Downregulation of the tyrosine degradation pathway extends lifespan.

TitleDownregulation of the tyrosine degradation pathway extends lifespan.
Publication TypeJournal Article
Year of Publication2020
AuthorsParkhitko, AA, Ramesh, D, Wang, L, Leshchiner, D, Filine, E, Binari, R, Olsen, AL, Asara, JM, Cracan, V, Rabinowitz, JD, Brockmann, A, Perrimon, N
JournalElife
Volume9
Date Published2020 12 15
ISSN2050-084X
KeywordsAging, Animals, Drosophila melanogaster, Electron Transport Chain Complex Proteins, Longevity, Mitochondria, Tigecycline, Tyrosine, Tyrosine Transaminase
Abstract

<p>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 . 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 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.</p>

DOI10.7554/eLife.58053
Alternate JournalElife
PubMed ID33319750
PubMed Central IDPMC7744100
Grant ListK99 AG057792 / AG / NIA NIH HHS / United States
K08 NS109344 / NS / NINDS NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
R00 GM121856 / GM / NIGMS NIH HHS / United States
12P4167 / / National Centre for Biological Sciences / International
L30 NS108208 / NS / NINDS NIH HHS / United States
R00 AG057792 / AG / NIA NIH HHS / United States
R01 GM084947 / GM / NIGMS NIH HHS / United States