JNK modifies neuronal metabolism to promote proteostasis and longevity.

Lifen Wang,Bradford W Gibson,Sina Ghaemmaghami,Heinrich Jasper,Martin Borch Jensen,Cagsar Apaydin,Sonnet S Davis,Imilce A Rodriguez‐Fernandez,Birgit Schilling,Arvind Ramanathan,Gabor Juhasz

doi:10.1111/acel.12849

Lifen Wang, Bradford W Gibson + Show 9 more

Open Access

https://doi.org/10.1111/acel.12849

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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.

Highlights

Studies in model organisms have generated significant insight into the genetic factors and environmental conditions that influence, cause, and prevent aging (Kennedy et al, 2014; Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013)
The focus on Jun‐N‐terminal kinase (JNK) signaling allowed us to explore the cellular consequences of a perturbation that extends lifespan through modulation of stress‐responsive gene expression changes and that directly influences metabolism by repressing the insulin/IGF signaling (IIS) pathway: JNK is activated by numerous stressors and can protect cells by inducing protective gene expression programs (Biteau et al, 2011; Karpac & Jasper, 2009; Karpac, Hull‐Thompson, Falleur, & Jasper, 2009; Oh et al, 2005; Wang et al, 2003, 2005 )
Our results provide an integrated view of the cellular consequences of these diverse effects of JNK activation in the brain

Summary

| INTRODUCTION

Studies in model organisms have generated significant insight into the genetic factors and environmental conditions that influence, cause, and prevent aging (Kennedy et al, 2014; Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013). Lifespan can further be extended in all tested model organisms by inhibiting insulin‐IGF signaling (IIS) and Tor, a central nutrient sensor that influences protein homeostasis by a number of mechanisms (Kenyon, 2005; Lopez‐Otin et al, 2013; Partridge et al, 2011) Together, these studies point to metabolic perturbations and the loss of proteostasis as central drivers of deleterious aging phenotypes and age‐related diseases (Labbadia & Morimoto, 2015; Lopez‐Otin et al, 2013; Taylor & Dillin, 2011). Our combined proteomic and metabolomic analysis suggests that JNK activation extends lifespan through metabolic reprogramming that promotes neuronal proteostasis

| RESULTS

| DISCUSSION

Findings

| MATERIALS AND METHODS