Human TERT mRNA

Researchers' interest in treating vascular aging with mRNA encoding human telomerase (TERT) stems from studies over the past 25 years that have linked vascular aging to endothelial disease that promotes the atherosclerotic process. For example, Chang and Harley measured telomere length in human cadaveric iliac and mammary arteries and found that telomere length shortens with age. In addition, telomeres in the iliac arteries (which are more susceptible to atherosclerosis) were shorter at all ages. Aged human endothelial cells produce less nitric oxide (NO), more superoxide anions (O2-), synthesize more adhesion molecules, have increased adhesion to monocytes, and have reduced proliferation capacity and ability to comply with fluid shear stress. These properties promote vascular inflammation and atherogenesis. In contrast, when telomerase was overexpressed using a retroviral vector, telomere lengthening was associated with retroviral treatment of age-related endothelial disease and restored endothelial cell proliferation and function.

However, retroviral integration of telomerase into human cells may raise concerns about growth disorders. Therefore, the researchers used mRNA TERT to transiently express telomerase, increase telomere length, enhance replication capacity, and reverse signs of senescence in human cells. Telomerase activity did not last more than 72 hours after each transfection (as measured by TRAP). Nevertheless, 1-3 treatments increased telomere length in fibroblasts, endothelial cells, and myoblasts, promoted cell population doublings, and reduced expression of the senescence marker β-galactosidase (β gal), although these cells eventually reached a growth plateau (Figure 1).

Figure 1. Growth curves of human fibroblasts treated once, twice or thrice in succession at 48 h interval with human telomerase (TERT) mRNA, catalytically inactive (CI) TERT mRNA, or vehicle only, shows increase in population doubling. (Chanda P K, Sukhovershin R, Cooke J P., 2021)