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

van der Goot, A. T., Zhu, W., Vazquez-Manrique, R. P., Seinstra, R. I., Dettmer, K., Michels, H., Farina, F., Krijnen, J., Melki, R., Buijsman, R. C., Silva, M. R., Thijssen, K. L., Kema, I. P., Neri, C., Oefner, P. J. & Nollen, E. A. A., 11-Sep-2012, In : Proceedings of the National Academy of Sciences of the United States of America. 109, 37, p. 14912-14917 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Annemieke T. van der Goot
  • Wentao Zhu
  • Rafael P. Vazquez-Manrique
  • Renee I. Seinstra
  • Katja Dettmer
  • Helen Michels
  • Francesca Farina
  • Jasper Krijnen
  • Ronald Melki
  • Rogier C. Buijsman
  • Mariana Ruiz Silva
  • Karen L. Thijssen
  • Ido P. Kema
  • Christian Neri
  • Peter J. Oefner
  • Ellen A. A. Nollen

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 alpha-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-beta 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.

Original languageEnglish
Pages (from-to)14912-14917
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
Publication statusPublished - 11-Sep-2012



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