Age-associated inflammation is accompanied by JAK1-STAT1 signaling activation, megakaryocyte apoptosis, and enhanced thrombopoiesis in naturally aged mice.

BACKGROUND

Aging is accompanied by chronic inflammation and altered apoptotic signaling in megakaryocytes, the precursor cells of platelets. However, it remains unclear whether activation of the JAK1-STAT1 pathway is associated with age-related megakaryocyte apoptosis and thereby promotes thrombopoiesis.

OBJECTIVES

Bone marrow megakaryocytes were isolated from naturally aged C57BL/6J mice aged 4, 12, 18, 22, 24, and 26 months. Megakaryocyte proliferation, maturation, differentiation, and polyploidization were systematically characterized. Non-targeted proteomic profiling analysis was conducted to identify age-associated alterations in protein expression, while platelet counts and functional properties were simultaneously evaluated.

RESULTS

Klotho expression declined significantly with age (P < 0.05), whereas pro-inflammatory cytokines and oxidative stress markers increased. Megakaryocyte proliferation decreased, while maturation and differentiation were enhanced (P < 0.05). The proportion of highly polyploid (64 N) megakaryocytes increased markedly in 24- and 26-month-old mice (P < 0.05). Apoptosis was significantly elevated, as evidenced by increased Annexin V+ cells and Caspase-3 expression (P < 0.05). Proteomic analysis revealed pronounced upregulation of IL6ST (gp130; P < 0.0001), accompanied by increased JAK1 and STAT1 expression (P < 0.05) in 24-month-old mice compared with 4-month-old controls. These changes were associated with increased platelet production, reflected by elevated reticulocyte levels and peripheral platelet counts, as well as enhanced thrombin-induced platelet aggregation and activation (P < 0.05).

CONCLUSION

Age-associated inflammation is accompanied by activation of the IL6ST/JAK1-STAT1 signaling pathway, increased megakaryocyte apoptosis, and enhanced thrombopoiesis in aged mice. These findings suggest that inflammation-driven megakaryocyte remodeling may represent a compensatory mechanism for sustaining platelet production during aging and may contribute to the heightened thrombotic risk observed in older individuals.