2. Academic Validation
  3. Endothelial senescent-cell-specific clearance alleviates metabolic dysfunction in obese mice

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

  • Cell Metab. 2025 Dec 2;37(12):2455-2465.e6. doi: 10.1016/j.cmet.2025.10.009.
Masayoshi Suda 1,  Selim Chaib 2,  Larissa G P Langhi Prata 2,  Yi Zhu 3,  Utkarsh Tripathi 4,  Karl H Paul 5,  Allyson K Palmer 6,  Tamar Pirtskhalava 2,  Vagisha Kulshreshtha 7,  Christina L Inman 5,  Kurt O Johnson 4,  Nino Giorgadze 8,  Runqing Huang 9,  Carolyn M Roos 9,  Luisa F Leon-Sanchez 9,  Jordan D Miller 9,  Thomas White 4,  Linshan Laux 10,  Laura J Niedernhofer 10,  Paul D Robbins 10,  Sara Espinoza 8,  Nicolas Musi 11,  Sundeep Khosla 4,  Stefan G Tullius 12,  Tamar Tchkonia 2,  James L Kirkland 13
Affiliations

Affiliations

  • 1 Center 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. Electronic address: [email protected].
  • 2 Center 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.
  • 3 Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 4 Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA.
  • 5 Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA.
  • 6 Division of Hospital Internal Medicine, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA.
  • 7 Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA.
  • 8 Center for Advanced Gerotherapeutics, Cedars-Sinai Medical Center, Pacific Design Center, 8687 Melrose Avenue, West Hollywood, CA 90048, USA.
  • 9 Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA; Department of Cardiovascular Surgery, Mayo Clinic College of Medicine, 200 First St., S.W., Rochester, MN 55905, USA.
  • 10 Masonic Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, E, Nils Hasselmo Hall, 312 Church Street S.E., Minneapolis, MN 55455, USA.
  • 11 Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
  • 12 Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 45 Francis St., Boston, MA 02115, USA.
  • 13 Center 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. Electronic address: [email protected].
PMID: 41270738 DOI: 10.1016/j.cmet.2025.10.009
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.

Keywords

SASP factors; TNFα; cellular senescence; diabetes; endothelial cells; fisetin; glucose intolerance; obesity; p16(Ink4a); senolytics.

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