JNK modifies neuronal metabolism to promote proteostasis and longevity

Wang, Lifen and Davis, Sonnet S. and Borch Jensen, Martin and Rodriguez-Fernandez., Imilce A. and Cagsar, Apaydin and Juhász, Gábor (2019) JNK modifies neuronal metabolism to promote proteostasis and longevity. AGING CELL, 18 (3). pp. 1-16. ISSN 1474-9718 (print); 1474-9726 (online)

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Abstract

Aging is associated with a progressive loss of tissue and metabolic homeostasis. This loss can be delayed by single-gene perturbations, increasing lifespan. How such perturbations affect metabolic and proteostatic networks to extend lifespan remains unclear. Here, we address this question by comprehensively characterizing age-related changes in protein turnover rates in the Drosophila brain, as well as changes in the neuronal metabolome, transcriptome, and carbon flux in long-lived animals with elevated Jun-N-terminal Kinase signaling. We find that these animals exhibit a delayed age-related decline in protein turnover rates, as well as decreased steady-state neuronal glucose-6-phosphate levels and elevated carbon flux into the pentose phosphate pathway due to the induction of glucose-6-phosphate dehydrogenase (G6PD). Over-expressing G6PD in neurons is sufficient to phenocopy these metabolic and proteostatic changes, as well as extend lifespan. Our study identifies a link between metabolic changes and improved proteostasis in neurons that contributes to the lifespan extension in long-lived mutants.

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