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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (p16 Ink4a -LOX-ATTAC mice) with Tie2-Cre mice (Tie2-Cre;p16 Ink4a -LOX-ATTAC) to enable identification and inducible, selective elimination of p16 Ink4a+ senescent endothelial cells. Targeted removal of senescent endothelial cells from obese Tie2-Cre;p16 Ink4a -LOX-ATTAC mice attenuated the pro-inflammatory senescence-associated secretory phenotype and alleviated metabolic dysfunction. Conversely, transplanting senescent endothelial cells into lean mice caused adipose tissue inflammation and metabolic dysfunction. Consistent with these findings, the senolytic, fisetin, which targets senescent endothelial cells among other senescent cell types, reduced adipose tissue senescent endothelial cell abundance and improved glucose metabolism in obese mice or mice transplanted with senescent mouse endothelial cells. Our results indicate that specifically eliminating p16 Ink4a+ senescent endothelial cells is a potential therapeutic strategy for metabolic disea

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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