Octopamine Enhances Oxidative Stress Resistance Through the Fasting-Responsive Transcription Factor DAF-16/FOXO in C. elegans

Dietary restriction regimens lead to enhanced stress resistance and extended lifespan in many species through the regulation of fasting and/or diet responsive mechanisms. The fasting stimulus is perceived by sensory neurons and causes behavioral and metabolic adaptations. Several studies have implicated that the nervous system is involved in the regulation of longevity. However, it remains largely unknown whether the nervous system contributes to the regulation of lifespan and/or stress resistance elicited by fasting. In this study, we first investigated the role of the nervous system in fasting-elicited longevity and stress resistance. We found that lifespan extension in Caenorhabditis elegans caused by an intermittent fasting (IF) regimen was suppressed by functional defects in sensory neurons. The IF-induced longevity was also suppressed in a mutant that lacks the enzyme required for the synthesis of an amine neurotransmitter, octopamine (OA), which acts in the absence of food, i.e., under fasting conditions. Although OA administration did not significantly extend the lifespan, it enhanced organismal resistance to oxidative stress. This enhanced resistance was suppressed by a mutation of the OA receptors, SER-3 and SER-6. Moreover, we found that OA administration promoted the nuclear translocation of DAF-16, the key transcription factor in fasting responses, and that the OA-induced enhancement of stress resistance required DAF-16. Altogether, our results suggest that OA signaling, which is triggered by the absence of food, shifts the organismal state to a more protective one to prepare for environmental stresses. To investigate the involvement of DAF-16 and octopamine receptors (SER-3 and SER-6) in octopamine-induced genome-wide transcriptome alterations, we conducted transcriptome analysis.饮食限制方案可通过调控禁食或饮食响应机制，在众多物种中提升机体抗逆性并延长寿命。禁食刺激可被感觉神经元感知，并引发行为与代谢层面的适应性变化。多项研究已表明神经系统参与寿命调控过程，但目前尚不明确神经系统是否参与禁食所诱导的寿命及抗逆性调控。本研究首先探究了神经系统在禁食诱导的长寿与抗逆性中的作用。我们发现，间歇性禁食（intermittent fasting, IF）方案诱导的秀丽隐杆线虫（Caenorhabditis elegans）寿命延长，可被感觉神经元的功能缺陷所抑制。在缺失胺类神经递质章鱼胺（octopamine, OA，在无食物即禁食条件下发挥作用）合成所需酶的突变体中，IF诱导的长寿表型同样受到抑制。尽管章鱼胺给药并未显著延长线虫寿命，却可提升机体的氧化应激抗性。该抗性增强效应可被章鱼胺受体SER-3与SER-6的突变所阻断。此外，我们还发现，章鱼胺给药可促进禁食响应关键转录因子DAF-16的核转位，且章鱼胺诱导的抗逆性增强依赖于DAF-16的参与。综上，本研究结果表明，由食物匮乏触发的章鱼胺信号通路，可将机体状态调整至更具保护能力的状态，以应对环境应激。为探究DAF-16与章鱼胺受体（SER-3及SER-6）在章鱼胺诱导的全基因组转录组变化中的作用，我们开展了转录组分析。