Long-lived mutants daf-2(e1370) and eat-2 (ad465) expression profilings

Analysis of gene expression in two long-lived daf-2 mutant (mutation in the insulin/IGF-1 receptor) and eat-2 mutant (caloric restriction model), comparison of gene expression profiles of two long-lived mutants provide novel insight into longevity Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two well-established interventions to prolong lifespan in worm C. elegans. Although many studies using -omics approaches have gained informative knowledges on key longevity regulators in either IIS or CR models, few of those investigated the shared regulators between these two longevity interventions and integrated the messages from different omics studies. In this study, we aimed to identify key pathways and metabolite fingerprints of longevity shared between the two interventions in worms using a multi-omics integration approach. We collected transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared with N2 strain. We detected many key pathways that were upregulated at the gene expression level in both long-lived mutants, such as defense response and lipid storage, while synthesis of macromolecules and developmental processes were downregulated at the transcript level. From our polar metabolite analysis, we discovered several shared metabolic features between the two long-lived mutants, including glycerol-3P, adenine, xanthine and AMP. In addition, we detected a lowered amino acid pool and two fatty acid species, C18:0 and C17:1, that behaved similarly in both long-lived mutants. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism in both long-lived mutants compared to N2 worms. Overall, our findings point towards the existence of shared metabolic pathways that are important for lifespan extension and provide novel insight of potential regulators and metabolic fingerprints for longevity.本研究针对两种长寿突变体——daf-2突变体（胰岛素/胰岛素样生长因子1受体（insulin/IGF-1 receptor）突变）与eat-2突变体（热量限制（caloric restriction, CR）模型）开展基因表达分析，并对比二者的基因表达谱，可为长寿研究提供全新视角。 损伤的胰岛素/胰岛素样生长因子1信号通路（insulin/IGF-1 signaling, IIS）与热量限制（CR）是秀丽隐杆线虫（Caenorhabditis elegans）中两种公认的延寿干预手段。尽管诸多组学研究已在IIS或CR单模型中解析出关键长寿调控因子，但鲜有研究同时探究这两种延寿干预手段的共享调控因子，也未整合不同组学研究的相关信息。 本研究旨在通过多组学整合分析方法，鉴定秀丽隐杆线虫中两种干预手段共享的关键长寿通路与代谢指纹。我们收集了两种长寿突变体线虫菌株（即daf-2，IIS通路损伤型；eat-2，CR模型）的转录组学（transcriptomics）与代谢组学（metabolomics）数据，并与野生型N2菌株进行对比。 我们在两种长寿突变体的基因表达层面检测到多条上调的关键通路，如防御反应与脂质储存；而大分子合成与发育过程在转录水平呈现下调趋势。通过极性代谢物分析，我们发现两种长寿突变体存在多个共享的代谢特征，包括甘油-3-磷酸、腺嘌呤、黄嘌呤与腺苷一磷酸（adenosine monophosphate, AMP）。此外，我们还检测到两种长寿突变体中氨基酸池水平降低，以及两种脂肪酸组分C18:0与C17:1呈现相似的变化模式。 基于京都基因与基因组百科全书（KEGG）的注释信息整合转录组与代谢组数据后，结果显示：与野生型N2线虫相比，两种长寿突变体均呈现嘧啶代谢下调、嘌呤代谢上调的特征。 综上，本研究的发现证实了存在对寿命延长至关重要的共享代谢通路，同时为长寿相关的潜在调控因子与代谢指纹提供了全新的研究见解。