JNK modifies neuronal metabolism to promote proteostasis and longevity
Lifen Wang,
Sonnet S. Davis,
Martin Borch Jensen,
Imilce A. Rodriguez-Fernandez,
Cagsar Apaydin,
Gabor Juhasz,
Bradford W. Gibson,
Birgit Schilling,
Arvind Ramanathan,
Sina Ghaemmaghami,
Heinrich Jasper,
Lifen Wang
The Buck Institute for Research on Aging, Novato, California
Genentech Inc., South San Francisco, California
Search for more papers by this authorSonnet S. Davis
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorMartin Borch Jensen
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorImilce A. Rodriguez-Fernandez
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorCagsar Apaydin
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorGabor Juhasz
Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest, Hungary
Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary
Search for more papers by this authorBradford W. Gibson
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorBirgit Schilling
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorArvind Ramanathan
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorSina Ghaemmaghami
Department of Biology, University of Rochester, Rochester, New York
Search for more papers by this authorCorresponding Author
Heinrich Jasper
The Buck Institute for Research on Aging, Novato, California
Genentech Inc., South San Francisco, California
Correspondence
Heinrich Jasper, The Buck Institute for Research on Aging, Novato, CA.
Email: [email protected]
Search for more papers by this authorLifen Wang,
Sonnet S. Davis,
Martin Borch Jensen,
Imilce A. Rodriguez-Fernandez,
Cagsar Apaydin,
Gabor Juhasz,
Bradford W. Gibson,
Birgit Schilling,
Arvind Ramanathan,
Sina Ghaemmaghami,
Heinrich Jasper,
Lifen Wang
The Buck Institute for Research on Aging, Novato, California
Genentech Inc., South San Francisco, California
Search for more papers by this authorSonnet S. Davis
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorMartin Borch Jensen
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorImilce A. Rodriguez-Fernandez
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorCagsar Apaydin
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorGabor Juhasz
Department of Anatomy, Cell and Developmental Biology, Eotvos Lorand University, Budapest, Hungary
Institute of Genetics, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary
Search for more papers by this authorBradford W. Gibson
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorBirgit Schilling
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorArvind Ramanathan
The Buck Institute for Research on Aging, Novato, California
Search for more papers by this authorSina Ghaemmaghami
Department of Biology, University of Rochester, Rochester, New York
Search for more papers by this authorCorresponding Author
Heinrich Jasper
The Buck Institute for Research on Aging, Novato, California
Genentech Inc., South San Francisco, California
Correspondence
Heinrich Jasper, The Buck Institute for Research on Aging, Novato, CA.
Email: [email protected]
Search for more papers by this authorAbstract
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.
CONFLICT OF INTERESTS
The authors declare no competing interests.
Supporting Information
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