Overview of Vascular Calcification and Fisetin’s Role

Vascular calcification is a non‐atherosclerotic process where phosphate in the bloodstream precipitates calcium crystals within the arterial wall, leading to stiff, narrow vessels. Unlike cholesterol‐driven plaque, calcification arises from dysregulated mineral metabolism, especially in conditions like chronic kidney disease and systemic inflammation. Recent research highlights fisetin, a flavonol found in various plants, as a promising senolytic that may mitigate this process.

How Calcification Develops in Arteries

Under healthy conditions, arteries maintain flexibility through balanced regulatory proteins. However, when vascular smooth muscle cells (VSMCs) become senescent due to excessive phosphate or glucose, they shift toward an osteogenic phenotype. Key markers of this shift include upregulated BMP2, CBFA1 and ALPL, which drive calcium crystal deposition.

Fisetin’s Mechanism of Action

The core discovery centers on fisetin’s ability to elevate levels of dual‐specificity phosphatase 1 (DUSP1). DUSP1 dephosphorylates and deactivates the p38 mitogen‐activated protein kinase (p38/MAPK) pathway, a major driver of calcification. In cellular experiments, introducing as little as one micromole of fisetin under pro‐calcific conditions brought calcification markers almost back to baseline.

Key Experimental Findings

• Cell Culture: Human aortic cells exposed to phosphate and calcium showed significant increases in BMP2, CBFA1 and ALPL. Fisetin reduced these markers to control levels.
• Senescence Model: In a uremic cell model mimicking chronic kidney disease, fisetin lowered both calcification and senescence markers.
• Mouse Aortae Explants: Ex vivo aortae in pro‐calcific media demonstrated reduced mineral deposition when treated with fisetin.
• In Vivo Mice: Mice given cholecalciferol to induce calcification exhibited near‐normal arterial appearances when co‐treated with fisetin.

Implications for Longevity and Vascular Health

These findings suggest that senolytic compounds targeting cell‐signaling pathways can address vascular aging at its root. By clearing senescent cells and blocking osteogenic signals, fisetin may preserve arterial elasticity in at‐risk populations, such as those with chronic kidney disease.

Next Steps and Clinical Considerations

• Clinical Trials: Although fisetin is an over‐the‐counter supplement, rigorous studies are needed to confirm dosing, long‐term safety and sex‐based responses in humans.
• Model Limitations: Existing animal models don’t fully capture vitamin D depletion seen in kidney disease, warranting tailored human research protocols.
• Combination Therapies: Exploring fisetin alongside phosphate binders or anti‐inflammatory agents may enhance vascular protection.

By targeting the root causes of vascular calcification rather than its late‐stage symptoms, fisetin represents a promising avenue for extending healthy vascular lifespan.

Key points

• Fisetin increases DUSP1 to inhibit p38/MAPK, reducing vascular calcification markers in cells.
• Mouse studies confirm fisetin’s ability to prevent arterial calcium deposition in vivo.
• Targeting senescence pathways offers a novel intervention for blood vessel stiffening, especially in CKD models.