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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 | Eun-Soo Kwon
Nature communications | 2023

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.

Pubmed ID: 36653384

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