<i>Paederoside</i> Promotes Longevity and Fitness in <i>C. elegans</i> Through Ubiquitination and Degradation of DAF-2/IGF1R, Activating DAF-16/FOXO and SKN-1/NRF2 Transcription Factors.

<i>Paederia scandens</i> (<i>Lour</i>.) <i>Merr</i> is a substance exhibiting medicine-food homology (MFH), commonly used in China. However, the antioxidant and anti-aging effects of <i>paederoside</i> (PSG) have not been thoroughly investigated; therefore, in this study, <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) was treated with PSG to investigate these effects. We found that 50, 80, and 100 μg/mL of PSG could prolong the lifespan of <i>C. elegans</i>, and administration of 100 μg/mL PSG significantly reduced the accumulation of lipofuscin. Under conditions of oxidative stress, RT-qPCR analysis revealed that PSG treatment significantly up-regulated the expression of key antioxidant gene <i>skn-1</i> and longevity-associated gene <i>daf-16</i>. In addition, PSG increased the activity of the antioxidant enzymes SOD and CAT and reduced the level of MDA. When DAF-2 activity is reduced or inhibited in <i>C. elegans</i>, DAF-16 and SKN-1 are activated and translocate to the nucleus to promote stress resistance and prolong lifespan. Finally, by utilizing HeLa cell models, we demonstrated that the core component of <i>Paederia scandens</i>, PSG, promotes targeted degradation of IGF1R through the ubiquitin-proteasome system. Our results suggest that feeding <i>C. elegans</i> PSG is effective in extending this organism's lifespan by improving oxidative stress resistance; thus, PSG has significant potential for development as an anti-aging food product and drug.