BACKGROUND: Calcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells. METHODS: Human control and calcific aortic valve disease aortic valve leaflets and patient-specific human aortic valve interstitial cells were used in in vivo and in vitro calcification assays. Loss of function experiments in human aortic valve interstitial cells and cells isolated from RESULTS: TERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary human aortic valve interstitial cells. CONCLUSIONS: TERT's non-canonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification.