Hydroxysafflor yellow A from safflower enhances stress resilience and proteostasis in Caenorhabditis elegans.

Dietary bioactive compounds from edible plants are increasingly recognized for their roles in promoting healthy aging and protecting against stress-induced cellular damage. Hydroxysafflor yellow A (HSYA), a water-soluble chalcone glycoside abundant in safflower (Carthamus tinctorius L.), is widely used as a natural pigment and has emerging potential as a functional food ingredient. Here, we investigated the effects of HSYA on lifespan and stress resistance using Caenorhabditis elegans (C. elegans). HSYA significantly extended lifespan by up to 78 % under heat stress, 29.03 % under oxidative stress, and also 8.49 % under normal conditions. Mechanistic studies showed that HSYA enhanced DAF-16 nuclear translocation, upregulated HSF-1 and heat shock proteins (HSP), and activated unfolded protein response and autophagy pathways, thereby preserving proteostasis. In addition, HSYA strengthened defenses, reduced reactive oxygen species, and increased the activity of superoxide dismutase (SOD), peroxidase (POD) activities, and glutathione-S-transferase (GST). Importantly, HSYA alleviated toxic protein aggregation in Alzheimer's- and Parkinson's-like worm models, delaying paralysis and supporting neuronal health. Collectively, these findings demonstrate that HSYA exerts dual antioxidant and proteostasis-regulating activities in vivo, highlighting its promise as a plant-derived dietary bioactive with potential applications in functional foods targeting aging and age-related disorders.