Norathyriol delays aging through DAF-16- and SKN-1-associated antioxidant responses in Caenorhabditis elegans.

Abstract

Norathyriol (NOR), the aglycone of mangiferin, exhibits diverse biological activities, but the mechanisms underlying its effects on aging remain incompletely understood. We investigated the effects of NOR on lifespan, locomotor performance, and antioxidant responses in Caenorhabditis elegans. Among the concentrations tested (10-50 μM), 20 μM NOR produced the greatest observed improvements in locomotor performance and extended median lifespan by 13.3% without an evident reduction in fecundity. Target prediction highlighted FoxO-related signaling, while molecular docking with the predicted C. elegans DAF-16 Forkhead domain suggested a potential interaction (-6.0 kcal/mol). NOR promoted DAF-16 nuclear translocation, as demonstrated by DAF-16::GFP localization analysis, and daf-16 RNAi abolished the detectable locomotor and lifespan benefits. NOR also increased gst-4::GFP fluorescence and the expression of antioxidant-associated genes, including ctl-1, ctl-2, sod-3, and gst-4. Knockdown of either daf-16 or skn-1 prevented a significant NOR-associated increase in gst-4::GFP fluorescence. Furthermore, daf-16, skn-1, or gst-4 RNAi diminished the observed locomotor and reactive oxygen species (ROS) -related fluorescence responses to NOR. Together, these findings support the involvement of DAF-16- and SKN-1-associated antioxidant responses, including GST-4, in the beneficial effects of NOR on aging-related phenotypes.