Endothelial cell-specific reduction of mTOR ameliorates age-related arterial and metabolic dysfunction

Md Torikul Islam¹, Shelby A Hall¹, Tavia Dutson², Samuel I Bloom¹, R Colton Bramwell², John Kim², Jordan Tucker², Daniel R Machin², Anthony J Donato^1,2,3,4, and Lisa A Lesniewski^1,2,3

Abstract

Systemic inhibition of mammalian target of rapamycin (mTOR) delays aging and many
age-related conditions including arterial and metabolic dysfunction. However, the mechanisms
and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate
that the vascular endothelium is a major contributor to arterial p-S6K, a downstream effector of
mTOR, that is markedly enhanced by advancing age. Induction of endothelial cell (EC)-specific
deletion of mTOR reduced protein expression by 60-70%, which did not significantly alter
arterial and metabolic function in young mice. Notably, endothelial mTOR reduction reversed
arterial stiffness and improved endothelium-dependent dilation (EDD) in old mice, which are the
major hallmarks of age-related arterial dysfunction. In old mice, improved arterial function was
concomitant to suppressed cellular senescence, inflammation and oxidative stress in arteries.
Reduction in endothelial mTOR also improved glucose tolerance in old mice primarily due to
attenuated hepatic gluconeogenesis but independent of peripheral insulin resistance and
pancreatic beta cell function. This intervention also improved lipid tolerance in old mice without
changing baseline plasma lipids. Lastly, we found that endothelial mTOR reduction suppressed
gene expression of senescence and inflammatory markers in endothelial rich (i.e., lung) and
metabolic (i.e., liver and adipose tissue) organs, which may have contributed to the
improvement in metabolic function in old mice. This is the first evidence demonstrating a critical
role of endothelial mTOR in arterial and metabolic function in old mice and has implications for
future drug development.