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Objectives Resveratrol ( trans-3,4′,5-trihydroxystilbene ( 1)) was previously shown to extend the lifespan of different model organisms. However, its pharmacological efficiency is controversially discussed. Therefore, the bioactivity of four newly synthesized stilbenes ( trans-3,5-dimethoxy-4-fluoro-4′-hydroxystilbene ( 3), trans-4′-hydroxy-3,4,5-trifluorostilbene ( 4), trans-2,5-dimethoxy-4′-hydroxystilbene ( 5), trans-2,4′,5-trihydroxystilbene ( 6)) was compared to ( 1) and pterostilbene ( trans-3,5-dimethoxy-4′-hydroxystilbene ( 2)) in the established model organism Caenorhabditis elegans. Methods Trolox equivalent antioxidant capacity ( TEAC), 2′,7′-dichlorofluorescein ( DCF), thermotolerance assays, C. elegans lifespan analyses. Key findings All compounds exert a strong in-vitro radical scavenging activity ( 6 > 1 > 5 > 2 = 3 = 4), but in vivo, only ( 3) and ( 6) reduce reactive oxygen species ( ROS) accumulation. Furthermore, ( 3) and ( 6) increased the mobility of aged nematodes and prolonged their mean lifespans, while these compounds decreased the thermal stress resistance. Using daf-16 (FoxO), skn-1 (Nrf2) and sir-2.1 (sirtuin) loss-of-function mutant strains, the in vivo antioxidant effects of compounds ( 3) and ( 6) were abolished, showing the necessity of these evolutionary highly conserved factors. However, short-time treatment with stilbenes ( 3) and ( 6) did not modulate the cellular localization of the transcription factors DAF-16 and SKN-1. Conclusion In contrast to resveratrol, the synthetic stilbene derivatives ( 3) and ( 6) increase the lifespan of C. elegans, rendering them promising candidates for pharmacological anti-ageing purposes. [ABSTRACT FROM AUTHOR]