Longitudinal Metabolomic Profiles Reveal Sex-specific Adjustments to Long-duration Spaceflight and Return to Earth

Abstract Spaceflight entails a variety of environmental and psychological stressors that may have long-term physiological and genomic consequences. Metabolomics, an approach that investigates the terminal metabolites of complex physiological alterations, takes into account the dynamic state of the human body and allows the identification and quantification of down-stream metabolic outputs linked to up-stream physiological and genomic regulation by stress. Employing a metabolomics-based approach, this study investigated the longitudinal metabolic perturbations of male (n=40) and female (n=11) astronauts on 4-6-month missions to the International Space Station. Proton nuclear magnetic resonance (1H-NMR) spectroscopy followed by univariate, multivariate and machine learning analyses were used on blood serum to examine sex-specific metabolic changes at various time points throughout the astronauts’ missions, and the metabolic effects of long-duration space travel. Space travel generated sex-specific changes in energy metabolism, bone mineral and muscle regulation, immunity, and macromolecule maintenance and synthesis. Additionally, metabolic signatures suggest differential metabolic responses especially during the recovery period, with females requiring more time to adjust to return to Earth. These findings provide insight into the perturbations in glucose and amino acid metabolism and macromolecule biosynthesis that result from the stressors of long-duration spaceflight. Metabolomic biomarkers may provide a viable approach to predicting and diagnosing health risks associated with prolonged space travel and other physiological challenges on Earth.