This study presents an electrochemical strategy to generate the redox-active flufenamic acid-drug metabolite, FFA-Redox, which extends the lifespan of C. elegans worm-by up to 80% under pathogenic infection. The metabolite reduces intracellular ROS levels and enhances superoxide dismutase expression, suggesting a potent antioxidant-driven “de-aging” mechanism with promising biomedical potential.

Abstract

The search for drugs that extend lifespan in human-like biological models is a frontier area in biomedical research. In this study, we report a novel electrochemical approach using flufenamic acid (FFA), a widely known nonsteroidal anti-inflammatory drug (NSAID), to generate and detect its pharmacologically active metabolites. Electrochemical oxidation of FFA on multi-walled carbon nanotubes(MWCNT)-modified electrode yielded hydroxylated derivatives, primarily 4-hydroxy FFA (m/z 297.05 g/mol) and a polyhydroxylated product termed FFA-Redox (m/z 243.05 g/mol), as surface-confined species (MWCNT@FFA-Redox). To establish biological relevance, Caenorhabditis elegans (C. elegans) were exposed to FFA, resulting in in vivo formation of metabolites identical to those generated electrochemically. This confirmed the physiological significance of the electrosynthesized compounds. Lifespan assays demonstrated that FFA-Redox prolonged the survival of C. elegans by up to 40% under Klebsiella pneumoniae infection and by up to 80% under Staphylococcus aureus infection. This protective effect was attributed to reduced levels of intracellular reactive oxygen species (ROS). Mechanistic insights suggest that FFA-Redox induces a “de-aging” response by enhancing the expression of superoxide dismutase (SOD), a key antioxidant enzyme activated during oxidative stress.