Senescence-associated metabolic alterations aggravate calcific aortic valve disease.

Summary

Integrating human valve transcriptomics, genetically modified mice, and human proteomics/MR, the study shows that endothelial NAD+ salvage failure (via NAMPT suppression) triggers inflammaging, while macrophage NAMPT and extracellular NAMPT amplify endothelial inflammation through TLR4. Early nicotinamide mononucleotide repletion reduced inflammation and calcification, and genetic/epidemiologic data linked elevated plasma NAMPT to higher aortic stenosis risk.

Key Findings

• Valve endothelial cells in aged human tissue showed the steepest suppression of NAMPT-mediated NAD+ salvage, causing NAD+ depletion, SIRT1 inactivation, NF-κB hyper-acetylation, and an ICAM-1–rich inflammaging phenotype.
• Macrophages upregulated NAMPT and secreted extracellular NAMPT that signaled via TLR4 on endothelial cells, amplifying inflammation; elevated plasma NAMPT was associated with higher aortic stenosis risk by UK Biobank proteomics and Mendelian randomization.
• Myeloid Nampt deletion accelerated leaflet calcification via FOXA2 acetylation and MMP13-mediated matrix disruption; early (but not late) nicotinamide mononucleotide therapy restored NAD+, reduced inflammation, and attenuated calcification.

Clinical Implications

Findings support early-stage trials of NAD+ repletion strategies and biomarker-driven risk stratification using plasma NAMPT; they also motivate selective NAMPT/TLR4 pathway modulation to blunt inflammaging in valve disease.

Limitations

• Predominantly preclinical with translational uncertainty regarding dose, timing, and safety of NAD+ or NAMPT-targeted interventions
• Heterogeneity of human valve disease etiology may influence generalizability

Future Directions

Early-phase clinical trials of NAD+ repletion in at-risk valve disease; development of NAMPT/TLR4 pathway modulators; longitudinal studies linking plasma NAMPT to progression and outcomes.