Downregulation of the tyrosine degradation pathway extends Drosophila lifespan
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...
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| Format: | Article |
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eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/58053 |
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| author | Andrey A Parkhitko Divya Ramesh Lin Wang Dmitry Leshchiner Elizabeth Filine Richard Binari Abby L Olsen John M Asara Valentin Cracan Joshua D Rabinowitz Axel Brockmann Norbert Perrimon |
| author_facet | Andrey A Parkhitko Divya Ramesh Lin Wang Dmitry Leshchiner Elizabeth Filine Richard Binari Abby L Olsen John M Asara Valentin Cracan Joshua D Rabinowitz Axel Brockmann Norbert Perrimon |
| author_sort | Andrey A Parkhitko |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T03:51:14Z |
| format | Article |
| id | doaj.art-430b94e27ac94c7287b72b8741fecbc9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:51:14Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-430b94e27ac94c7287b72b8741fecbc92022-12-22T02:03:16ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.58053Downregulation of the tyrosine degradation pathway extends Drosophila lifespanAndrey A Parkhitko0https://orcid.org/0000-0001-9852-8329Divya Ramesh1https://orcid.org/0000-0003-1387-7832Lin Wang2https://orcid.org/0000-0002-9370-6891Dmitry Leshchiner3Elizabeth Filine4Richard Binari5Abby L Olsen6John M Asara7Valentin Cracan8https://orcid.org/0000-0002-3280-0593Joshua D Rabinowitz9Axel Brockmann10https://orcid.org/0000-0003-0201-9656Norbert Perrimon11https://orcid.org/0000-0001-7542-472XDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States; Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, United StatesNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India; Department of Biology, University of Konstanz, Konstanz, GermanyDepartment of Chemistry, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United StatesDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United StatesDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United StatesDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States; Howard Hughes Medical Institute, Boston, United StatesDepartment of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesDivision of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, United StatesScintillon Institute, San Diego, United States; Department of Chemistry, The Scripps Research Institute, La Jolla, United StatesDepartment of Chemistry, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United StatesNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, IndiaDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States; Howard Hughes Medical Institute, Boston, United StatesAging 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.https://elifesciences.org/articles/58053tyrosine aminotransferaseTATtigecyclinemitochondrianeurotransmittersETC Complex I |
| spellingShingle | Andrey A Parkhitko Divya Ramesh Lin Wang Dmitry Leshchiner Elizabeth Filine Richard Binari Abby L Olsen John M Asara Valentin Cracan Joshua D Rabinowitz Axel Brockmann Norbert Perrimon Downregulation of the tyrosine degradation pathway extends Drosophila lifespan eLife tyrosine aminotransferase TAT tigecycline mitochondria neurotransmitters ETC Complex I |
| title | Downregulation of the tyrosine degradation pathway extends Drosophila lifespan |
| title_full | Downregulation of the tyrosine degradation pathway extends Drosophila lifespan |
| title_fullStr | Downregulation of the tyrosine degradation pathway extends Drosophila lifespan |
| title_full_unstemmed | Downregulation of the tyrosine degradation pathway extends Drosophila lifespan |
| title_short | Downregulation of the tyrosine degradation pathway extends Drosophila lifespan |
| title_sort | downregulation of the tyrosine degradation pathway extends drosophila lifespan |
| topic | tyrosine aminotransferase TAT tigecycline mitochondria neurotransmitters ETC Complex I |
| url | https://elifesciences.org/articles/58053 |
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