Anti-aging & Regenerative Medicine Research Institution, School of Life Sciences, Shandong University of Technology, Zibo 255049, China.
National Engineering Research Center for Biotechnology (Shenzhen), Carson International Cancer Center, Medical Research Center, Shenzhen University Health Science Center, Shenzhen, China.
Sci Adv. 2020 Feb 19;6(8):eaay5556. doi: 10.1126/sciadv.aay5556. eCollection 2020 Feb.
Vascular dysfunction is a typical characteristic of aging, but its contributing roles to systemic aging and the therapeutic potential are lacking experimental evidence. Here, we generated a knock-in mouse model with the causative Hutchinson-Gilford progeria syndrome (HGPS) mutation, called progerin. The ;TC mice with progerin expression induced by exhibit defective microvasculature and neovascularization, accelerated aging, and shortened life span. Single-cell transcriptomic analysis of murine lung endothelial cells revealed a substantial up-regulation of inflammatory response. Molecularly, progerin interacts and destabilizes deacylase Sirt7; ectopic expression of alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium-targeted gene therapy, driven by an promoter, improves neovascularization, ameliorates aging features, and extends life span in ;TC mice. These data support endothelial dysfunction as a primary trigger of systemic aging and highlight gene therapy as a potential strategy for the clinical treatment of HGPS and age-related vascular dysfunction.
血管功能障碍是衰老的典型特征，但它对系统性衰老的贡献及其治疗潜力缺乏实验证据。在这里，我们生成了一种带有亨廷顿舞蹈病 1 型（Huntington disease type 1）突变的敲入小鼠模型，称为 progerin。表达 progerin 的 ;TC 小鼠表现出微血管和新血管生成缺陷、加速衰老和缩短寿命。对小鼠肺内皮细胞的单细胞转录组分析显示，炎症反应显著上调。分子上，progerin 相互作用并破坏脱乙酰酶 Sirt7；内皮细胞中 progerin 引起的炎症反应可以通过异位表达 来缓解。由 启动子驱动的血管内皮细胞靶向 基因治疗可改善新血管生成，改善衰老特征，并延长 ;TC 小鼠的寿命。这些数据支持内皮功能障碍作为系统性衰老的主要触发因素，并强调基因治疗作为治疗 HGPS 和与年龄相关的血管功能障碍的一种潜在策略。
