Senescence-associated metabolic alterations aggravate calcific aortic valve disease

BACKGROUND AND AIMS: Calcific aortic valve disease lacks effective pharmacotherapy and is tightly linked to ageing. Since nicotinamide adenine dinucleotide (NAD+) steadily declines with age, this study investigated whether cell-type-specific disruption of NAD+ salvage metabolism drives valvular inflammation and calcification. METHODS: This study combined integrated human aortic-valve bulk RNA-seq with single-cell transcriptomics to map NAD+ pathways. Effects of nicotinamide phosphoribosyltransferase (NAMPT) loss or gain were tested in heterozygous, endothelial-specific, and myeloid-specific Nampt-knockout mice and in cultured valvular endothelial cells and macrophages. Therapeutic potential was evaluated with early vs late nicotinamide mononucleotide supplementation. UK Biobank proteomics and Mendelian randomization examined associations between circulating NAMPT and aortic stenosis. RESULTS: In aged human valves, NAMPT-mediated salvage exhibited the steepest suppression within valvular endothelial cells, triggering NAD+ depletion, SIRT1 inactivation, and hyper-acetylated nuclear factor kappa-B, thereby resulting in an ICAM-1-rich inflammaging profile. Recruited macrophages displayed paradoxical NAMPT up-regulation and secreted extracellular NAMPT that signalled through TLR4 on endothelial cells, amplifying valvular inflammation. Genomic analyses revealed that elevated plasma NAMPT conferred a higher risk of aortic stenosis. On the other side, myeloid Nampt deletion generated a senescent phenotype marked by FOXA2 acetylation and MMP13-driven collagen disruption, accelerating leaflet calcification. Early nicotinamide mononucleotide therapy restored valvular NAD+, dampened endothelial inflammation, limited macrophage infiltration, and attenuated calcification, while delayed treatment was less effective. CONCLUSIONS: Calcific aortic valve disease is initiated by endothelial NAD+ insufficiency and magnified by metabolically diverse macrophages. This compartmentalized NAD+ circuit couples inflammaging to matrix catastrophe. Early NAD+ repletion via nicotinamide mononucleotide and interventions targeting NAMPT warrant clinical evaluation as potential therapies for calcific aortic valve disease.