Caloric (or dietary) restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in laboratory mammals. Two of the major questions faced by researchers in this field are the applicability to humans and the biochemical mechanism(s) involved in the actions of CR. Studies in nonhuman primates are beginning to address the former; studies in phylogenetically lower organisms such as yeast and Drosophila are beginning to address the latter. de Cabo and colleagues now provide evidence that some aspects of CR can be reproduced in mammalian tissue culture cells exposed to sera from rats and monkeys subjected to CR. This work presents the initial development of a new model with which to approach mechanistic studies of CR and provides a new form of direct evidence that CR exerts at least some of its effects in trans.