Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice

Area of Science:

• Cellular senescence
• Endothelial cell biology
• Metabolic disorders

Background:

• Cellular senescence contributes to age-related diseases, including metabolic dysfunction.
• The role of senescent endothelial cells in metabolic disorders is not well understood.
• Previous work showed senolytic drugs alleviate obesity-induced metabolic dysfunction.

Purpose of the Study:

• To investigate the contribution of senescent endothelial cells to metabolic disorders.
• To determine if selective elimination of senescent endothelial cells can ameliorate metabolic dysfunction.
• To explore senescent endothelial cells as a therapeutic target for metabolic disease.

Main Methods:

• Generated Tie2-Cre;p16^Ink4a-LOX-ATTAC mice for inducible, selective elimination of senescent endothelial cells.
• Administered senolytic drug fisetin to obese mice and mice transplanted with senescent endothelial cells.
• Assessed adipose tissue inflammation and metabolic parameters, including glucose metabolism.

Main Results:

• Targeted removal of senescent endothelial cells from obese mice reduced inflammation and improved metabolic dysfunction.
• Transplantation of senescent endothelial cells into lean mice induced adipose tissue inflammation and metabolic dysfunction.
• Fisetin treatment reduced senescent endothelial cell burden and improved glucose metabolism in obese or senescent cell-transplanted mice.

Conclusions:

• Senescent endothelial cells play a critical role in driving metabolic dysfunction.
• Selective elimination of senescent endothelial cells is a promising therapeutic strategy for metabolic diseases.
• Targeting senescent endothelial cells with senolytics like fisetin can improve metabolic health.