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.


CONCLUSIONS
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.
Carter
Todd A
TA
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. tcarter@salk.edu
Greenhall
Jennifer A
JA
Yoshida
Shigeo
S
Fuchs
Sebastian
S
Helton
Robert
R
Swaroop
Anand
A
Lockhart
David J
DJ
Barlow
Carrolee
C
D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000166:cytology; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000737:chemistry / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D016220:Fibroblast Growth Factor 1 / Q000235:genetics; D020869:Gene Expression Profiling; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology; D013045:Species Specificity
C515460:CCL19 protein, human; C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D012333:RNA, Messenger; D016220:Fibroblast Growth Factor 1