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Hexosamine pathway metabolites enhance protein quality control and prolong life

Item Type:Article
Title:Hexosamine pathway metabolites enhance protein quality control and prolong life
Creators Name:Denzel, M.S., Storm, N.J., Gutschmidt, A., Baddi, R., Hinze, Y., Jarosch, E., Sommer, T., Hoppe, T. and Antebi, A.
Abstract:Aging entails a progressive decline in protein homeostasis, which often leads to age-related diseases. The endoplasmic reticulum (ER) is the site of protein synthesis and maturation for secreted and membrane proteins. Correct folding of ER proteins requires covalent attachment of N-linked glycan oligosaccharides. Here, we report that increased synthesis of N-glycan precursors in the hexosamine pathway improves ER protein homeostasis and extends lifespan in C. elegans. Addition of the N-glycan precursor N-acetylglucosamine to the growth medium slows aging in wild-type animals and alleviates pathology of distinct neurotoxic disease models. Our data suggest that reduced aggregation of metastable proteins and lifespan extension depend on enhanced ER-associated protein degradation, proteasomal activity, and autophagy. Evidently, hexosamine pathway activation or N-acetylglucosamine supplementation induces distinct protein quality control mechanisms, which may allow therapeutic intervention against age-related and proteotoxic diseases.
Keywords:Amino Acid Sequence, Autophagy, Biosynthetic Pathways, Caenorhabditis elegans, Endoplasmic Reticulum, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Hexosamines, Longevity, Molecular Sequence Data, Mutation, Protein Biosynthesis, Proteins, Sequence Alignment, Tunicamycin, Animals
Publisher:Cell Press / Elsevier
Page Range:1167-1178
Date:13 March 2014
Official Publication:https://doi.org/10.1016/j.cell.2014.01.061
PubMed:View item in PubMed

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