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

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.

[1]  C. Uyttenhove,et al.  Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase , 2012, Proceedings of the National Academy of Sciences.

[2]  R. Morimoto,et al.  A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network , 2011, PLoS genetics.

[3]  P. Oefner,et al.  Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography–tandem mass spectrometry , 2011, Analytical and bioanalytical chemistry.

[4]  M. Brauner,et al.  Caenorhabditis elegans selects distinct crawling and swimming gaits via dopamine and serotonin , 2011, Proceedings of the National Academy of Sciences.

[5]  R. Schwarcz,et al.  Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration , 2011, Cell.

[6]  R. Schwarcz,et al.  The Kynurenine Pathway Modulates Neurodegeneration in a Drosophila Model of Huntington's Disease , 2011, Current Biology.

[7]  G. Lithgow,et al.  Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan , 2011, Nature.

[8]  N. Perrimon,et al.  FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis during Aging , 2010, Cell.

[9]  D. Rubinsztein,et al.  Identification of MOAG-4/SERF as a Regulator of Age-Related Proteotoxicity , 2010, Cell.

[10]  Alma L. Burlingame,et al.  Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans , 2010, PLoS biology.

[11]  L. Partridge,et al.  Invertebrate models of age-related muscle degeneration. , 2009, Biochimica et biophysica acta.

[12]  Elizabeth A Miller,et al.  Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging , 2009, Proceedings of the National Academy of Sciences.

[13]  F. Hartl,et al.  Converging concepts of protein folding in vitro and in vivo , 2009, Nature Structural &Molecular Biology.

[14]  M. Kaeberlein,et al.  Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans , 2009, Science.

[15]  D. Karger,et al.  Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity , 2009, Nature Genetics.

[16]  B. Kennedy,et al.  Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf‐1‐dependent mechanism in Caenorhabditis elegans , 2008, Aging cell.

[17]  R. Breitling,et al.  C. elegans Model Identifies Genetic Modifiers of α-Synuclein Inclusion Formation During Aging , 2008, PLoS genetics.

[18]  Richard I. Morimoto,et al.  Adapting Proteostasis for Disease Intervention , 2008, Science.

[19]  T. Shirokawa,et al.  Changes in brain tryptophan metabolism elicited by ageing, social environment, and psychological stress in mice , 2008, Stress.

[20]  J. Roder,et al.  Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and Protects Caenorhabditis elegans Neurons against Mutant Polyglutamine Toxicity , 2007, The Journal of Neuroscience.

[21]  Steven J. M. Jones,et al.  High-Throughput In Vivo Analysis of Gene Expression in Caenorhabditis elegans , 2007, PLoS biology.

[22]  Albert-László Barabási,et al.  Genome-scale analysis of in vivo spatiotemporal promoter activity in Caenorhabditis elegans , 2007, Nature Biotechnology.

[23]  G. Ruvkun,et al.  Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability , 2007, PLoS genetics.

[24]  Ehud Cohen,et al.  Opposing Activities Protect Against Age-Onset Proteotoxicity , 2006, Science.

[25]  R. Nass,et al.  Identification of gene expression changes in transgenic C. elegans overexpressing human α-synuclein , 2006, Neurobiology of Disease.

[26]  Richard I. Morimoto,et al.  Progressive Disruption of Cellular Protein Folding in Models of Polyglutamine Diseases , 2006, Science.

[27]  Laurent Seroude,et al.  Differential patterns of apoptosis in response to aging in Drosophila. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  E. Lambert,et al.  Neuroprotection par l’activation des sirtuines dans des modèles simplifiés de chorée de Huntington , 2005 .

[29]  Paolo Guidetti,et al.  A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease , 2005, Nature Genetics.

[30]  Christian Néri,et al.  Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons , 2005, Nature Genetics.

[31]  C. Kenyon.  The Plasticity of Aging: Insights from Long-Lived Mutants , 2005, Cell.

[32]  K. Nair,et al.  Aging muscle. , 2005, The American journal of clinical nutrition.

[33]  P. Sternberg,et al.  The L-Type Cyclin CYL-1 and the Heat-Shock-Factor HSF-1 Are Required for Heat-Shock-Induced Protein Expression in Caenorhabditis elegans , 2004, Genetics.

[34]  R. Morimoto,et al.  Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. , 2003, Molecular biology of the cell.

[35]  Cynthia Kenyon,et al.  Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor , 2003, Science.

[36]  D. Hall,et al.  Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans , 2002, Nature.

[37]  Richard I. Morimoto,et al.  The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Goedert,et al.  The α‐Synucleinopathies: Parkinson's Disease, Dementia with Lewy Bodies, and Multiple System Atrophy , 2000 .

[39]  D. Pawlak,et al.  Serotonergic and kynurenic pathways in rats exposed to foot shock , 2000, Brain Research Bulletin.

[40]  G. Ruvkun,et al.  Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant , 2000, Nature.

[41]  M. Goedert,et al.  The alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. , 2000, Annals of the New York Academy of Sciences.

[42]  Hans Lehrach,et al.  Huntingtin-Encoded Polyglutamine Expansions Form Amyloid-like Protein Aggregates In Vitro and In Vivo , 1997, Cell.

[43]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[44]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[45]  M G Spillantini,et al.  Alpha-synuclein in Lewy bodies. , 1997, Nature.

[46]  C. Link,et al.  Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  L. Avery,et al.  The genetics of feeding in Caenorhabditis elegans. , 1993, Genetics.

[48]  Milton W. Taylor,et al.  Relationship between interferon‐γ, indoleamine 2,3‐dioxygenase, and tryptophan catabolism , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  N. Munakata.  [Genetics of Caenorhabditis elegans]. , 1989, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[50]  C. Masters,et al.  Amyloid plaque core protein in Alzheimer disease and Down syndrome. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[51]  P H Crandall,et al.  Corticosteroid Responses to Limbic Stimulation in Man: Localization of Stimulus Sites , 1966, Science.