Background: While our body ages, skin cells progressively lose their pluripotency and proliferative capacities, as well as remodeling driver role, among other activities. This loss of capacities leads to visible aging signs such as wrinkles, under-eye bags or even aging spots. We studied if the stimulation of cell pluripotency and proliferation by a natural molecule could be an innovative anti-ageing strategy for skin rejuvenation. Methods: The activity of sericoside, a compound extracted from the bark of Terminalia sericea roots, was evaluated at a concentration of 0.02% in vitro. This assessment involved transcriptomic analysis on fibroblasts after 24 hours, as well as proliferation tests on aged fibroblasts after 72 hours. A clinical study was then conducted on 40 volunteers between the ages of 35 and 55. For four weeks, volunteers applied a cream twice daily containing either sericoside or blank emulsion (control group). Skin elasticity was measured by cutometry with R2 parameter. Skin texture and roughness was analyzed by an in vivo 3D scanner. Results: Transcriptomic analysis showed that sericoside improved the set of gene expressions involved in cell cycle (+85% MKI67), cell proliferation (+250% IGF1), DNA repair (+56% OGG1), pluripotency transcription factors (+36% NANOG) and stem cells maintenance (+200% SOX2). We substantiated a decrease of proliferation factor with aged cells compared to young cells by 50%, while sericoside increased this proliferation factor by +46%, a similar rate to that of a 22-year-old donor. Clinically, the anti-aging effects of sericoside were evident: the use of sericoside resulted in a 17% increase in skin elasticity and a 10% reduction in skin roughness, underscoring the smoothing effect with sericoside. Conclusions: The study highlighted an innovative anti-aging strategy that involves re-activating cells’ memory to reprogram cell pluripotency by stimulating the natural tools available in our DNA.