1) background: The desire to live longer lives demans novel strategies to perform this target. For that reason, in this work [1] the increase of the Caenorhabditis elegans (C.elegans) lifespan extension using hyper-branched cyclodextrin-based nanosponges (CD-NS) complexing oxyresveratrol (OXY) was evaluated. 2) Methods: The titration displacement of fluorescein was used to calculate the apparent complexation constant (K_F) between CD-NS and OXY. Moreover, PDE4 was expressed, purified and refolded in presence of cyclodextrins (CDs) to study its possible inhibition as pharmacological target of OXY. 3) Results: The effect of OXY on PDE4 displayed a competitive in vitro inhibition corroborated in silico. A maximum increase of the in vivo life expectancy of about 9.6% of using OXY/CD-NS complexes in comparison with the control was obtained without toxicity. 4) Conclusions: These results as a whole represent new opportunities to use OXY and CD-NS in lifespan products.