APPA Increases Lifespan and Stress Resistance via Lipid Metabolism and Insulin/IGF-1 Signal Pathway in Caenorhabditis elegans

Animal studies have proven that 1-acetyl-5-phenyl-1H-pyrrol-3-yl acetate (APPA) is a powerful antioxidant as a novel aldose reductase inhibitor independently synthesized by our laboratory; however, there is no current information on APPA’s anti-aging mechanism. Therefore, this study examined the impact and mechanism of APPA’s anti-aging and anti-oxidation capacity using theCaenorhabditis elegansmodel. The results demonstrated that APPA increasesC. elegans’ longevity without affecting the typical metabolism ofEscherichia coliOP50 (OP50). APPA also had a non-toxic effect onC. elegans, increased locomotor ability, decreased the levels of reactive oxygen species, lipofuscin, and fat, and increased anti-stress capacity. QRT-PCR analysis further revealed that APPA upregulated the expression of antioxidant genes, includingsod-3,gst-4, andhsp-16.2, and the critical downstream transcription factors,daf-16,skn-1, andhsf-1of the insulin/insulin-like growth factor (IGF) receptor,daf-2. In addition,fat-6andnhr-80were upregulated. However, the APPA’s life-prolonging effects were absent on thedaf-2,daf-16,skn-1, andhsf-1mutants implying that the APPA’s life-prolonging mechanism depends on the insulin/IGF-1 signaling system. The transcriptome sequencing also revealed that the mitochondrial route was also strongly associated with the APPA life extension, consistent withmev-1andisp-1mutant life assays. These findings aid in the investigation of APPA’s longevity extension mechanism.Keywords:APPA;lifespan;stress resistant;insulin/IGF-1;Caenorhabditis elegans