ULTRA running accelerates red blood cell ageing through inflammatory and oxidative pathways, with molecular damage resembling that observed during blood bank storage, according to new multi omics research in endurance athletes.
Ultra endurance running places exceptional demands on oxygen transport, yet the molecular response of red blood cells has remained poorly characterised. Investigators integrated plasma and red blood cell multi omics with haematology and haemorheology in athletes sampled before and after two trail races of different duration: a 40 km marathon and a 171 km ultramarathon. Both events triggered systemic inflammation, but the ultramarathon was associated with more pronounced biological disruption.
Molecular Signatures of Red Blood Cell Ageing
The 171 km race was marked by substantial increases in interleukin 6 and kynurenine, alongside induction of acute phase proteins and extensive lipid remodelling. Within red blood cells, accumulation of acylcarnitines and depletion of pantothenate indicated activation of the Lands cycle. Oxidised lipid species were also observed. Alterations in purine salvage and carboxylate metabolism suggested redox sensitive rerouting of energy pathways.
Proteomic analyses revealed non-random oxidation patterns, including methionine oxidation affecting antioxidant enzymes, metabolic proteins, and proteasome components. These molecular lesions correlated with impaired deformability, as demonstrated by rheological testing. Elevated copper concentrations provided an additional correlate of reduced red blood cell mechanical function.
Inflammation And Oxidative Stress Beyond Mechanical Trauma
Despite minimal evidence of intravascular haemolysis, plasma bilirubin and hypoxanthine concentrations increased following ultra running. These changes were consistent with extravascular clearance of damaged red blood cells, suggesting splenic sequestration rather than acute mechanical destruction within the circulation.
The data indicate that ultra running accelerates red blood cell ageing primarily through inflammatory and oxidative mechanisms rather than mechanical trauma alone. Interleukin 6 driven systemic inflammation appears to be linked to oxidative molecular damage and downstream biomechanical dysfunction.
Translational Implications for Haematology
Importantly, the in vivo red blood cell damage observed after ultra endurance events mirrored molecular changes typically seen during ex vivo storage under blood bank conditions. This parallel provides translational insight into oxidative lesions that limit red blood cell survival in transfusion medicine and inflammatory disease settings.
Collectively, these findings identify potential biomarkers of exercise induced haemolysis and highlight red blood cell ageing as a measurable consequence of extreme endurance activity, with broader implications for understanding red blood cell lifespan and resilience under inflammatory stress.
Reference
Nemkov T et al. Long-distance trail running induces inflammatory-associated protein, lipid, and purine oxidation in red blood cells. bioRxiv. 2025:2025.04.09.648006.
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