Downregulation of the tyrosine degradation pathway extends Drosophila lifespan.

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.

journal_name

Elife

journal_title

eLife

authors

Parkhitko AA,Ramesh D,Wang L,Leshchiner D,Filine E,Binari R,Olsen AL,Asara JM,Cracan V,Rabinowitz JD,Brockmann A,Perrimon N

doi

10.7554/eLife.58053

subject

Has Abstract

pub_date

2020-12-15 00:00:00

issn

2050-084X

pii

58053

journal_volume

9

pub_type

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