TY - JOUR TI - 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 A2 - Kapahi, Pankaj A2 - Tyler, Jessica K A2 - Kapahi, Pankaj A2 - Walker, David VL - 9 PY - 2020 DA - 2020/12/15 SP - e58053 C1 - eLife 2020;9:e58053 DO - 10.7554/eLife.58053 UR - https://doi.org/10.7554/eLife.58053 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. KW - tyrosine aminotransferase KW - TAT KW - tigecycline KW - mitochondria KW - neurotransmitters KW - ETC Complex I JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -