Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor...

Area of Science:

• Cardiovascular Biology
• Aging Research
• Cellular Senescence

Background:

• Advancing age is the primary risk factor for cardiovascular diseases (CVDs), largely due to progressive vascular endothelial dysfunction.
• Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by increasing oxidative stress and inflammation, reducing nitric oxide (NO) bioavailability.
• The specific molecular changes in senescent endothelial cells (ECs) and their precise role in aging-related endothelial dysfunction are not fully understood.

Purpose of the Study:

• To identify EC-related signaling pathways and endothelial-associated SASP factors contributing to aging-related endothelial dysfunction.
• To investigate the impact of these factors on endothelial function in aging.
• To explore the potential of senolytic treatment with fisetin to reverse these age-related changes.

Main Methods:

• Single-cell transcriptomics on mouse aortas from young and old mice, with and without in vivo fisetin treatment.
• Measurement of circulating SASP factors to assess systemic changes.
• Plasma exposure experiments on isolated mouse arteries and cultured human aortic ECs to determine causal roles of SASP factors.

Main Results:

• Senescent ECs showed elevated SASP factor expression, notably CXCL12, which fisetin reversed.
• Circulating CXCL12 levels correlated with EC senescence and were reduced by fisetin.
• Plasma from old mice impaired endothelial function, induced senescence, reduced NO, increased oxidative stress, and promoted endothelial-to-mesenchymal transition, effects partially mediated by CXCL12 and prevented by fisetin.

Conclusions:

• The SASP and CXCL12 are identified as key drivers of age-related endothelial dysfunction.
• Mechanisms of senolytic intervention with fisetin involve reversing SASP-associated endothelial dysfunction.
• This study provides insights into molecular targets for mitigating age-related vascular decline.