Mutation
Summary And Future Prospects
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.
JAN VIJG
See also ACCELERATED AGING: ANIMAL MODELS; ACCELERATED AGING: HUMAN PROGEROID SYNDROMES; CELLULAR AGING: CELL DEATH; GENETICS; LONGEVITY: REPRODUCTION; LONGEVITY: SELECTION; NUTRITION: CALORIC RESTRICTION; STRESS; THEORIES OF BIOLOGICAL AGING.
BIBLIOGRAPHY
BRONSON, R. T. "Rate of Occurrence of Lesions in 20 Inbred and Hybrid Genotypes of Rats and Mice Sacrificed at 6 Month Intervals During the First Years of Life." In Genetics of Aging, Vol. 2. Edited by D. E. Harrison. Caldwell, N.J.: Telford Press, 1990. Pages 280–358.
CURTIS, H. J. "Biological Mechanisms Underlying the Aging Process." Science 141 (1963): 686–694.
DEMPSEY, J. L.; PFEIFFER, M.; and MORLEY, A. A. "Effect of Dietary Restriction on in Vivo Somatic Mutation in Mice." Mutation Research 291 (1993): 141–145.
DOLLÉ, M. E. T.; GIESE, H.; HOPKINS, C. L.; MARTUS, H. J.; HAUSDORFF, J. M.; and VIJG, J. "Rapid Accumulation of Genome Rearrangements in Liver but not in Brain of Old Mice." Nature Genetics 17 (1997): 431–434.
DOLLÉ, M. E. T.; SNYDER, W. K.; GOSSEN, J. A.; LOHMAN, P. H. M.; and VIJG, J. "Distinct Spectra of Somatic Mutations Accumulated with Age in Mouse Heart and Small Intestine." Proceedings of the National Academy of Sciences of the United States of America 97 (2000): 8403–8408.
FAILLA, G. "The Aging Process and Carcinogenesis." Annals of the New York Academy of Science 71 (1958): 1124–1135.
FUKUCHI, K.; MARTIN, G. M.; and MONNAT, R. J., JR. "Mutator Phenotype of Werner Syndrome is Characterized by Extensive Deletions." Proceedings of the National Academy of Sciences of the United States of America 86 (1989): 5893–5897.
GOSSEN, J. A.; DE LEEUW, W. J. F.; TAN, C. H. T.; LOHMAN, P. H. M.; BERENDS, F.; KNOOK, D. L.; ZWARTHOFF, E. C., and VIJG, J. "Efficient Rescue of Integrated Shuttle Vectors from Transgenic Mice: A Model for Studying Gene Mutations in Vivo." Proceedings of the National Academy of Sciences of the United States of America 86 (1989): 7971–7975.
GOSSEN, J. A., and VIJG, J. "Transgenic Mice as Model Systems for Studying Gene Mutations In Vivo." Trends in Genetics 9 (1993): 27–31.
GRIST, S. A.; MCCARRON, M.; KUTLACA, A.; TURNER, D. R.; and MORLEY, A. A. "In Vivo Human Somatic Mutation: Frequency and Spectrum with Age." Mutation Research 266 (1992): 189–196.
LEE, A. T.; DESIMONE, C.; CERAMI, A.; and BUCALA, R. "Comparative Analysis of DNA Mutations in lacI Transgenic Mice with Age." Federation of American Societies for Experimental Biology Journal 8 (1994): 545–550.
LOEB, L. A. "Endogenous Carcinogenesis: Molecular Oncology into the Twenty-First Century—Presidential Address." Cancer Research 49 (1989): 5489–5496.
MARTIN, G. M.; OGBURN, C. E.; COLGIN, L. M.; GOWN, A. M.; EDLAND, S. D., and MONNAT, R. J., JR. "Somatic Mutations are Frequent and Increase with Age in Human Kidney Epithelial Cells." Human Molecular Genetics 5 (1996): 215–221.
MASORO, E. J. "Dietary Restriction and Aging." Journal of the American Geriatrics Society 41 (1993): 994–999.
ODAGIRI, Y.; UCHIDA, H.; HOSOKAWA, M.; TAKEMOTO, K.; MORLEY, A. A.; and TAKEDA, T. "Accelerated Accumulation of Somatic Mutations in the Senescence-Accelerated Mouse." Nature Genetics 19, no. 2 (1998): 116–117.
ONO, T.; IKEHATA, H.; NAKAMURA, S.; SAITO, Y.; HOSOI, Y.; TAKAI, Y.; YAMADA, S.; ONODERA, J.; and YAMAMOTO, K. "Age-Associated Increase of Spontaneous Mutant Frequency and Molecular Nature of Mutation in Newborn and Old lacZ-Transgenic Mouse." Mutation Research 447 (2000): 165–177.
PERLS, T. T.; BUBRICK, E.; WAGER, C. G.; VIJG, J.; and KRUGLYAK, L. "Siblings of Centenarians Live Longer." Lancet 351 (1998): 1560.
RUDOLPH, K. L.; CHANG, S.; LEE, H. W.; BLASCO, M.; GOTTLIEB, G. J.; GREIDER, C.; and DEPINHO, R. A. "Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice." Cell 96 (1999): 701–712.
TURKER, M. S., and MARTIN, G. M. "Genetics of Human Disease, Longevity and Aging." In Principles of Geriatric Medicine and Gerontology, 4th ed. Edited by W. R. Hazzard, J. P. Blass, W. H. Ettinger, Jr., J. B. Halter, and J. G. Ouslander. New York: McGraw-Hill, 1999.
VIJG J. "Somatic Mutations and Aging: A Re-Evaluation.". Mutation Research 447 (2000): 117–135.
VOGEL, H.,; LIM, D. S.; KARSENTY, G.; FINEGOLD, M.; and HASTY, P. "Deletion of Ku86 Causes Early Onset of Senescence in Mice." Proceedings of the National Academy of Sciences of the United States of America 96 (1999): 10770–10775.
WARNER, H. R., and JOHNSON, T. E. "Parsing Age, Mutations and Time." Nature Genetics 17 (1997): 368–370.
Additional topics
Medicine EncyclopediaAging Healthy - Part 3Mutation - Gross Chromosomal Alterations, Mutations Detected In Selectable Marker Genes, Mutations In Transgenic Mouse Reporter Genes