Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism and cardiovascular health. However, its upregulation in aging and age-related disorders suggests the presence of FGF21 resistance. This study aimed to elucidate the mechanisms underlying senescence-associated FGF21 resistance in human umbilical vein endothelial cells (HUVECs) and to explore potential therapeutic interventions. Transcriptomic analysis revealed a significant reduction in the number of FGF21-regulated genes in senescent HUVECs compared to young cells, indicating the onset of FGF21 resistance. In young HUVECs, FGF21 inhibited inflammatory cytokines and upregulated mitochondrial ribosomal protein genes. Conversely, senescent HUVECs showed a downregulation of β-klotho, an essential co-receptor for FGF21, at the cell membrane, concomitant with an upregulation of ADAM10, a protease involved in β-klotho degradation. These changes were also observed in aged mouse aortas. ADAM10 was shown to bind directly to β-klotho and promote its degradation, contributing to FGF21 resistance. Inhibition of ADAM10 or overexpression of β-klotho restored FGF21 responsiveness in senescent HUVECs. Moreover, pharmacologically high concentrations of FGF21 were effective in overcoming resistance and restoring its regulatory effects on senescent cells. These findings suggest that ADAM10-mediated degradation of β-klotho is a central mechanism in the development of FGF21 resistance, and that targeting the ADAM10/β-klotho axis could represent a novel therapeutic approach to restore FGF21 sensitivity. Pharmacological administration of FGF21 may hold promise in treating vascular aging and its associated cardiovascular pathologies.

成纤维细胞生长因子 21 （FGF21） 是新陈代谢和心血管健康的关键调节因子。然而，它在衰老和年龄相关疾病中的上调表明存在 FGF21 耐药性。本研究旨在阐明人脐静脉内皮细胞 （HUVEC） 中衰老相关 FGF21 耐药的机制，并探索潜在的治疗干预措施。转录组学分析显示，与年轻细胞相比，衰老 HUVEC 中 FGF21 调节基因的数量显着减少，表明 FGF21 耐药性的开始。在年轻的 HUVEC 中，FGF21 抑制炎性细胞因子并上调线粒体核糖体蛋白基因。相反，衰老的 HUVEC 显示细胞膜上 β-klotho（FGF21 的重要共受体）下调，同时上调 ADAM10（一种参与 β-klotho 降解的蛋白酶）。在老年小鼠主动脉中也观察到这些变化。ADAM10 被证明直接与 β-klotho 结合并促进其降解，从而导致 FGF21 耐药。抑制 ADAM10 或 β-klotho 过表达可恢复衰老 HUVEC 的 FGF21 反应性。此外，药理学上高浓度的 FGF21 可有效克服耐药性并恢复其对衰老细胞的调节作用。这些发现表明，ADAM10 介导的 β-klotho 降解是 FGF21 耐药性发展的核心机制，靶向 ADAM10/β-klotho 轴可能代表一种恢复 FGF21 敏感性的新型治疗方法。FGF21 的药物给药可能在治疗血管衰老及其相关的心血管病变方面具有前景。