Hymecromone Promotes Longevity and Insulin Sensitivity in Mice
Nadine Nagy,
Kathryn S. Czepiel,
Gernot Kaber,
Darko Stefanovski,
Aviv Hargil,
Nina Pennetzdorfer,
Robert Targ,
Saranya C. Reghupaty,
Thomas N. Wight,
Robert B. Vernon,
Rebecca L. Hull-Meichle,
Payton Marshall,
Carlos O. Medina,
Hunter Martinez,
Anissa Kalinowski,
Rudolph D. Paladini,
Stavros Garantziotis,
Joshua W. Knowles,
Paul L. Bollyky
Affiliations
Nadine Nagy
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Kathryn S. Czepiel
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Gernot Kaber
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Darko Stefanovski
Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA
Aviv Hargil
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Nina Pennetzdorfer
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Robert Targ
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Saranya C. Reghupaty
Department of Pathology, School of Medicine, Stanford University, Stanford, CA 94305, USA
Thomas N. Wight
Benaroya Research Institute, 1201 9th Ave, Seattle, WA 98101, USA
Robert B. Vernon
Benaroya Research Institute, 1201 9th Ave, Seattle, WA 98101, USA
Rebecca L. Hull-Meichle
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA 98108, USA
Payton Marshall
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Carlos O. Medina
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Hunter Martinez
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
Anissa Kalinowski
Halo Biosciences, 125 University St., Palo Alto, CA 94301, USA
Rudolph D. Paladini
Halo Biosciences, 125 University St., Palo Alto, CA 94301, USA
Stavros Garantziotis
Immunity, Inflammation and Disease Laboratory, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA
Joshua W. Knowles
Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA
Paul L. Bollyky
Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA
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.
