M.R. Capecchi

Gene targeting provides the means for creating strains of mice with designed alteration in any chosen genetic locus. This technology permits the evaluation of the functions of genes in the intact mammal and the systematic dissection of the most complex biological processes from embryogenesis to aging. With virtually complete control over how a gene's DNA sequence is modified, the investigator can disrupt the gene in the germline, and as a consequence every cell of the mouse carries the disrupted gene, or the modification can be implemented conditionally, thereby restricting the function of the gene in chosen tissues and/or temporal periods of the animal, including adulthood.

Because of all of the model organisms, the mouse's genome and physiology is most similar to ours, it would appear that this creature is likely to be the most informative experimental organism to evaluate the multiple facets that affect the process of aging and permit evaluation of the genetic and environmental factors that most significantly alter the aging process. Is it reasonable to anticipate that the life span of the laboratory mouse can be significantly changed through genetic manipulations? Comparisons among the life spans of different mammalian species of comparable size and physiology suggest that it should be. For example, the average life span of the laboratory mouse is approximately two years. However, the microbat species Myotis lucifugus readily attains a life expectancy of thirty years. These two species are nearly identical in size and have very similar physiological parameters such as heart rates, blood pressure, body temperatures and so on. It is not unreasonable to assume that such enormous differences in life expectancies between these two species is determined in part by genetic differences. We will explore technologies that use the mouse as a surrogate and may allow the identification of such genetic determinants.

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mouse models of human aging