Aging Aging

Genetically Engineered Mice 367number of animals, thereby increasing the probability that the differencebetween the phenotype in the genetically altered mice vs control animals isstatistically significant and decreasing sampling error. Another solution is tobackcross into an inbred strain prior to phenotypic analysis. The most commonlyused inbred strain in aging studies is C57B1, which is often thebackground of choice for many studies owing to its extensive characterization;the 129 strain from which the original ES cells are often derived have uniquebehavioral and neuroanatomical anomalies, are difficult to breed, and are proneto a number of diseases (46,47). However, if an allelic modifier gene is linked,that is, in close physical proximity to the genetically altered gene, then backcrossinginto the desired strain will not be sufficient to alleviate the effects ofthe modifier unless it is done numerous times, which can be both incrediblytime consuming and expensive. In terms of phenotype in knockout mousestrains, one possible solution is to see if transgenic gene replacement negatesthe effects of loss of gene function (47).Lastly, it is also important to be aware that genetic alteration, such as administrationof pharmacological agents, can have pleiotropic effects leading to aplethora of compensatory changes that result in secondary phenotypical alterationsunrelated to the effects of alteration of expression in the original geneproduct. Therefore, whatever gene is altered or background strain is used, it isimportant to be aware that considerable care must be taken in intepreting theresults of genetic manipulation experiments in mice.7. Examples of Genetically Engineered Mice Constructedto Test Molecular Theories of AgingTransgenic mouse lines with extended lifespans have not yet been reported.However, likely candidates for such analyses based on studies in lower organismssuch as Drosophila would include such genetically engineered models assuperoxide/catalase double transgenic lines and those containing metabolicgenes found to be important in dietary restriction paradigms in rodents (48).Although the use of genetic engineering has yet to produce any longer-livedmouse strains, engineered lines have been used to assess the validity of somecurrent popular molecular theories of aging including the roles of replicativesenescence and DNA damage and repair on longevity, examples of whichare described in the following subheadings.7.1. Replicative SenescenceFibroblasts cultured in vivo undergo a limited number of cell divisions beforethey enter a senescent phase where they can remain for long periods of timewithout undergoing further rounds of mitosis. This phenomenon is known asreplicative senescence (49). It has been suggested that the loss of proliferative