Genes regulated by caloric restriction have unique roles within transcriptional networks

Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.