Additive regulation of hepatic gene expression by dwarfism and caloric restriction.

Disrupted growth hormone/insulin-like growth factor-1 signaling (DF) and caloric restriction (CR) extend life span and delay the onset of age-related diseases in rodents. In combination, these interventions additively extend life span. To investigate the molecular basis for these effects, we performed genome-wide, microarray expression analysis of liver from homozygous and heterozygous Ames dwarf mice fed ad libitum or CR. CR and DF additively affected a group of 95 genes. Individually and together, DF and CR independently affected the expression of 212 and 77 genes, respectively. These results indicate that DF and CR affect overlapping sets of genes and additively affect a subset of genes. Together, the interventions produced changes in gene expression consistent with increased insulin, glucagon and catecholamine sensitivity, gluconeogenesis, protein turnover, lipid beta-oxidation, apoptosis, and xenobiotic and oxidant metabolism; and decreased cell proliferation, lipid and cholesterol synthesis, and chaperone expression. These data suggest that the additive effects of DF and CR on life span develop from their additive effects on the level of expression of some genes and from their independent effects on other genes. These results provide a novel and focused group of genes closely associated with the regulation of life span in mammals.