Abstract: Developing functional foods to improve the quality of life for elderly people has great economic and social impact. Searching for and validating ingredients with in vivo antioxidant effects is one of the key steps in developing this kind of food. Here we describe the combined use of simple biological models and transcriptomics to define the functional intracellular molecular targets of a polyphenol-enriched cocoa powder. Cocoa powder supplemented culture medium led to increased resistance to oxidative stress, in both the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans, and, in the latter, lifespan was also increased. These effects are fully dependent on the polyphenols present in the cocoa powder and on the sirtuins Hst3 (yeast) and SIR-2.1 (worm). The transcription factor DAF-16 also plays an important role in the case of the nematode, indicating that the insulin/IGF-1 (insulin-like growth factor) signaling pathway is related with the antioxidative effect of cocoa polyphenols. All in all, these results confirm that this polyphenol-enriched cocoa powder, with antioxidant activity, has great potential use as a functional food ingredient for elderly people. Furthermore, this work reveals the value of using simple biological models to screen for compounds that are of interest for the food and pharmacological industry.