TY - JOUR
T1 - Downregulation of the tyrosine degradation pathway extends drosophila lifespan
AU - Parkhitko, Andrey A.
AU - Ramesh, Divya
AU - Wang, Lin
AU - Leshchiner, Dmitry
AU - Filine, Elizabeth
AU - Binari, Richard
AU - Olsen, Abby L.
AU - Asara, John M.
AU - Cracan, Valentin
AU - Rabinowitz, Joshua D.
AU - Brockmann, Axel
AU - Perrimon, Norbert
N1 - Funding Information:
National Institute on AgingK99/R00 AG057792 Andrey A Parkhitko National Institutes of Health5P01CA120964 Norbert Perrimon National Centre for Biological Sciences12P4167 Axel Brockmann American Foundation for Aging Research Norbert Perrimon.
Funding Information:
We thank Trudy Mackay for providing the B3, O1 and O3 flies, John Tower for the GeneSwitch fly stocks and hsp22-GFP line, Scott Pletcher for providing the TIGS-2 and 3XElav Gene-Switch driver lines, David Walker for providing UAS-dPGC-1/Spargel line, Mel Feany for providing Syb-QF2; QUAS-a-synuclein line, Udai Pandey for GFP-CL1 line, Dirk Bohmann for GstD-GFP line. We thank Jay Hirsh for comments on measuring neurotransmitters and Kit Tuen for excellent technical assistance. We thank Stephanie Mohr for critical reading of the manuscript. We thank the TRiP at Harvard Medical School supported by NIH/NIGMS R01-GM084947 for providing transgenic RNAi lines and NCBS institutional fund to AB (12P4167) to support the quantification of neurotransmitters. This work was supported by NIA K99/R00 AG057792 (AP), 5P01CA120964 (NP) and AFAR (NP). NP is an investigator of the Howard Hughes Medical Institute.
Publisher Copyright:
© Parkhitko et al.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098674506&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098674506&partnerID=8YFLogxK
U2 - 10.7554/ELIFE.58053
DO - 10.7554/ELIFE.58053
M3 - Article
C2 - 33319750
AN - SCOPUS:85098674506
SN - 2050-084X
VL - 9
SP - 1
EP - 27
JO - eLife
JF - eLife
M1 - e58053
ER -