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

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, 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 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.