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Updated: Jan 10, 2026
Isolation and Identification of Vascular Endothelial Cells from Distinct Adipose Depots for Downstream Applications
Published on: June 10, 2022
Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice
Masayoshi Suda1, Selim Chaib2, Larissa G P Langhi Prata2
1Center for Advanced Gerotherapeutics, Cedars-Sinai Medical Center, Pacific Design Center, 8687 Melrose Avenue, West Hollywood, CA 90048, USA; Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract:
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 (p16Ink4a-LOX-ATTAC mice) with Tie2-Cre mice (Tie2-Cre;p16Ink4a-LOX-ATTAC) to enable identification and inducible, selective elimination of p16Ink4a+ senescent endothelial cells. Targeted removal of senescent endothelial cells from obese Tie2-Cre;p16Ink4a-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 p16Ink4a+ senescent endothelial cells is a potential therapeutic strategy for metabolic disease.
Insights
Senescent endothelial cells drive metabolic dysfunction and inflammation. Eliminating these cells improves metabolic health, offering a potential therapeutic strategy for metabolic diseases.
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;p16Ink4a-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.
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