RT Journal Article SR Electronic T1 Vascular endothelium–targeted Sirt7 gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model JF Science Advances JO Sci Adv FD American Association for the Advancement of Science SP eaay5556 DO 10.1126/sciadv.aay5556 VO 6 IS 8 A1 Sun, Shimin A1 Qin, Weifeng A1 Tang, Xiaolong A1 Meng, Yuan A1 Hu, Wenjing A1 Zhang, Shuju A1 Qian, Minxian A1 Liu, Zuojun A1 Cao, Xinyue A1 Pang, Qiuxiang A1 Zhao, Bosheng A1 Wang, Zimei A1 Zhou, Zhongjun A1 Liu, Baohua YR 2020 UL http://advances.sciencemag.org/content/6/8/eaay5556.abstract AB 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) LmnaG609G mutation, called progerin. The Lmnaf/f;TC mice with progerin expression induced by Tie2-Cre 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 Sirt7 alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium–targeted Sirt7 gene therapy, driven by an ICAM2 promoter, improves neovascularization, ameliorates aging features, and extends life span in Lmnaf/f;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.