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Objective: The mechanisms responsible for the age-related increase in the incidence of calcific aortic valve stenosis (CAS) are unclear but may include telomere-driven cellular senescence. Because telomere length varies widely among individuals of the same age, we hypothesized that patients with shorter telomeres would be prone to develop CAS late in life., Methods and Results: Mean telomere length was measured in leukocytes from a cohort of 193 patients > or =70 years of age with and without CAS. Pilot experiments performed in 30 patients with CAS and controls pair-matched for age, sex, and presence or absence of coronary disease demonstrated significantly shorter telomeres in the CAS group both by Southern blot hybridization (5.75+/-0.55 kbp versus 6.27+/-0.7 kbp, P=0.0023) and by a quantitative polymerase chain reaction-based technique (relative telomere length 0.88+/-0.19 versus 1.0+/-0.19, P=0.01). This finding was then confirmed in the whole cohort (CAS n=64, controls n=129, relative telomere length=0.86+/-0.16 versus 0.94+/-0.12, P=0.0003). Both groups were comparable for potential confounding characteristics. Subgroup analysis according to the presence or absence of coronary disease demonstrated no association of this disorder with telomere length., Conclusions: In the elderly, calcific aortic stenosis, but not coronary disease, is associated with shorter leukocyte telomere length.

Objective: Telomerase plays a major role in the control of replicative capacity, a critical property for successful angiogenesis and maintenance of endothelial integrity. In this study, we examined the relationship between telomerase activity and endothelial cell proliferation as well as the regulation of this enzyme by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor-A (VEGF)., Methods and Results: Telomerase was repressed in endothelial cells freshly derived from intact endothelium, whereas activity was present during logarithmic growth in culture. In cultured human umbilical vein endothelial cells (HUVECs), mRNA levels of hTERT-the catalytic subunit of telomerase-and enzyme activity decreased reversibly on induction of quiescence. Treatment of quiescent HUVECs with FGF-2 restored telomerase activity in a time- and dose-dependent manner, whereas VEGF had no such effect, although both factors induced comparable mitogenic responses. FGF-2, but not VEGF, upregulated the mRNA levels for hTERT and for the hTERT gene transactivation factor Sp1. Serial passage in the presence of individual growth factors accelerated the accumulation of senescent cells in VEGF-treated cultures compared with cultures treated with FGF-2., Conclusions: FGF-2, but not VEGF, restores telomerase activity and maintains the replicative capacity of endothelial cells.