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

Abstract

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 the Caenorhabditis elegans model. The results demonstrated that APPA increases C. elegans’ longevity without affecting the typical metabolism of Escherichia coli OP50 (OP50). APPA also had a non-toxic effect on C. 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, including sod-3, gst-4, and hsp-16.2, and the critical downstream transcription factors, daf-16, skn-1, and hsf-1 of the insulin/insulin-like growth factor (IGF) receptor, daf-2. In addition, fat-6 and nhr-80 were upregulated. However, the APPA’s life-prolonging effects were absent on the daf-2, daf-16, skn-1, and hsf-1 mutants 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 with mev-1 and isp-1 mutant life assays. These findings aid in the investigation of APPA’s longevity extension mechanism.

Sulforaphane Exposure Prevents Cadmium-Induced Toxicity and Mitochondrial Dysfunction in the Nematode Caenorhabditis elegans by Regulating the Insulin/Insulin-like Growth Factor Signaling (IIS) Pathway

“…It has been previously reported that SFN extends lifespan and improves health in C. elegans by regulating IIS pathway signaling and activating the nuclear transcription factor DAF-16/FoxO [47]. Recent studies confirm our assumptions and show that various natural compounds use insulin signaling to enhance the oxidative stress response [97,98]. Notably, in mammals, SFN also regulates Nrf2 activation, the ortholog of the skn-1c gene.…”

4,4′-methylenediphenol reduces Aβ-induced toxicity in a Caenorhabditis elegans model of Alzheimer’s disease

“…DAF-16 (FOXO transcription factor homolog) is a major regulator of the insulin signaling pathway and its overexpression can delay aging and extend lifespan in worms ( Wang et al, 2016 ). skn-1 , gst-4 , and sod-3 are target genes of DAF-16, and all are associated with longevity and protection against oxidative stress ( Liu et al, 2023 ; Wang et al, 2023 ). In this study, we first determined the nuclear localization of DAF-16 and the expression of SKN-1.…”