Vascular endothelium–targeted <i>Sirt7</i> gene therapy rejuvenates blood vessels and extends life span in a Hutchinson-Gilford progeria model

Abstract

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) <i>Lmna^G609G</i> mutation, called progerin. The <i>Lmna^f/f</i> ;TC mice with progerin expression induced by <i>Tie2-Cre</i> 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 <i>Sirt7</i> alleviates the inflammatory response caused by progerin in endothelial cells. Vascular endothelium-targeted <i>Sirt7</i> gene therapy, driven by an <i>ICAM2</i> promoter, improves neovascularization, ameliorates aging features, and extends life span in <i>Lmna^f/f</i> ;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.