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.