Exploring the relationship between artificial sweeteners and aging based on network toxicology approaches

Abstract Artificial sweeteners (AS) are widely used as sugar substitutes in obese and diabetic populations to control sugar intake and blood glucose levels. However, recent studies indicate that their consumption may not only fail to alleviate obesity but also increase the incidence and mortality of age-related cardiovascular diseases and cancers. Currently, research on their direct association with aging remains very limited. Toxicity analysis of seven common artificial sweeteners (aspartame, Acesulfame-K, sucralose, saccharin, neotame, sodium cyclamate, and NHDC) was conducted using ADMETlab 3.0. Their targets (from CTD, SwissTargetPrediction, and SEA databases) were intersected with aging-related targets (from GeneCards, OMIM, and Aging Atlas databases) to identify common targets. Finally, enrichment analysis was performed through the Metascape platform. The PPI network constructed by STRING was analyzed using Cytoscape, and molecular docking and dynamics simulations were employed to validate the interactions of key targets. The results demonstrated that these AS exhibited genotoxicity and shared 139 targets with aging processes. GO analysis associated them with oxygen response and extracellular matrix, while KEGG enrichment analysis highlighted the significance of cancer and PI3K-Akt pathways. INS and AKT1 were identified as key targets, with molecular docking confirming stable binding characteristics of AS-AKT1. SA-β-gal and WB showed NHDC, Neotame promote senescence with P21 and P53 upregulation. This study demonstrated that AS may influence the human aging process by binding to AKT1 and interfering with pathways such as PI3K-Akt, which provides further research directions for elucidating their functional relationship and strengthening the application foundation of AS.