Recent evidence has prompted the notion of gut-microbial signatures as an indirect marker of aging and aging-associated decline in humans. However, the underlying host-symbiont molecular interactions contributing to these signatures remain poorly understood. In this study, we address this gap using cheminformatic analyses to elucidate potential gut microbial metabolites that may perturb the longevity-associated NAD+ metabolic network. In silico ADMET, KEGG interaction analysis, molecular docking, molecular dynamics simulation, and molecular mechanics calculation predict a large number of safe and bioavailable microbial metabolites to be direct and/or indirect activators of NAD+-dependent sirtuin proteins. Our simulation results suggest dihydropteroate, phenylpyruvic acid, indole-3-propionic acid, phenyllactic acid, all-trans-retinoic acid, and multiple deoxy-, methyl-, and cyclic nucleotides from intestinal microbiota as the best-performing regulators of NAD+ metabolism. Retracing these molecules to their source microorganisms also suggest commensal Escherichia, Bacteroides, Bifidobacteria, and Lactobacilli to be associated with the highest number of pro-longevity metabolites. These findings from our early-stage study, therefore, provide an informatics-based context for previous evidence in the area and grant novel insights for future clinical investigation intersecting anti-aging drug discovery, probiotics, and gut microbial signatures.

中文翻译：

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计算机洞察 NAD+ 代谢和寿命的潜在肠道微生物调节

最近的证据提示了将肠道微生物特征作为人类衰老和衰老相关衰退的间接标志的概念。然而，导致这些特征的潜在宿主-共生体分子相互作用仍然知之甚少。在这项研究中，我们使用化学信息学分析来解决这一差距，以阐明可能扰乱与长寿相关的 NAD+ 代谢网络的潜在肠道微生物代谢物。在 silico ADMET、KEGG 相互作用分析、分子对接、分子动力学模拟和分子力学计算中，预测大量安全​​且生物可利用的微生物代谢物是 NAD+ 依赖性沉默调节蛋白的直接和/或间接激活剂。我们的模拟结果表明二氢蝶酸、苯丙酮酸、吲哚-3-丙酸、苯乳酸、全反式维甲酸、肠道微生物群中的多种脱氧核苷酸、甲基核苷酸和环核苷酸是 NAD+ 代谢的最佳调节剂。将这些分子追溯到它们的源微生物也表明共生大肠杆菌、拟杆菌属、双歧杆菌和乳酸杆菌与最多的长寿代谢物有关。因此，我们早期研究的这些发现为该领域先前的证据提供了基于信息学的背景，并为未来与抗衰老药物发现、益生菌和肠道微生物特征相​​交叉的临床研究提供了新的见解。