Population-scale mass spectrometry proteomics of 13,091 blood donors establishes that RBC molecular composition encodes genetically regulated aging clocks that predict chronological age with high accuracy, are modifiable by iron status and hemolytic conditions, and prospectively forecast hemolytic propensity, transfusion efficacy, and long-term donor retention over a 12-year period, positioning RBC proteomics as a scalable biomarker of biological aging and transfusion outcomes.

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 ΔAge at FN1, C4/IKZF1, CRAT, PFAS, TRIM58. Across independent cohorts, ΔAge 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.

Dzieciatkowska et al. generate the first population-scale atlas of the RBC proteome across 13,000 donors and develop proteomic and metabolomic aging clocks that quantify biological age. Molecular ΔAge is reproducible across donations, genetically encoded and accelerated in G6PD deficiency, sickle cell trait/disease, and iron deficiency - yet reset by iron repletion, tracking with cognitive function and brain iron/myelin. RBC aging clocks predict hemolytic fragility, transfusion efficacy, and donor activity 12 years later.

Highlights

RBC proteome atlas of 13,091 donors reveals demographic and genetic programs

Genetically encoded RBC aging clocks identify regulators of molecular Δage

Molecular aging features predict hemolysis and transfusion response across cohorts

RBC molecular age forecasts long-term donor activity over a 12-year follow-up