Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging

Aging Cell. 2024 Jun;23(6):e14138. doi: 10.1111/acel.14138. Epub 2024 Mar 12.

Abstract

It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.

Keywords: accelerated aging; endothelial; hypoxia; knockout; metabolism; mitochondrial disease; senescence; telomerase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging* / metabolism
  • Animals
  • Cellular Senescence* / genetics
  • Endothelial Cells* / metabolism
  • Mice
  • Mice, Knockout*
  • Mitochondria / metabolism
  • Telomerase* / genetics
  • Telomerase* / metabolism
  • Telomere* / genetics
  • Telomere* / metabolism

Substances

  • Telomerase
  • Tert protein, mouse