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Mutation - Summary And Future Prospects

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In summary, there is now conclusive evidence that mutations accumulate with age in most organs and tissues of the mouse and in white blood cells of mice and humans. A considerable fraction of this loss of stability of the nuclear genome consists of genome rearrangements. Genome rearrangements in the form of illegitimate recombinations are likely to be due to misrepair and misannealing of double-strand breaks or other DNA lesions opposite one another on the two DNA strands. In view of the elevated occurrence of this type of mutation in white blood cells of patients with segmental progeroid syndromes, it is tempting to speculate that if mutations contribute to the adverse effects associated with aging, genome rearrangements play a major role. Indeed, it is unlikely that randomly induced point mutations will have a major effect on cell functioning. Cellular systems are robust, and insensitive to many mutations. However, sizable genome rearrangements, even a relatively small number, could seriously affect normal regulation, through gene dosage or position effects. A dosage effect is another standard term in biology and means that an additional copy of the gene (or additional copies) will increase the amount of proteins that are produced. (And the other way around, i.e., when one of your two copies of gene X is deleted you may produce less of protein X). In actively proliferating cell compartments one of the predicted effects would be hyperplasia, neoplasia, and tissue atrophy. Hyperplasia is like neoplasia, but a forestage. In many cases (perhaps most) it stays with that and a tumor never results. Atrophy simply means a reduction in mass because of cell loss. In postmitotic cells it could affect a variety of functional pathways leading to a mosaic of cells at different stages and finally to cell death.

Future research in the area of mutation accumulation as a possible cause of aging is likely to focus on two topics. First, more and more emphasis is now given to mouse models genetically manipulated to have defects in genome stability systems. As outlined above, many of these mice also show signs of accelerated aging. By using so-called knock-in models in which natural genes are replaced by genes with subtle alterations rendering them less effective, it should be possible to generate models with overall less effective genome preservation systems without the total absence of one important gene function. If aging is caused by mutation accumulation, it is likely that such mice will mimic the aging phenotype more fully than single-gene knockouts.

Second, a more recent approach, made possible by the completion of the Human Genome Project, is to analyze all genome instability genes for polymorphic variation in different populations of elderly individuals. Gene variants, alone or in combination with others, can then be studied for association with natural differences in life span, functional decline, and age-related disease among elderly persons. Studies of individuals over one hundred years old have provided evidence that genes may play an increasingly prominent role in the ability to achieve older and older age beyond average life expectancy (Perls et al., 1998). It is possible that a combination of optimal genome stability genotypes contributes to the longevity in centenarians.



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