 9 ± 3 day-long fasting periods (250 kcal/day). We will assess changes in the composition of organs, bones and blood lipid profiles before and after fasting, as well as high-density lipoprotein (HDL) transport and storage, untargeted metabolomics of peripheral blood mononuclear cells (PBMCs), protein persulfidation and shotgun metagenomics of the gut microbiome. The first 32 subjects, fasting for 12 days, will be examined in more detail by magnetic resonance imaging (MRI) and spectroscopy to provide quantitative information on changes in organ volume and function, followed by an additional follow-up examination after 1 and 4 months. The study protocol was approved by the ethics board of the State Medical Chamber of Baden-Württemberg on 26.07.2021 and registered at ClinicalTrials.gov (NCT05031598). The results will be disseminated through peer-reviewed publications, international conferences and social media.

Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05031598].

Keywords: lipoprotein metabolism; long-term fasting; magnetic resonance imaging (MRI); metabolomics; microbiome; organ size; protein utilisation.

FIGURE 1

Main outcomes of the GENESIS study. By pooling knowledge acquired by macroscopic multi-organ fat distribution and composition provided by magnetic resonance imaging (MRI), with erythrocyte fatty acids, lipoprotein, peripheral blood mononuclear cell (PBMC) metabolome, protein persulfidation, and gut microbiome profiles, we aim to gain a deeper comprehension of molecular and physiological changes during fasting and food reintroduction.

FIGURE 2

Study design. Specific sessions for the subjects enrolled in the first stage of the projects are indicated in blue. The estimated numbers of volunteers needed to recruit the sample size of 100 subjects are indicated in gray.

FIGURE 3

Summary of the magnetic resonance imaging/spectroscopy (MRI/MRS) measurements. Body composition after a 12 days fasting period by means of MRI/MRS scans with a focus on the brain (A), liver (B), skeletal muscle (C), and myocardium (D–F). Beyond brain morphometry (A), myocardial mass, function and regional deformation (F), and abdominal organs sizing (B) calculated from localized dedicated scans (side panels). Subcutaneous, visceral, extra-visceral and bone marrow fat quantification and total lean mass will be calculated from whole body acquisition (middle panel). MR spectroscopy of the liver (B), leg muscle (C), and heart (E) allows complementary fat decomposition, triglycerides and metabolites concentrations quantification. Advanced myocardium tissue characterization will include relaxometry and diffusion parameters mapping, as well as myocardial fiber orientation and local deformation (D). Muscle legs volume and strength (maximum voluntary contraction) will be compared to MRS 31P data and extracted biomarkers of the oxidative metabolism (C).