Aspartame enhances innate immunity and extends lifespan in Caenorhabditis elegans via autophagy pathway.

Aspartame (ASP) is a common artificial sweetener used in food and beverages. There is currently significant controversy surrounding the safety of aspartame. However, the molecular mechanisms of aspartame on innate immunity and lifespan remain poorly understood. In this study, by screening six different artificial sweeteners (aspartame, sucralose, erythritol, sodium cyclamate, acesulfame potassium, and stevioside), we discovered that only ASP (1, 10, and 100 μM) enhanced resistance to pseudomonas aeruginosa in a dose-dependent manner. 100 μM ASP reduced the bacterial burden in the worms intestine to increase pathogen resistance rather than affecting pathogen proliferation or virulence. Transcriptome sequencing and GO functional enrichment analysis exhibited autophagy pathway enrichment. RT-qPCR experiments confirmed that aspartame (100 μM) treatment upregulated the mRNA levels of key autophagy genes bec-1, unc-51, lgg-1, lgg-2, and atg-5. Observation under a fluorescence microscope revealed that aspartame induced an increase in lgg-1:: gfp. Given autophagy's role in regulating various stresses, we found that ASP also extends lifespan and antioxidant capacity in C. elegans via autophagy pathway. In addition, ASP improved the health status of aging nematodes, including the accumulation of aging pigments and movement ability. This study reveals that aspartame can enhance innate immunity, extend lifespan and healthspan, and improve antioxidant capacity in Caenorhabditis elegans by activating the evolutionarily conserved autophagy pathway. These findings provide a new perspective for comprehensive understanding the biological effects of aspartame and suggest its potential beneficial value.