A new AMPK isoform mediates glucose-restriction induced longevity non-cell autonomously by promoting membrane fluidity

Jin-Hyuck Jeong, Jun-Seok Han, Youngae Jung, Seung-Min Lee, So-Hyun Park, Mooncheol Park, Min-Gi Shin, Nami Kim, Mi Sun Kang, Seokho Kim, Kwang-Pyo Lee, Ki-Sun Kwon, Chun-A. Kim, Yong Ryoul Yang, Geum-Sook Hwang () and Eun-Soo Kwon ()
Additional contact information
Jin-Hyuck Jeong: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jun-Seok Han: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Youngae Jung: Korea Basic Science Institute
Seung-Min Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
So-Hyun Park: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Mooncheol Park: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Min-Gi Shin: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Nami Kim: Korea Basic Science Institute
Mi Sun Kang: Korea Basic Science Institute
Seokho Kim: Dong-A University
Kwang-Pyo Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ki-Sun Kwon: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Chun-A. Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Yong Ryoul Yang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Geum-Sook Hwang: Korea Basic Science Institute
Eun-Soo Kwon: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Dietary restriction (DR) delays aging and the onset of age-associated diseases. However, it is yet to be determined whether and how restriction of specific nutrients promote longevity. Previous genome-wide screens isolated several Escherichia coli mutants that extended lifespan of Caenorhabditis elegans. Here, using 1H-NMR metabolite analyses and inter-species genetics, we demonstrate that E. coli mutants depleted of intracellular glucose extend C. elegans lifespans, serving as bona fide glucose-restricted (GR) diets. Unlike general DR, GR diets don’t reduce the fecundity of animals, while still improving stress resistance and ameliorating neuro-degenerative pathologies of Aβ42. Interestingly, AAK-2a, a new AMPK isoform, is necessary and sufficient for GR-induced longevity. AAK-2a functions exclusively in neurons to modulate GR-mediated longevity via neuropeptide signaling. Last, we find that GR/AAK-2a prolongs longevity through PAQR-2/NHR-49/Δ9 desaturases by promoting membrane fluidity in peripheral tissues. Together, our studies identify the molecular mechanisms underlying prolonged longevity by glucose specific restriction in the context of whole animals.

Date: 2023
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DOI: 10.1038/s41467-023-35952-z

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