Phytochemicals-induced hormesis protects Caenorhabditis elegans against α-synuclein protein aggregation and stress through modulating HSF-1 and SKN-1/Nrf2 signaling pathways

Mild stress activates the adaptive cellular response for the subsequent severe stress called hormesis. Hormetic stress plays a vital role to activate multiple stress-responsive genes for the benefit of an organism. In tropical regions of world, tubers of Dioscorea spp. has been extensively used in folk medicine and also consumed as food. In this study, we report that the phytochemicals of Dioscorea alata L., tubers extends the lifespan of nematode model Caenorhabditis elegans by hormetic mechanism. We showed that the low dose of tubers extract at 200 and 300 mu g/mL extends the mean lifespan of wild-type worms, whereas higher doses are found to be toxic. Supplementation of tubers extract slightly increased the intracellular ROS in second-day adult worms and it might activate the adaptive stress response, which protects the worms from oxidative and thermal stress. Transgenic reporter gene expression assay showed that extract treatment enhanced the expression of stress protective genes such as hsp-16.2, hsp-6, hsp-60 and gst-4. Further studies proved that the transcription factors HSF-1 and SKN-1/Nrf2 were implicated in hormetic stress response of the worms. Moreover, pretreatment of extract reduced the high glucose-mediated lipid accumulation by enhancing the expression of glyoxalase-1. It was also found that the aggregation of Parkinson's related protein alpha-synuclein reduced in the transgenic strain NL5901 and extended its lifespan. Finally, our results concluded that the presences of hormetic dietary phytochemicals in tubers might drive the stress response in C. elegans via HSF-1 and SKN-1/Nrf2 signaling pathways.