Genetic and environmental manipulations, such as dietary restriction (DR), 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 DR 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 DR model that is associated with lengthened lifespan and reproductive potential (Angelo and Van Gilst 2009). As the metabolic pathways regulating ARD have not yet been explored in 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 find 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. We also discovered that fatty acid β-oxidation regulates ARD initiation through a pathway involving the O-GlcNAc cycling enzyme, OGT-1, acting with the nuclear hormone receptor NHR-49. Consistent with these findings, our analysis revealed a change in levels of neutral lipids associated with ARD entry defects. Our findings thus identify novel conserved genetic pathways required for ARD entry and recovery and identify new genetic interactions that provide insight into the role of OGT and OGA.

中文翻译：

---

秀丽隐杆线虫成年生殖滞育的营养传感途径

遗传和环境操纵，例如饮食限制（DR），可以改善包括人类在内的多种生物的健康寿命和寿命。营养素摄入的变化通常会触发重叠的代谢途径，这些代谢途径可能会根据多种因素产生不同甚至相反的输出，例如在生物的生命周期中发生DR的时间或营养素变化的性质。由于代谢途径的复杂性和产出的多样性，调节饮食相关的长寿的基本机制尚未得到很好的理解。秀丽隐杆线虫的成年生殖滞育（ARD）是一种DR模型，与寿命延长和生殖潜能相关（Angelo和Van Gilst，2009年）。由于尚未深入探讨调节ARD的代谢途径，因此我们进行了基于候选人的遗传筛选，分析了选定的营养敏感途径，以确定它们对ARD调节的贡献。着眼于ARD的三个阶段（启动，维持和恢复），我们发现ARD的启动受脂肪酸代谢，sirtuins，AMPK和O-连接的N-乙酰基氨基葡萄糖（O-GlcNAc）途径的调节。尽管我们屏幕上的养分传感器对ARD的维持没有显着影响，但我们发现ARD的恢复受能量感应，应激反应，胰岛素样信号传导和TOR途径的调节。我们还发现，脂肪酸β氧化通过涉及O-GlcNAc循环酶OGT-1的途径调节ARD的启动，O-Glc-1与核激素受体NHR-49相互作用。与这些发现一致，我们的分析揭示了与ARD进入缺陷相关的中性脂质水平的变化。因此，我们的发现确定了ARD进入和恢复所需的新型保守遗传途径，并鉴定了提供对OGT和OGA作用的洞察力的新遗传相互作用。