Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34141, Korea.
Nat Commun. 2023 Jan 18;14(1):288. doi: 10.1038/s41467-023-35952-z.
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 H-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 Aβ. 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.
饮食限制（DR）可延缓衰老和与年龄相关疾病的发生。然而，目前尚不清楚是否以及如何限制特定营养素可以促进长寿。先前的全基因组筛选分离出了几种大肠杆菌突变体，这些突变体延长了秀丽隐杆线虫的寿命。在这里，我们使用 H-NMR 代谢物分析和种间遗传学，证明耗尽细胞内葡萄糖的大肠杆菌突变体能延长秀丽隐杆线虫的寿命，可作为真正的葡萄糖限制（GR）饮食。与一般的 DR 不同，GR 饮食不会降低动物的繁殖力，同时仍能提高应激抗性并改善 Aβ 的神经退行性病变。有趣的是，AAK-2a，一种新的 AMPK 同工型，是 GR 诱导长寿所必需和充分的。AAK-2a 专门在神经元中通过神经肽信号调节 GR 介导的长寿。最后，我们发现 GR/AAK-2a 通过促进外周组织中的膜流动性，通过 PAQR-2/NHR-49/Δ9 去饱和酶延长寿命。总之，我们的研究在整体动物的背景下，确定了通过特定的葡萄糖限制延长寿命的分子机制。
