Hutchinson–Gilford progeria syndrome (HGPS) is caused by an LMNA mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin‐induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA‐approved drug, should be further evaluated as a drug candidate in HGPS therapy.

中文翻译：

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JAK1/2 抑制剂鲁索替尼可延缓过早衰老表型。

哈钦森-吉尔福德早衰综合征 (HGPS) 是由LMNA引起的导致产生异常早老蛋白的突变。患有 HGPS 的儿童表现出过早衰老的表型，平均寿命为 13 年。我们早些时候发现，跨膜蛋白 PLA2R1 的靶向克服了衰老并改善了早衰小鼠模型的表型。PLA2R1 正在调节 JAK/STAT 信号，但我们还不知道直接靶向该通路是否会影响细胞和体内早衰表型。在这里，我们表明用鲁索替尼抑制 JAK1/2 可以挽救表达 progerin 的人类正常成纤维细胞中 progerin 诱导的细胞周期停滞、细胞衰老和畸形细胞核。此外，ruxolitinib 给药可减少几种过早衰老表型：骨折、骨矿物质含量、握力、以及在早衰症小鼠模型中增加存活率的趋势。因此，我们建议将 FDA 批准的药物鲁索替尼作为 HGPS 治疗的候选药物进行进一步评估。