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Hymecromone Promotes Longevity and Insulin Sensitivity in Mice.

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Hymecromone Promotes Longevity and Insulin Sensitivity in Mice. Cells Nagy, N., Czepiel, K. S., Kaber, G., Stefanovski, D., Hargil, A., Pennetzdorfer, N., Targ, R., Reghupaty, S. C., Wight, T. N., Vernon, R. B., Hull-Meichle, R. L., Marshall, P., Medina, C. O., Martinez, H., Kalinowski, A., Paladini, R. D., Garantziotis, S., Knowles, J. W., Bollyky, P. L. 2024; 13 (20)

Abstract

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.

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