Aspartame induces autophagy to extend healthspan in Caenorhabditis elegans via mTORC1/LET-363-TFEB/HLH-30 pathway

High-sugar diets are associated with multiple health risks, such as obesity, metabolic disorders, and cardiovascular diseases. To mitigate the adverse effects of high sugar intake on biological health, aspartame (ASP) is widely used as one of the sugar substitutes. In this study, we used Caenorhabditis elegans ( C. elegans ) as the model to reveal the specific mechanism by which ASP affects healthy lifespan. Our results showed that ASP (1, 10, 100 μmol/L) significantly extended the lifespan of C. elegans and improved health indicators in dose dependent manner, including reduced lipofuscin accumulation and enhanced motility, but did not influence the fertility of worms. Furthermore, by screening the classic signaling pathways, we discovered ASP extended healthspan via mechanistic target of rapamycin complex 1 (mTORC1) pathway. In addition, we found that ASP inhibited mTORC1 activity to promote the nuclear translocation of helix-loop-helix protein 30 (HLH-30), the nematode homolog of transcription factor EB (TFEB), and subsequently upregulated autophagy-related genes such as autophagy-related gene 5 ( atg-5 ), beclin 1 ( bec-1 ), LC3, GABARAP, GATE-16 family member 1 ( lgg-1 ) and LC3, GABARAP, GATE-16 family member 2 ( Lgg-2 ). This ultimately activated the autophagy process, thereby delaying aging. This finding elucidates that ASP induces autophagy to enhance healthspan in C. elegans dependent on the mTORC1/TFEB pathway, offering a novel approach for anti-aging research.