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A metabolic switch at the center of JNK-induced proteostasis and longevity

ABSTRACT: Aging is associated with a progressive loss of tissue and metabolic homeostasis. Changes in the cellular management of the proteome, as well as changes in cellular metabolism have been implicated in this decline, yet our understanding of causal relationships between these changes remains incomplete. Genetic studies have shown that single-gene perturbations are sufficient to significantly impact the aging process, delaying all associated cellular deficiencies, and thus increasing lifespan. Here, we explore metabolic and proteostatic changes associated with lifespan extension by one such perturbation. Focusing on the Drosophila brain, we comprehensively characterize protein turnover rates and assess metabolic flux to identify changes in protein and metabolic homeostasis in long-lived animals. Using organism-wide 15N labeling, we observe that the turnover rates of ~2000 proteins in the fly head decline with age, and that this decline is prevented in animals with lifespan-extending elevation of Jun-N-terminal Kinase (JNK) activity. Combining transcriptomic, metabolomic, and metabolic flux analysis, we find that JNK activation in the brain results in decreased steady-state Glucose-6-phosphate levels coupled to elevated carbon flux into the pentose phosphate pathway due to the transcriptional induction of Glucose-6-phosphate Dehydrogenase. This metabolic change promotes proteostasis in the aging brain, likely via increased NADPH against oxidative stress response. Through a comprehensive characterization of the cellular and biochemical changes elicited by a lifespan extending mutation, our study thus identifies a JNK-induced metabolic switch that increases lifespan by promoting neuronal proteostasis.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Drosophila Melanogaster (ncbitaxon:7227)

SUBMITTER: Henri Jasper, Brad Gibson, Birgit Schilling

PROVIDER: MSV000080118 | MassIVE |

REPOSITORIES: MassIVE

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A metabolic switch at the center of JNK-induced proteostasis and longevity

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