Laboratory of Cell Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States America.
Johns Hopkins University Department of Biology, Baltimore, MD, United States America.
PLoS One. 2022 Sep 16;17(9):e0274076. doi: 10.1371/journal.pone.0274076. eCollection 2022.
Genetic and environmental manipulations, such as dietary restriction, can improve both health span and lifespan in a wide range of organisms, including humans. Changes in nutrient intake trigger often overlapping metabolic pathways that can generate distinct or even opposite outputs depending on several factors, such as when dietary restriction occurs in the lifecycle of the organism or the nature of the changes in nutrients. Due to the complexity of metabolic pathways and the diversity in outputs, the underlying mechanisms regulating diet-associated pro-longevity are not yet well understood. Adult reproductive diapause (ARD) in the model organism Caenorhabditis elegans is a dietary restriction model that is associated with lengthened lifespan and reproductive potential. To explore the metabolic pathways regulating ARD in greater depth, we performed a candidate-based genetic screen analyzing select nutrient-sensing pathways to determine their contribution to the regulation of ARD. Focusing on the three phases of ARD (initiation, maintenance, and recovery), we found that ARD initiation is regulated by fatty acid metabolism, sirtuins, AMPK, and the O-linked N-acetyl glucosamine (O-GlcNAc) pathway. Although ARD maintenance was not significantly influenced by the nutrient sensors in our screen, we found that ARD recovery was modulated by energy sensing, stress response, insulin-like signaling, and the TOR pathway. Further investigation of downstream targets of NHR-49 suggest the transcription factor influences ARD initiation through the fatty acid β-oxidation pathway. Consistent with these findings, our analysis revealed a change in levels of neutral lipids associated with ARD entry defects. Our findings identify conserved genetic pathways required for ARD entry and recovery and uncover genetic interactions that provide insight into the role of OGT and OGA.
遗传和环境操作，如饮食限制，可以改善包括人类在内的广泛生物的健康跨度和寿命。营养摄入的变化会引发通常重叠的代谢途径，这些途径会根据几个因素产生不同甚至相反的输出，例如饮食限制发生在生物体的生命周期中或营养素变化的性质。由于代谢途径的复杂性和输出的多样性，调节与饮食相关的长寿的潜在机制尚不完全清楚。模式生物秀丽隐杆线虫中的成年生殖滞育 (ARD) 是一种与延长寿命和生殖潜力相关的饮食限制模型。为了更深入地研究调节 ARD 的代谢途径，我们进行了基于候选基因的遗传筛选，分析了选定的营养感应途径，以确定它们对 ARD 调节的贡献。我们专注于 ARD 的三个阶段（启动、维持和恢复），发现脂肪酸代谢、沉默调节蛋白、AMP 激活蛋白激酶和 O-连接的 N-乙酰氨基葡萄糖 (O-GlcNAc) 途径调节 ARD 的启动。虽然我们的筛选中没有发现营养传感器对 ARD 维持有显著影响，但我们发现 ARD 恢复受能量感应、应激反应、胰岛素样信号和 TOR 途径调节。对 NHR-49 的下游靶标的进一步研究表明，转录因子通过脂肪酸β-氧化途径影响 ARD 的启动。这些发现与中性脂质水平的变化一致，与 ARD 进入缺陷相关。我们的研究结果确定了 ARD 进入和恢复所需的保守遗传途径，并揭示了遗传相互作用，为 OGT 和 OGA 的作用提供了深入了解。
