Journal
CELL
Volume 156, Issue 6, Pages 1167-1178Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.01.061
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Funding
- EMBO fellowship
- Marie-Curie Career Integration Grant
- Max Planck Society
- BMBF/Sybacol
- Deutsche Forschungsgemeinschaft (DFG)/CECAD
- DFG
- DIP8 grant [2014376]
- CECAD [FOR885, KFO286, SFB635]
- German-Israel Project Cooperation DIP
- [JA 1830/1-2]
- [SFB 740]
- [1365]
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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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