Downregulation of the tyrosine degradation pathway extends Drosophila lifespan
- Harvard Medical School, United States
- National Centre for Biological Sciences, India
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, United States
- Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, United States
- Beth Israel Deaconess Medical Center, United States
- Scintillon Institute, United States
- Princeton University, United States
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Additional metabolomics data are available upon request.
Article and author information
Author details
Andrey A Parkhitko
Funding
NIA (K99/R00 AG057792)
- Andrey A Parkhitko
NIH (5P01CA120964)
- Norbert Perrimon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Parkhitko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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