In silico insights into potential gut microbial modulation of NAD+ metabolism and longevity

Abstract

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.

3-phenyllactic acid promotes healthspan through SKN-1/ATFS-1-mediated mitochondrial activation and stress resilience

“…Encouraged by these findings, we delved deeper into the potential advantages of PLA for organismal fitness and mitochondrial activity. Guided by the perspectives on the roles of energy metabolism, we explored phenylpyruvic acid, a metabolic precursor of PLA, which was predicted as an NAD + activator through in silico analysis 51 . The observed increase in longevity was found to be contingent on its conversion to PLA.…”

Microbial dysbiosis and the aging process: a review on the potential age-deceleration role of Lactiplantibacillus plantarum

“…showed promising effects on the aging model ( Ni et al, 2019 ; Vaiserman et al, 2020 ). Compounds derived from microbes such as melleolide and microbial invertase may confer rejuvenating and positive effects on several types of aging cells ( Gupta et al, 2019 ; Salekeen et al, 2021 ). A recent experiment suggests that gut-microbes-associated compounds such as indole-3-propionic acid, dihydropteroate, phenyllactic acid, phenylpyruvic acid, all-trans-retinoic acid, and multiple deoxy-, methyl-, and cyclic nucleotides from gut microbiota are the considerable regulators of NAD+ metabolism and could be the indirect markers for aging-associated degeneration in humans ( Rabe et al, 2006 ; Chen et al, 2023 ).…”

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…For instance, MD has recently predicted the inhibition of gut bacterial β-glucuronidases by the biflavanoid, amentoflavone; these findings could aid the prevention of microbiome-led drug metabolism, as many drugs are known to be biotransformed by bacterial β-glucuronidases [255]. Elsewhere, molecular modelling (including MD) has discovered the influence of microbial metabolites on longevity-associated metabolic pathways; this could lead to the identification of novel therapies to support healthy ageing through the gut [256]. From a drug development perspective, MD has many potential applications for formulation design.…”