A population-scale red blood cell proteome reveals genetically encoded aging clocks predictive of hemolysis and blood donor activity

Dzieciatkowska, M., Issaian, A. V., Keele, G. R., Saviola, A., Stephenson, D., Bevers, S., Reisz, J. A., Haiman, Z. B., Nemkov, T., Fang, F., Moore, A., Deng, X., Stone, M., Kleinman, S., Norris, P. J., Wang, X., Thein, S.-L., Hod, E. A., Busch, M. P., Roubinian, N. H., Page, G. P., Hansen, K., D'Alessandro, A.

University of Colorado Anschutz Medical Campus · biorxiv

Paper

Abstract

As the most abundant human cell and the foundation of transfusion medicine, red blood cells (RBCs) offer a unique readout of systemic health, yet they have never been characterized at population scale. We generated a proteome atlas of 13,091 blood donors with multi-omics longitudinal phenotyping, characterizing the influence of demographics and genetic variation on the reproducibility of RBC proteomes across donations. Elastic-net aging clocks captured biological aging with high accuracy and uncovered genetic regulators of {Delta}Age at FN1, C4/IKZF1, CRAT, PFAS, TRIM58. Across independent cohorts, {Delta}Age was accelerated in G6PD deficiency, sickle cell trait/disease, and iron deficiency, reversed by iron repletion, and slowed in high-frequency donors, linking molecular aging to brain iron/myelin and cognitive performance. Molecular aging signatures predicted storage, osmotic, and oxidative hemolysis, hemoglobin increments after transfusion, and long-term donor activity over 12-years. These results establish RBC proteomics as a scalable biomarker of aging, donor healthspan, and transfusion outcomes.

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Research summary

The paper claims that red blood cell proteomics can serve as a scalable biomarker for biological aging and donor healthspan. This research is relevant as it explores molecular aging mechanisms and their implications for transfusion outcomes, linking them to systemic health and aging processes.

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