The lexical-semantic organization of the mental lexicon is bound to change across the lifespan. Nevertheless, the effects of lexical-semantic factors on word processing are usually based on studies enrolling young adult cohorts. The current study aims to investigate to what extent age-specific semantic organization predicts performance in referential word production over the lifespan, from school-age children to older adults. In Study 1, we conducted a free semantic association task with participants from six age-groups (ranging from 10 to 80 years old) to compute measures that capture age-specific properties of the mental lexicon across the lifespan. These measures relate to lifespan changes in the Available Richness of the mental lexicon and in the lexical-semantic Network Prototypicality of concrete words. In Study 2, we used the collected data to predict performance in a picture-naming task on a new group of participants within the same age-groups as for Study 1. The results show that age-specific semantic Available Richness and Network Prototypicality affect word production speed while the semantic variables collected only in young adults do not. A richer and more prototypical semantic network across subjects from a given age-group is associated with faster word production speed. The current results indicate that age-specific semantic organization is crucial to predict lexical-semantic behaviors across the lifespan. Similarly, these results also provide cues to the understanding of the lexical-semantic properties of the mental lexicon and to lexical selection in referential tasks.