Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States; Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, United States
National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India; Department of Biology, University of Konstanz, Konstanz, Germany
Department of Chemistry, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
Dmitry Leshchiner
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
Elizabeth Filine
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
Richard Binari
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States; Howard Hughes Medical Institute, Boston, United States
Abby L Olsen
Department of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, United States
John M Asara
Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, United States
Scintillon Institute, San Diego, United States; Department of Chemistry, The Scripps Research Institute, La Jolla, United States
Joshua D Rabinowitz
Department of Chemistry, Princeton University, Princeton, United States; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
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.
