Kukoamine A from the root bark of Lycium chinense Miller enhances mobility in an aged Caenorhabditis elegans model by regulating mitochondrial function through HSF-1-mediated upregulation of heat shock proteins

ETHNOPHARMACOLOGICAL RELEVANCE: Lycium chinense Miller has long been used in East Asian medicine for muscle and bone support. Kukoamine A (KA), a bioactive compound from its root bark, has not been previously studied for its potential to counteract age- and heat-induced locomotor decline. AIM OF THE STUDY: This study aims to investigate whether KA improves mobility in aged animal models and to elucidate its underlying mechanism. MATERIALS AND METHODS: Caenorhabditis elegans were treated with KA, and their growth rate, locomotor performance under aging and heat-stressed conditions were evaluated. ROS levels, muscle mitochondrial morphology, and mitochondrial membrane potential were measured via fluorescence microscopy. The nuclear localization of SKN-1 and the expression levels of HSF-1 and its downstream HSPs were measured in the transgenic GFP-tagged strains. The necessity of HSF-1 and HSPs was tested using corresponding mutant worms. RESULTS: KA treatment ameliorated the age-related decrease in swimming activity and preserved muscle mitochondrial morphology in aged worms. Furthermore, it attenuated the age-associated increase in ROS levels. The treatment significantly increased the expression of HSF-1, as well as its downstream targets, HSP-6, HSP-4, and HSP-16.2, whereas SKN-1 nuclear translocation was not observed with the 24 h of L4-stage regimen. The locomotor benefits of KA supplementation were abolished in HSF-1 and HSP-deficient mutants, with speed preserved only in the HSP-16.2 mutant. Furthermore, it prevented heat stress-induced mobility impairment. CONCLUSION: KA treatment mitigated age-related locomotor decline by enhancing mitochondrial health and inducing HSF-1-mediated HSP activation across multiple cellular compartments.