Telomerase Therapy Reverses Vascular Senescence and Extends Lifespan in Progeria Mice

The effect of HGPS on endothelial cells (HGPS ECs) and their modulation of neighboring vascular smooth muscle cells (VSMCs) is relatively unexplored. Given the primacy of the endothelium in vascular homeostasis, we hypothesized that targeting the causes of senescence in HGPS ECs would be a promising therapeutic avenue for HGPS. The ribonucleoprotein telomerase maintains telomere length. We have previously shown that transient delivery of modified mRNA encoding human telomerase (hTERT) in aged human cells can extend telomere length, reverse features of senescence and restore replicative capacity. Here we show that hTERT treatment of HGPS ECs extends telomere length, restores endothelial function and gene expression, increases sirtuin 1 (SIRT1) expression, reduces markers of DNA damage, and reverses adverse paracrine effects on vascular smooth muscle cells. Furthermore, we show that mTERT therapy in a mouse model of HGPS reverses endothelial activation, reduces endothelial DNA damage, and extends lifespan. Our work suggests a novel approach for age-related vascular diseases.