Synergistic effects of 3-O-methylquercetin and polyphenols on longevity, healthspan, and neuroprotection via FOXO/Nrf2.

Polyphenols are emerging as promising candidates for promoting healthy aging and neuroprotection. Here, we investigated the effects of quercetin (Q), luteolin (L), and 3-O-methylquercetin (3OMQ), individually and in combination (FORM), on lifespan, healthspan(definition), and neurobehavioral functions in Caenorhabditis elegans. Wild-type and mutant strains (including daf-2, daf-16, and skn-1) were exposed to the compounds, followed by assessments of longevity, motility, senescence(definition) biomarkers (lipofuscin and red autofluorescence), and neuroprotection against PTZ- and methylmercury-induced damage. 3OMQ and FORM significantly extended lifespan (+ 20-24%) and improved motility and stress resilience, with effects dependent on the DAF-16/FOXO and SKN-1/Nrf2 pathways, but independent of DAF-2/IGF1R signalling. Both compounds induced DAF-16 nuclear translocation and upregulated SKN-1 expression. Furthermore, they attenuated neurodegeneration and cholinesterase hyperactivity following manganese and methylmercury exposure. These findings support the potential of 3OMQ and its polyphenol combination as anti-aging and neuroprotective agents, acting through conserved longevity and oxidative stress pathways.