The role of senescence, telomere dysfunction and shelterin in vascular aging

Abstract

In the United States and other westernized nations, CVDs are the leading cause of death in adults over 65 years of age. Large artery stiffness and endothelial dysfunction are increased with age and age-associated arterial dysfunction is an important antecedent of CVDs. One age-associated change that may contribute to vascular dysfunction and CVD risk is an increase in the number of resident senescent cells in the vasculature. Senescent cells display a pro-oxidant, pro-inflammatory phenotype known as the SASP. However, the mechanisms that drive the SASP and the vascular aging phenotype remain elusive. A putative mechanism is the involvement of oxidative stress and inflammation in telomere function. Telomeres are the end caps of chromosomes which are maintained by a six-protein complex known as shelterin. Disruption of shelterin can uncap telomeres and induce cellular senescence. Accordingly, in this review, we propose that oxidative stress and inflammation disrupt shelterin in vascular cells, driving telomere dysfunction and that this mechanism may be responsible for the induction of SASP. The proposed mechanisms may represent some of the initial changes that lead to vascular dysfunction in advanced age.

Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting protein

“…Furthermore, the cotransport into the cytoplasm of TERF2IP with TRF2 removes the latter from the nucleus, thereby promoting TL shortening, senescence, and subsequent apoptosis. Thus, inflammatory signaling and TL shortening are coupled through this mechanism, providing a new explanation for the linkage between the SASP and TL shortening (35). In addition, we found that the depletion of endothelial TERF2IP inhibited d-flow-induced plaque formation in mice.…”

miR‑20b inhibits the senescence of human umbilical vein endothelial cells through regulating the Wnt/β‑catenin pathway via the TXNIP/NLRP3 axis

“…Manifested as growth stagnation and changes in gene expression profiles, cell senescence is of tissues and organs, is the major risk factor for developing cardiovascular disease (6). A previous study demonstrated that aging of endothelial cells is triggered by a variety of factors such as oxidative stress, ionizing radiation and telomere dysfunction (25). Oxidative stress plays a crucial role in the occurrence of endothelial dysfunction and is characterized by increased oxygen free radical level and damage to organs and tissues (26,27).…”

Aging, Cerebrovascular Burden, and Cognitive Decline

“…The shortened telomeres in mouse vascular tissue have been shown to be sufficient to induce endothelial dysfunction [54], whereas human VSMCs still have a normal phenotype sustaining plaque stability regardless of telomere length [55]. Although telomere shortening is common in vascular aging and CVD, it remains unclear whether telomere shortening is sufficient to lead to cellular senescence and vascular degeneration in aged vessels [56].…”