Gene expression profile of long-lived Ames dwarf mice and Little mice

Abstract

Ames dwarf mice (Prop1df/df) and Little mice (Ghrhrlit/lit) are used as models of delayed aging and show significant increases in lifespan (50% and 25%, respectively) when compared with their wild-type siblings. To gain further insight into the molecular basis for the extended longevity of these mice, we used oligonucleotide microarrays to measure levels of expression of over 14 000 RNA transcripts in liver during normal aging at 3, 6, 12 and 24 months. We found that the Prop1df/df and Ghrhrlit/lit genotypes produce dramatic alterations in gene expression, which are predominantly maintained at all ages. We found 1125 genes to be significantly affected by the Prop1df/df genotype and 1152 genes were significantly affected by the Ghrhrlit/lit genotype; 547 genes were present in both gene lists and showed parallel changes in gene expression, suggesting common mechanisms for the extended longevity in these mutants. Some of the functional gene classes most affected in these mutants included: amino acid metabolism, TCA cycle, mitochondrial electron transport, fatty acid, cholesterol and steroid metabolism, xenobiotic metabolism and oxidant metabolism. We found that the Prop1df/df genotype, and to a minor extent the Ghrhrlit/lit genotype, also produced complex alterations in age-dependent changes in gene expression as compared with wild-type mice. In some cases these alterations reflected a partial delay or deceleration of age-related changes in gene expression as seen in wild-type mice but they also introduced age-related changes that are unique for each of these mutants and not present in wild-type mice.