Resistance to age-related hypercoagulability: insights from the naked mole rat

Background: Human aging is characterized by endothelial dysfunction that drives a systemic prothrombotic shift. In contrast, the long-lived naked mole rat (NMR) represents a unique model of delayed aging, exhibiting a notable resistance to age-related pathologies. However, while its cardiovascular stability is well-documented, the NMR hemostatic profile across its lifespan remains unexplored. Objectives: To assess whether NMRs undergo age-related hypercoagulability and to compare their hemostatic trajectory with that of humans. Methods: We compared young (2-year-old) and aged (20-year-old) NMRs. Assessments included clotting factor quantification, endothelial markers, and integrative thrombin generation assays. Plasma from human volunteers (20-year-old vs 80-year-old NMRs) were used as a reference point for typical hemostatic aging. Results: NMRs maintained cellular blood composition and showed no age-related increase in markers of endothelial activation (including von Willebrand factor, factor VIII, tissue factor pathway inhibitor, soluble thrombomodulin, and tissue plasminogen activator). While aged NMRs showed a modest increase in fibrinogen and D-dimer, this rise was significantly lower than the 2- to 5-fold elevations seen in elderly humans. Most notably, thrombin generation potential remained identical between young and aged NMRs. In contrast, humans exhibited a marked age-dependent shift toward accelerated and heightened thrombin production. Conclusion: NMRs possess the ability to bypass the pathologic clotting shifts that drive thrombotic events in humans, effectively decoupling chronologic aging from prothrombotic risk. By maintaining stable endothelial coagulation markers and an unchanged thrombin-forming capacity throughout their lifespan, NMRs appear naturally protected against age-dependent hypercoagulability.