近日，美国罗伯特和阿琳·科戈德老龄研究中心教授James L. Kirkland及其研究团队提出了内皮衰老细胞特异性清除减轻肥胖小鼠的代谢功能障碍。相关论文于2025年11月20日发表于国际顶尖学术期刊《细胞—代谢》杂志上。

课题组之前已经证明，通过抗衰老药物消除衰老细胞可以减轻肥胖引起的代谢功能障碍。

然而，衰老的内皮细胞对代谢紊乱的贡献仍然是未知的。因此，课题组将允许选择性消除衰老细胞的小鼠（p16^Ink4a-LOX-ATTAC mice）与Tie2-Cre小鼠（Tie2-Cre;p16^Ink4a-LOX-ATTAC）杂交，以鉴定和诱导选择性消除p16^Ink4a+衰老内皮细胞。肥胖Tie2-Cre衰老内皮细胞的靶向清除p16^Ink4a-LOX-ATTAC小鼠减轻了促炎衰老相关的分泌表型，减轻了代谢功能障碍。相反，将衰老的内皮细胞移植到瘦小鼠体内会引起脂肪组织炎症和代谢功能障碍。与这些发现一致的是，在其他衰老细胞类型中靶向衰老内皮细胞的抗衰老药物非瑟酮，在肥胖小鼠或移植了衰老单主题内皮细胞的小鼠中，减少了脂肪组织衰老内皮细胞的丰度，改善了葡萄糖代谢。他们的研究结果表明，特异性消除p16^Ink4a+衰老内皮细胞是代谢性疾病的潜在治疗策略。

据介绍，衰老细胞的积累是一生中多种疾病的关键因素，包括代谢功能障碍。

附：英文原文

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

Author: Masayoshi Suda, Selim Chaib, Larissa G.P. Langhi Prata, Yi Zhu, Utkarsh Tripathi, Karl H. Paul, Allyson K. Palmer, Tamar Pirtskhalava, Vagisha Kulshreshtha, Christina L. Inman, Kurt O. Johnson, Nino Giorgadze, Runqing Huang, Carolyn M. Roos, Luisa F. Leon-Sanchez, Jordan D. Miller, Thomas White, Linshan Laux, Laura J. Niedernhofer, Paul D. Robbins, Sara Espinoza, Nicolas Musi, Sundeep Khosla, Stefan G. Tullius, Tamar Tchkonia, James L. Kirkland

Issue&Volume: 2025-11-20

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.

DOI: 10.1016/j.cmet.2025.10.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00443-7