Hexosamine Pathway Metabolites Enhance Protein Quality Control and Prolong Life

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autophagy
  • Biosynthetic Pathways*
  • Caenorhabditis elegans / enzymology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / genetics
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / metabolism*
  • Hexosamines / metabolism*
  • Humans
  • Longevity*
  • Molecular Sequence Data
  • Mutation
  • Protein Biosynthesis
  • Proteins / metabolism*
  • Sequence Alignment
  • Tunicamycin / pharmacology

Substances

  • Caenorhabditis elegans Proteins
  • Hexosamines
  • Proteins
  • Tunicamycin
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)