Global Analysis of Age-Related Expression Profiles of Mouse Liver Genes: Toward Understanding Age-Related Homeostasis.

For understanding aging as well as various age-related diseases, it is critical to establish the basic regulatory mechanisms underlying age-related homeostatsis. Through systematic analyses of transgenic mice carrying factor IX and protein C genes, we recently discovered the first molecular mechanism of age-related homeostasis, ASE/AIE-mediated age-related regulatory mechanism of gene expression (Kurachi et. al., Science 1999; Zhang et. al., J. Biol. Chem. 2002; J. Thromb. Haemost. 2005). This laid the foundation for further studies toward an integrated understanding of age-related homeostasis. Here we report global analyses of age-related expression profiles of mouse liver genes. For quantification of expression levels of liver genes of mice at 1, 3, 6, 12, 18 and 24 month of age, Affymetrix GeneChip® Mouse Expression Array 430A (MOE430A with 23,643 probes) were used. These microarray analyses detected 9148 probes as qualified meaningful and the data were subjected to extensive analyses by GeneSpring and IPA network analysis softwares. Real time PCR analyses of representative genes were performed for verifying excellent reproducibility of age-related expression profiles determined by microarray analyses. Age-related stages, particularly of puberty and aging, were identified as the major phases for age-related changes in gene expression. Strong relationships between expression level and ontology, indicating that the highest expression gene group, next highest expression group and lowest level expression gene group are of secreted proteins, mitochondoreal proteins and nuclear regulatory protein, respectively. Most importantly, we successfully identified about a dozen unique and fundamental age-related gene expression patterns including those of age-related stable, gradual increase or decrease, and aging-related dramatic increase or decrease types of expression. These findings led us to a new hypothesis that complex and dynamic age-related regulations of genes are produced by a relatively small number of fundamental regulatory mechanisms. These mechanisms may function independently or in various combinations, thus explaining an essential feature of age-related homeostasis.