Tryptophan metabolism in aging and disease: Insights from Caenorhabditis elegans

Michels, H., 2017, [Groningen]: University of Groningen. 270 p.

Research output: ThesisThesis fully internal (DIV)Academic

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  • Title and contents

    Final publisher's version, 878 KB, PDF document

  • Chapter I

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  • Chapter II

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  • Chapter III

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  • Chapter IV

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  • Chapter V

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  • Chapter VI

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  • Chapter VII

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  • Chapter VIII

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  • Chapter IX

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  • Summary

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  • Samenvatting

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  • List of publications

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  • Appendix

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  • Acknowledgements

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  • Complete thesis

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  • Propositions

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  • Helen Michels
The increasing lifespan of the world’s population in the last few decades correlates with an increasing number of people with age-related disease. Tryptophan metabolism is involved in various age-related pathologies such as neurodegeneration, cancer and diabetes type 2, which attracted the attention for therapeutic interventions. In model organisms for cancer and neurodegeneration, inhibition of the tryptophan-degrading enzyme, tryptophan- 2,3 dioxygenase (TDO), improves health- and extends lifespan. Tryptophan metabolites play a role but do not explain all protective effects. This thesis is aimed to better understand how the nutrient tryptophan and its metabolism influences the aging process and how it acts in the development of age-related neurodegenerative pathologies.
Findings in this thesis were obtained with the help of the small nematode Caenorhabditis elegans, a model organism which enables easy genetic manipulation and in vivo longevity experiments.
We identified a new tryptophan metabolite-independent function of TDO: the regulation of mitochondrial energy metabolism. Other amino acid dioxygenases appear to regulate mitochondrial function, health- and lifespan in a similar manner. Mitochondria do play a central role in the aging process and their dysregulation is often a characteristic of age-related pathologies.
Furthermore, we identified an evolutionary conserved region in the TDO protein that is essential for the enzyme’s function and might be used as a target for the development of new TDO inhibitors.
Our results indicate that the inhibition of TDO or other amino acid dioxygenases can be explored as a therapeutic strategy to control mitochondrial metabolism, slow down aging and ameliorate age-related pathologies.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
Award date27-Sep-2017
Place of Publication[Groningen]
Print ISBNs978-94-028-0754-7
Electronic ISBNs978-94-034-0179-9
Publication statusPublished - 2017

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