Array-based expression analysis of mouse liver genes: Effect of age and of the longevity mutant Prop1^df

Ames dwarf mice, homozygous for the df allele at the Prop1 locus, live 40% to 70% longer than nonmutant siblings and represent the first single-gene mutant that extends life span in a mammal. To gain insight into the basis for the longevity of the Ames dwarf mouse, we measured liver mRNA levels for 265 genes in a group of 11 df/df mice, (three to four mice per age group), at ages 5, 13, and 22 months, and in 13 age- and sex-matched control mice. The analysis showed seven genes where the effects of age reach p < .01 in normal mice and six others with possible age effects in dwarf mice, but none of these met Bonferroni-adjusted significance thresholds. Thirteen genes showed possible effects of the df/df genotype at p < .01. One of these, insulin-like growth factor 1 (IGF-1), was statistically significant even after adjustment for multiple comparisons; and genes for two IGF-binding proteins, a cyclin, a heat shock protein, p38 mitogen-activated protein kinase, and an inducible cytochrome P450 were among those implicated by the survey. In young control mice, half of the expressed genes showed SDs that were more than 58% of the mean, and a simulation study showed that genes with this degree of interanimal variation would often produce false-positive findings when conclusions were based on ratio calculations alone (i.e., without formal significance testing). Many genes in our data set showed apparent young-to-old or normal-to-dwarf ratios above 2, but the large majority of these proved to be genes where high interanimal variation could create high ratios by chance alone, and only a few of the genes with large ratios achieved p <.05. The proportion of genes showing relatively large changes between 5 and 13 months, or from 13 to 22 months of age, was not diminished by the df/df genotype, providing no support for the idea that the dwarf mutation leads to global delay or deceleration of the pace of age-dependent changes in gene expression. These survey data provide the foundation for replication studies that should provide convincing proof for age- and genotype-specific effects on gene expression and thus reveal key similarities among the growing number of mouse models of decelerated aging.