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 (p < 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.
