RBC metabolism modulates hemoglobin oxygen binding and off-loading and, in so doing, modulates metabolic activity of the rest of bodily cells that, unlike RBCs, contain mitochondria ( Nemkov et al., 2018a). From classical clinical biochemistry to early clinical metabolomics approaches ( DвЂ™Alessandro et al., 2012), studies on RBC metabolism have furthered our understanding of systemic responses to aging, inflammation, and physiological (e.g., high altitude) or pathological (e.g., hemorrhage, ischemia) hypoxia. The choice to focus on this matrix and, specifically, on red blood cells (RBCs), stems from an appreciation that blood offers a window into systems metabolism. Embracing this philosophy, we embarked on the ZOOMICS project: by taking advantage of recent developments in high-throughput metabolomics ( Nemkov et al., 2017 Reisz et al., 2019), we set out to investigate common and diverging metabolic traits in the blood metabolome across various species. From LinnaeusвЂ™ taxonomical efforts to order nature into separate categories, to modern day DNA-based phylogenetic classifications, scientists have leveraged comparative biology to unravel NatureвЂ™s mysteries and learn more about humankind as a species. Mere scientific curiosity has historically led science to the discovery of novel natural phenomena that turned out to be mechanistically relevant to our understanding of human biology. Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.

For example, through a combination of steady state measurements and 13C 6 15N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Here we provide the first comparative metabolomics analysis of fresh and stored human ( n = 21, 10 males, 11 females), olive baboon ( n = 20), and rhesus macaque ( n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. 10Division of Hematology, Department of Medicine, University of Colorado Denver вЂ“ Anschutz Medical Campus, Aurora, CO, United StatesДЄs part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics.9Department of Pediatrics, Center for Blood Oxygen Transport and Hemostasis, University of Maryland School of Medicine, Baltimore, MD, United States.8Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, United States.7Department of Pathology and Laboratory Medicine, Milwaukee, WI, United States.6Blood Center of Wisconsin, Milwaukee, WI, United States.5Hemanext, Inc., Lexington, MA, United States.4Department of Pathology, University of Virginia, Charloteseville, VA, United States.

3Department of Pathology and Cell Biology, Columbia University, New York, NY, United States.

2Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.

1Department of Biochemistry and Molecular Genetics, University of Colorado Denver вЂ“ Anschutz Medical Campus, Aurora, CO, United States.

Buehler 8,9*вЂ and Angelo DвЂ™Alessandro 1,10*вЂ Zimring 4, Tatsuro Yoshida 5, Matthew Karafin 6,7, Joseph Schwartz 3, Krystalyn E. Morrison 1, Travis Nemkov 1, Tiffany Thomas 3, Richard O. Shin 2, Davide Stefanoni 1, Jin Hyen Baek 2, Yamei Gao 2, Evan J.

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