title: Hexosamine pathway metabolites enhance protein quality control and prolong life.
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.
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Denzel
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Nadia J
authors.initials: NJ
authors.lastname: Storm
authors.affiliation: 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.
authors.forename: Aljona
authors.initials: A
authors.lastname: Gutschmidt
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Baddi
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hinze
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch 13125, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Jarosch
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sommer
authors.affiliation: 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.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hoppe
authors.affiliation: 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.
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D053898:Biosynthetic Pathways; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics / Q000378:metabolism*; D006595:Hexosamines / Q000378:metabolism*; D006801:Humans; D008136:Longevity; D008969:Molecular Sequence Data; D009154:Mutation; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D016415:Sequence Alignment; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; D006595:Hexosamines; D011506:Proteins; D014415:Tunicamycin; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)