Our desire to live longer has led to an ever-increasing number of novel antiaging products. However, few molecules have any real effect and new ones need to be studied before they can be used commercially. In this contribution, activation of the caloric restriction (CR) pathway was studied using different three (resveratrol, oxyresveratrol and piceatannol)-a family with demonstrated bioactivity on phosphodiesterase activity. The high-affinity phosphodiesterase type 2 (PDE2) of was expressed in , purified and characterized. The activity and the inhibitory activity of each stilbene was studied, and the findings were compared in vitro and in silico with those obtained with roflumilast-a human PDE4 inhibitor widely used in chronic obstructive pulmonary diseases. Finally, an in vivo chronological lifespan assay using WT and ΔPDE2 strains was carried out. It was demonstrated that stilbenes can modulate yPDE2 activity, increasing the lifespan of the yeast by 18% over a control (in combination with other pathways). In addition, roflumilast increased the lifespan in the WT strain. The findings as a whole would increase the range of lifespan products available and suggest novel uses for approved drugs.