Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14912-7. doi: 10.1073/pnas.1203083109. Epub 2012 Aug 27.

Abstract

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra L-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Aging / physiology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Chromatography, Liquid
  • Computational Biology
  • DNA Primers / genetics
  • Fertility / genetics
  • Homeostasis / physiology*
  • Immunoblotting
  • Longevity / genetics
  • Peptides / metabolism
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tandem Mass Spectrometry
  • Tryptophan / chemistry
  • Tryptophan / metabolism*
  • Tryptophan Oxygenase / antagonists & inhibitors
  • Tryptophan Oxygenase / metabolism*
  • alpha-Synuclein / toxicity*

Substances

  • Amyloid beta-Peptides
  • DNA Primers
  • Peptides
  • alpha-Synuclein
  • polyglutamine
  • Tryptophan
  • Tryptophan Oxygenase