Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA.
Cells. 2024 Oct 18;13(20):1727. doi: 10.3390/cells13201727.
Given that the extracellular matrix polymer hyaluronan (HA) has been implicated in longevity, we asked whether 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, impacts lifespan in mice. We designed a prospective study of long-term administration of 4-MU with conventional C57BL/6J mice. We find that 4-MU extends median survival from 122 weeks (control) to 154 weeks (4-MU), an increase of 32 weeks ( < 0.0001 by Log-rank Mantel Cox test). The maximum lifespan of 4-MU treated mice increased from 159 to 194 weeks. In tandem with these effects, 4-MU enhances insulin sensitivity, a metabolic parameter known to regulate lifespan, as measured by insulin tolerance testing (ITT) as well as frequent sampling intra venous glucose tolerance tests (FSIVGTTs). We further observed that 4-MU treated mice weigh less while consuming the same amount of food, indicating that 4-MU treatment alters energy expenditure. However, we do not observe changes in tissue HA content in this model. We conclude that 4-MU promotes insulin sensitivity and longevity but that the underlying mechanism, and the contribution of HA is unclear. 4-MU, already approved in various countries for hepatobiliary conditions, is currently under investigation and clinical development as a therapy for several chronic inflammatory conditions. These data suggest that the beneficial effects of 4-MU on tissue metabolism may include effects on longevity.
鉴于细胞外基质聚合物透明质酸（HA）与长寿有关，我们想知道透明质酸合成抑制剂 4-甲基伞形酮（4-MU）是否会影响小鼠的寿命。我们设计了一项前瞻性研究，用 4-MU 对常规 C57BL/6J 小鼠进行长期给药。我们发现，4-MU 将中位生存期从 122 周（对照）延长至 154 周（4-MU），延长了 32 周（对数秩 Mantel Cox 检验，< 0.0001）。4-MU 处理的小鼠最大寿命从 159 周增加到 194 周。与这些效果相一致的是，4-MU 增强了胰岛素敏感性，作为衡量寿命的代谢参数，通过胰岛素耐量试验（ITT）和频繁采样静脉葡萄糖耐量试验（FSIVGTTs）进行测量。我们还观察到，4-MU 处理的小鼠在摄入相同量食物时体重减轻，表明 4-MU 处理改变了能量消耗。然而，我们在该模型中没有观察到组织中 HA 含量的变化。我们得出结论，4-MU 促进胰岛素敏感性和长寿，但潜在机制和 HA 的贡献尚不清楚。4-MU 已在多个国家获得批准用于肝胆疾病，目前正在作为几种慢性炎症性疾病的治疗方法进行研究和临床开发。这些数据表明，4-MU 对组织代谢的有益影响可能包括对寿命的影响。
