Abstract
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.
Highlights
Aging is the primary risk factor for many major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases (Lopez-Otın et al, 2013)
We previously demonstrated that many metabolites associated with methionine metabolism, a metabolic pathway playing a key role in regulation of aging, are dramatically different between 1-weekold wild-type and long-lived flies (Parkhitko et al, 2016)
To further extend our metabolic analysis and reveal new metabolites involved in the regulation of aging and lifespan, we compared differences in metabolomes in 1-week and 4-week-old wildtype (B3) and long-lived (O1 and O3) flies, searching for metabolites that are either different between control vs. long-lived flies of the same age and/or metabolites that change differently with age between control vs. long-lived flies
Summary
Aging is the primary risk factor for many major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases (Lopez-Otın et al, 2013). Untargeted and targeted metabolomics analysis in worms (Fuchs et al, 2010), flies (Hoffman et al, 2014; Avanesov et al, 2014; Parkhitko et al, 2016), mice (Tomas-Loba et al, 2013), and humans (Yu et al, 2012) have documented changes in the metabolome during the aging process. Manipulations of metabolic pathways that change with age might suppress aging and extend lifespan. Interventions that are known to extend lifespan, like dietary restriction, genetic selection or manipulations of specific pathways might reverse age-dependent metabolic reprogramming (Laye et al, 2015). While numerous studies have shown that metabolism changes with age and the role of several metabolic pathways in aging has been characterized, we do not completely understand what drives these metabolic alterations and how they affect other biological processes
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