Hexosamine pathway activation improves memory but does not extend lifespan in mice

• Published in: Aging cell 2022-10, Vol.21 (10), p.e13711-n/a
• Main Authors: Allmeroth, Kira, Hartman, Matías D., Purrio, Martin, Mesaros, Andrea, Denzel, Martin S.
• Format: Article
• Language: English
• Subjects: Acetylglucosamine - metabolism; Animals; Diabetes mellitus; Dietary supplements; Drinking Water; Female; GFAT1; Glucosamine; Glucose - metabolism; Glucose tolerance; Glycosylation; hexosamine biosynthetic pathway; Hexosamines - metabolism; Insulin; Insulins - metabolism; Life span; Longevity; Male; Mammals; memory; metabolism; Mice; mouse survival; Quality control; Survival; Tumors; Uridine Diphosphate - metabolism
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13711

Glucosamine feeding and genetic activation of the hexosamine biosynthetic pathway (HBP) have been linked to improved protein quality control and lifespan extension. However, as an energy sensor, the HBP has been implicated in tumor progression and diabetes. Given these opposing outcomes, it is imperative to explore the long‐term effects of chronic HBP activation in mammals. Thus, we asked if HBP activation affects metabolism, coordination, memory, and survival in mice. N‐acetyl‐D‐glucosamine (GlcNAc) supplementation in the drinking water had no adverse effect on weight in males but increased weight in young females. Glucose or insulin tolerance was not affected up to 20 months of age. Of note, we observed improved memory in young male mice supplemented with GlcNAc. Survival was not changed by GlcNAc treatment. To assess the effects of genetic HBP activation, we overexpressed the pathway's key enzyme GFAT1 and a constitutively activated mutant form in all mouse tissues. We detected elevated levels of the HBP product UDP‐GlcNAc in mouse brains, but did not find any effects on behavior, memory, or survival. Together, while dietary GlcNAc supplementation did not extend survival in mice, it positively affected memory and is generally well tolerated. The activation of the hexosamine biosynthetic pathway (HBP) is linked to improved protein quality control and lifespan extension. However, as an energy sensor, the HBP has been implicated in tumor progression and diabetes. Using chronic HBP activation and lifelong observation, we find no effect on survival but enhanced memory function in young male mice supplemented with GlcNAc.