Endothelial cell‐specific reduction in mTOR ameliorates age‐related arterial and metabolic dysfunction

• Published in: Aging cell 2024-02, Vol.23 (2), p.e14040-n/a
• Main Authors: Islam, Md Torikul, Hall, Shelby A., Dutson, Tavia, Bloom, Samuel I., Bramwell, R. Colton, Kim, John, Tucker, Jordan R., Machin, Daniel R., Donato, Anthony J., Lesniewski, Lisa A.
• Format: Article
• Language: English
• Subjects: Adipose tissue; Age; Aging; Aging - metabolism; Animals; arterial stiffness; Arteries; Arteries - metabolism; Beta cells; Clonal deletion; Coronary vessels; Drug development; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Endothelium, Vascular; Females; Gene expression; Gluconeogenesis; Glucose; Glucose tolerance; Inflammation; Insulin; Kinases; Laboratory animals; Lipids; Mammals - metabolism; metabolic function; Metabolism; Mice; Nitric oxide; Older people; Ostomy; Oxidative Stress; Physiology; Rapamycin; Senescence; Sirolimus - pharmacology; Smooth muscle; TOR protein; TOR Serine-Threonine Kinases - metabolism; vasodilation; Vasodilation - physiology; Veins & arteries
• ISSN: 1474-9718; 1474-9726; 1474-9726
• DOI: 10.1111/acel.14040

Systemic inhibition of the 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 activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell‐specific deletion of mTOR reduced protein expression by 60–70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium‐dependent dilation (EDD) in old mice, indicating an improvement in age‐related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial‐rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development. Although systemic mTOR inhibition improves age‐related physiological dysfunction, the cell types that mediate the beneficial effects remain elusive. Here, we demonstrate that endothelial cell‐specific reduction of mTOR ameliorates arterial and metabolic function in old age. These improvements are concomitant with reduced senescence burden, inflammation, and oxidative stress in arteries, lung, adipose tissue, and liver. These results support the exploration of therapeutic strategies targeting endothelial mTOR signaling.