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Mutation

Models For Genome Instability



Evidence that mutation accumulation does play a role in the functional decline and increased incidence of disease associated with aging can be derived from the work with mouse models having genetically engineered defects in genome stability systems. For example, cells in highly proliferating organs of telomerase-null mice (knockout or defective mice) showed erosion of telomeres, resulting in high levels of genetic instability (fusion and loss of chromosomes), accompanied by increased programmed cell death and a compromised capacity for cell renewal in spleen and bone marrow. In a subsequent study of third-generation telomerase-null mice, shortened life span was found to be accompanied by reduced capacity to respond to stresses, such as wound healing, and by an increased incidence of spontaneous malignancies (Rudolph et al., 1999). The results of these studies underscore that in proliferative organs (highly proliferating cells in organs of telomerase defective mice) the early initiation of genetic instability due to telomere erosion can greatly accelerate age-related loss of cell viability and increased tumor formation.



Other examples of genome stability mutants that point to accelerated aging are mouse models with inactivated genes involved in double-strand break repair. These animals prematurely exhibit symptoms of age-related degeneration in liver, skin, and bone (Vogel et al., 1999). Hence, it appears that genetic defects promoting genomic rearrangements are associated with symptoms of accelerated aging (for a review see Vijg, 2000). This would be in keeping with the results of studies involving patients with Werner syndrome. This genetic disease, caused by a heritable mutation in a single gene (the WRN gene), is characterized by the accelerated occurrence of certain aspects of the senescent phenotype, including cancer. The WRN gene contains both a helicase and an exonuclease function and is thought to play a role in suppressing genomic instability. Indeed, cultured somatic cells from patients with Werner syndrome display an increased rate of somatic mutations and a variety of cytogenetic abnormalities, such as deletions and translocations (Fukuchi et al., 1989). This high level of genomic instability could be the cause of the severe limitation of in vitro life span demonstrated in these cells. Other so-called progeroid syndromes, such ataxia telangiectasia and Bloom syndrome show increased genomic instability (for a review, see Turker and Martin, 1999).

Additional topics

Medicine EncyclopediaAging Healthy - Part 3Mutation - Gross Chromosomal Alterations, Mutations Detected In Selectable Marker Genes, Mutations In Transgenic Mouse Reporter Genes