Isorhamnetin-3-O-glucoside-7-O-rhamnoside (IGRh), a characteristic sea buckthorn leaf flavonoid, extended lifespan and improved healthspan markers in C. elegans — including motility, intestinal integrity, muscle structure, and lipid homeostasis — without reproductive penalty. Mechanistically, IGRh upregulated SIR-2.1 (SIRT1 ortholog), triggered nuclear translocation of transcription factors DAF-16 and HSF-1, elevated SOD and catalase activities, reduced ROS and MDA, and stimulated autophagy-lysosomal flux and mitochondrial quality control. Longevity effects vanished in sir-2.1, daf-16, hlh-30, bec-1, clk-1, and mev-1 mutants. Critically, metabolomic profiling identified IGRh's rapid biotransformation into quercetin-3-O-glucoside (Q3G), isorhamnetin, and protocatechuic acid — with Q3G showing the strongest SIR-2.1 binding affinity and independently replicating the anti-aging phenotype.
This work is mechanistically sophisticated for a plant-compound aging study, particularly the metabolite-first framing: IGRh may function as a prodrug whose bioactive derivatives drive the longevity signal. The SIR-2.1/DAF-16/IIS axis is well-established in C. elegans longevity research, so pathway activation here is confirmatory rather than paradigm-shifting. More compelling is the identification of Q3G — a quercetin glycoside already present in common foods — as a discrete SIR-2.1 ligand supported by CETSA thermal-shift validation. Limitations are significant: C. elegans findings translate poorly to mammals, the sirtuin-longevity link remains contested in higher organisms, and no mammalian bioavailability data exist for Q3G at relevant doses. Still, the metabolite-resolution methodology sets a useful template for flavonoid mechanism research.
