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Cell. 2014 Mar 13;156(6):1167-1178. doi: 10.1016/j.cell.2014.01.061.

Hexosamine pathway metabolites enhance protein quality control and prolong life.

Author information

1
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
2
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50674, Germany; Institute for Genetics, University of Cologne, Zülpicher Strasse 47a, Cologne 50674, Germany.
3
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch 13125, Germany.
4
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch 13125, Germany; Humboldt-University Berlin, Institute of Biology, Invalidenstrasse 43, Berlin 10115, Germany.
5
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany; Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50674, Germany. Electronic address: antebi@age.mpg.de.

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.

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PMID:
24630720
DOI:
10.1016/j.cell.2014.01.061
[Indexed for MEDLINE]
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