Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12

Sep 2, 2025bioRxiv : the preprint server for biology

Fisetin treatment may reverse age-related blood vessel problems linked to a specific aging-related factor

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Abstract

Senescent endothelial cells displayed elevated expression of senescence-associated secretory phenotype (SASP) factors, particularly CXCL12, which was reversed by fisetin supplementation.

Aging is associated with impaired endothelial function due to vascular cell senescence and reduced nitric oxide availability.
Circulating levels of SASP factors, including CXCL12, were found to contribute to age-related endothelial dysfunction.
Plasma from older mice induced vascular cell senescence and increased oxidative stress, which impaired endothelial function.
Fisetin treatment mitigated the effects of aging on endothelial cells by reversing elevated SASP factor expression and improving endothelial function.
CXCL12 was shown to play a significant role in promoting endothelial-to-mesenchymal transition, contributing to vascular dysfunction.

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BACKGROUND: Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging.

METHODS: Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and withoutsenolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Circulating levels of SASP factors were measured to validate transcriptional changes. Plasma exposure and protein addition and inhibiton experiments were conducted in isolated mouse arteries and cultured human endothelial cells to determine the causal role of the circulating SASP milieu and specific SASP factors in mediating endothelial dysfunction and underlying mechanisms-of-action. in vivo

RESULTS: Senescent endothelial cells exhibited elevated expression of SASP factors, particularly, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin. Cxcl12

CONCLUSIONS: These results identify the SASP and CXCL12 as drivers of age-related endothelial dysfunction and establish mechanisms of senolytic intervention with fisetin supplementation.

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Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12

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