Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

Elife. 2020 Dec 15;9:e58053. doi: 10.7554/eLife.58053.

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.

Keywords: D. melanogaster; ETC Complex I; TAT; genetics; genomics; mitochondria; neurotransmitters; tigecycline; tyrosine aminotransferase.

Publication types

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

MeSH terms

  • Aging / drug effects*
  • Animals
  • Drosophila melanogaster / metabolism
  • Electron Transport Chain Complex Proteins / drug effects
  • Longevity / drug effects
  • Longevity / physiology*
  • Mitochondria / metabolism
  • Tigecycline / pharmacology
  • Tyrosine / analysis
  • Tyrosine / metabolism*
  • Tyrosine / pharmacology*
  • Tyrosine Transaminase / metabolism*

Substances

  • Electron Transport Chain Complex Proteins
  • Tyrosine
  • Tigecycline
  • Tyrosine Transaminase