The progressive functional decline associated with aging is a primary risk factor for numerous chronic diseases. The discovery of natural compounds that can modulate conserved longevity pathways offers a promising strategy for promoting healthy aging. Hyperoside, a flavonoid abundant in edible plants such as hawthorn, possesses various pharmacological activities, but its specific role and molecular mechanisms in geroprotection remain poorly understood. This study aimed to elucidate the anti-aging effects of hyperoside and its underlying mechanisms using the model organism Caenorhabditis elegans (C. elegans). Our results showed that hyperoside treatment significantly extended the mean lifespan of wild-type C. elegans by up to 19.97% and robustly enhanced healthspan by improving motility and reducing the accumulation of the aging biomarker lipofuscin. Hyperoside could also alleviate Parkinsonism in neurodegeneration models, without disrupting lipid homeostasis or reproduction. Furthermore, hyperoside conferred increased resistance to thermal, oxidative, and pathogenic stress. Mechanistically, the lifespan-extending effects of hyperoside requires the transcription factors DAF-16/FOXO, SKN-1/Nrf2, and HSF-1, and factors involved in immune and anti-oxidative response, including the MAPKK SEK-1 and p38 MAPK PMK-1. Hyperoside treatment promoted the nuclear translocation of DAF-16 and SKN-1 and upregulated their respective downstream target genes, including sod-3 and gst-4. Hyperoside also increased the expression of genes that are the downstream target of both PMK-1 and SKN-1. Since the role of SKN-1 in immune and anti-oxidative response were regulated by PMK-1. Therefore, the beneficial effects of hyperoside might be mediated primarily by activating SEK-1 /PMK-1/ SKN-1 pathway, which subsequently activate HSF-1 to maintain proteostasis. These findings underscore the potential of hyperoside as a dietary-derived agent for combating age-related functional decline.
