Mechanisms of aging in senescence-accelerated mice

Background: Progressive neurological dysfunction is a key aspect of human aging. Because of underlying differences in the aging of mice and humans, useful mouse models have been difficult to obtain and study. We have used gene- expression analysis and polymorphism screening to study molecular senescence of the retina and hippocampus in two rare inbred mouse models of accelerated neurological senescence ( SAMP8 and SAMP10) that closely mimic human neurological aging, and in a related normal strain ( SAMR1) and an unrelated normal strain ( C57BL/ 6J). Results: The majority of age- related gene expression changes were strain- specific, with only a few common pathways found for normal and accelerated neurological aging. Polymorphism screening led to the identification of mutations that could have a direct impact on important disease processes, including a mutation in a fibroblast growth factor gene, Fgf1, and a mutation in and ectopic expression of the gene for the chemokine CCL19, which is involved in the inflammatory response. Conclusion: We show that combining the study of inbred mouse strains with interesting traits and gene- expression profiling can lead to the discovery of genes important for complex phenotypes. Furthermore, full- genome polymorphism detection, sequencing and gene- expression profiling of inbred mouse strains with interesting phenotypic differences may provide unique insights into the molecular genetics of late- manifesting complex diseases.