Downregulation of the tyrosine degradation pathway extends lifespan.
|Title||Downregulation of the tyrosine degradation pathway extends lifespan.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|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|
|Date Published||2020 Dec 15|
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 . 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 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.
|Grant List||K99/R00 AG057792 / AG / NIA NIH HHS / United States |
5P01CA120964 / GF / NIH HHS / United States