Downregulation of the tyrosine degradation pathway extends drosophila lifespan

Andrey A. Parkhitko, Divya Ramesh, Lin Wang, Dmitry Leshchiner, Elizabeth Filine, Richard Binari, Abby L. Olsen, John M. Asara, Valentin Cracan, Joshua D. Rabinowitz, Axel Brockmann, Norbert Perrimon

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived Drosophila melanogaster. Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.

Original languageEnglish (US)
Article numbere58053
Pages (from-to)1-27
Number of pages27
JournaleLife
Volume9
DOIs
StatePublished - Dec 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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