Telomerase Therapy to Reverse Cardiovascular Senescence

Abstract

Cellular senescence of endothelial cells plays an important role in the development of vascular lesions that ultimately lead to an atherosclerotic plaque. This review focuses on the age-related changes of endothelial and vascular smooth muscle cells that contribute to vascular disease and discusses potential new targets that could rejuvenate the vascular system and thereby prevent or delay atherosclerosis.

Keywords: aging; atherosclerosis; cellular senescence; endothelium; modified MRNA; prevention; telomerase.

Figures

T. Z. Nazari-Shafti, M.D.

J. P. Cooke, M.D. Ph.D.

Figure 1.

Telomere structure. The repetitive nucleotide sequences at the end of each chromatid are called telomeres. The “end-replication problem” during DNA replication results in a 3-prime overhang of the DNA in the telomere region (a). The shelterin complex protects the telomeres from degradation. It consists of six subunits, namely telomeric repeat-binding proteins 1 and 2 (TRF1 and 2), TRF1-interacting nuclear factor 2 (TIN2), tripeptidyl peptidase 1 (TPP1), protection of telomeres protein 1 (POT1), and ras-related protein 1 (RAP1) (a). Each DNA replication cycle is associated with the loss of nucleotides at the telomeres (b) and may be compensated in some cell types by activation of telomerase, a polymerase complex consisting of a reverse transcriptase (TERT, telomerase reverse transcriptase) and a guide RNA (TERC, telomerase RNA component) (a). Telomerase is tightly regulated by the shelterin complex and expression and activation is detectable in embryonic or induced pluripotent stem cells as well as in most malignant cell types.

Figure 2.

Role of the senescent endothelium in the development of atherosclerosis. Various factors such as disturbed flow, metabolic perturbations, telomere attrition, epigenetic modification and accumulation of misfolded proteins accelerate the aging process in endothelial cells. Cellular senescence of endothelial cells plays an important role in the early stages of vascular lesion development. This ultimately leads to growth of atherosclerotic plaque by increased expression of proinflammatory surface markers, a decrease in nitric oxide (NO) production, and change of structural phenotype that compromises the barrier function of the endothelial monolayer of arterial vessel walls. The proposed target product profile described an agent that reverses senescence in endothelial cells by transient expression of TERT. eNOS: endothelial nitric oxygen synthase; VSMC: vascular smooth muscle cells; TERT: telomerase reverse transcriptase.