Molecular biomedicineJul 6, 2026

Lack of Sirtuin 1 links long-term kidney disease inflammation to heart and blood vessel hardening

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jul 7, 2026

Abstract

Chronic kidney disease (CKD) is linked to accelerated aortic stenosis and increased calcification of aortic valves.

CKD is associated with accelerated ageing and heightened risk for aortic stenosis.
In human aortic valves, Sirtuin 1 (SIRT1) levels are decreased, while the NLRP3 pathway is activated specifically in valve interstitial cells.
An inverse relationship exists between SIRT1 expression and the risk of calcific aortic valve disease (CAVD).
SIRT1 deficiency leads to increased glycolysis, NF-κB activation, and NLRP3 inflammasome signaling, promoting osteogenic differentiation and calcification of valve interstitial cells.
In vivo studies show that inhibiting NLRP3 reduces valve calcification, highlighting the significance of the SIRT1-NF-κB-NLRP3 pathway in linking CKD to CAVD.
Semaglutide has been identified as a potential therapeutic agent that restores the SIRT1/NLRP3 balance and reduces calcification.

Simplified

Chronic kidney disease (CKD) markedly accelerates calcific aortic valve disease (CAVD), yet the underlying mechanisms and therapeutic targets remain poorly defined. Here, we integrate population-scale analyses, single-cell transcriptomics, genetic inference and functional experiments to identify a central role for Sirtuin 1 (SIRT1) in CKD-associated aortic valve calcification. Analysis of UK Biobank data linked CKD to accelerated ageing and increased aortic stenosis risk. Single-cell RNA sequencing of human aortic valves identified SIRT1 downregulation and NLRP3 pathway activation specifically in myofibroblast valve interstitial cells (VICs), coupled with enhanced senescence and osteogenic programmes. Consistently, genetic analyses, including eQTL-based Mendelian randomization, supported an inverse association between SIRT1 expression and CAVD risk. SIRT1 deficiency was associated with enhanced glycolysis, increased NF-κB activation and NLRP3 inflammasome signalling, accompanied by augmented osteogenic differentiation and calcification of VICs. Pharmacological or genetic inhibition of NLRP3 attenuated valve calcification in vivo, establishing the SIRT1-NF-κB-NLRP3 axis as a critical pathway linking CKD to CAVD. Finally, screening of anti-diabetic compounds identified semaglutide as a potent modulator that restores the SIRT1/NLRP3 balance and alleviates calcification in vitro and in vivo. These findings define a metabolic-inflammatory coupling mechanism underlying CKD-induced CAVD and highlight SIRT1 as a therapeutic target. Modulation of the SIRT1-NLRP3 axis, particularly by semaglutide, may represent a promising strategy for preventing valve calcification.