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

Area of Science:

• Metabolic pathways
• Aging research
• Neuroscience

Background:

• The hexosamine biosynthetic pathway (HBP) plays a dual role, linked to lifespan extension and protein quality control, but also implicated in tumor progression and diabetes.
• Opposing outcomes necessitate investigation into chronic HBP activation's long-term effects in mammals.

Purpose of the Study:

• To investigate the long-term effects of chronic hexosamine biosynthetic pathway (HBP) activation on metabolism, coordination, memory, and survival in mice.
• To evaluate both dietary supplementation with N-acetyl-D-glucosamine (GlcNAc) and genetic activation of HBP.

Main Methods:

• Mice received N-acetyl-D-glucosamine (GlcNAc) in drinking water.
• Genetic activation of HBP was achieved by overexpressing GFAT1 and a constitutively activated mutant form.
• Metabolic parameters, behavior, memory, and survival were assessed up to 20 months of age.

Main Results:

• Dietary GlcNAc supplementation did not adversely affect male weight but increased young female weight.
• Glucose and insulin tolerance remained unaffected up to 20 months.
• Improved memory was observed in young male mice receiving GlcNAc.
• Genetic HBP activation led to elevated UDP-GlcNAc in brains but did not alter behavior, memory, or survival.
• GlcNAc treatment did not change overall survival rates.

Conclusions:

• Dietary GlcNAc supplementation is generally well-tolerated in mice and positively impacts memory, particularly in males.
• Chronic HBP activation, whether dietary or genetic, did not extend lifespan in this mouse model.
• Further research is warranted to elucidate the complex role of HBP in mammalian physiology and aging.