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

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 disease.