One of the most important considerations in choosing a rodent model is the genetic background. There are advantages and disadvantages of different genetic backgrounds that must be weighed equally. Inbred strains have the advantage that all individuals of the strain are genetically identical, providing a uniform population for study. Small sample sizes are sufficient for most studies because of the genetic homogeneity. Care must be taken to note the substrain being used, as there can be genetic differences between substrains, particularly those that diverged a long time ago. Most laboratory strains of mice originated 80 to 100 years ago, and because embryo cryopreservation is a relatively new technology, for most of their existence they were maintained by constant breeding. Roderick et al. (1985) illustrate the pitfalls of breeding the strains in different laboratories for many generations, describing the many substrains of BALB/c mice in existence now. For example, BALB/cJ and BALB/ cByJ share most alleles, but there are some genetic differences and some biological differences between them. BALB/cJ mice are more aggressive than BALB/ cByJ, have larger brain weights, and different susceptibility to induced diabetes. While these differences are minor considerations for most studies, they illustrate the need to understand the genetic background.
While no one strain is a perfect model for all aspects of human aging, different strains have characteristics valuable for modeling specific aspects of human physiology or disease, and the use of inbred strains allows the investigator to choose a model with characteristics pertinent to the questions at hand. For example, DBA/2 mice are useful for modeling epilepsy and related seizure disorders, as they are very sensitive to audiogenic and electrogenic seizures, while C57BL/6 mice are resistant to both audiogenic and electrogenic seizures (Seyfried et al., 1986). F344 female rats have very low femoral bone strength compared to other inbred rat strains and have been used to model age-associated bone loss (Turner et al., 2001).
There are also disadvantages to using inbred strains, notably strain-specific pathologies that can reach very high levels of incidence, confounding interpretation of results. F344 rats, for example, develop tumors in a large proportion of the population by old age, as well as a high incidence of nephropathy (Lipman et al., 1999). Some strains of mice, particularly the albino strains, experience degeneration of visual acuity with age, as reported for 129 mice by Hengemihle et al. (1999), rendering them unsuitable for studies requiring the use of visual cues, such as maze training. And some strains have extremely short lifespans due to susceptibility to specific diseases. AKR mice develop T cell lymphoma and die by about a year of age, because of interactions between retroviruses that the strain carries (Brayton et al., 2001). Clearly this strain would not be useful for aging studies.
Other strain-specific pathologies are unrelated to the biology of aging but nevertheless may impact aging studies by causing losses in the study population. One commonly encountered problem is the ulcerative dermatitis found in C57BL/6 mice, one of the most popular strains for aging research. Many factors play a role in the development of this pathology, including genetics, diet and husbandry. The etiology of this problem has been reported to be an immune complex-induced vasculitis (Andrews et al., 1994). While the incidence of ulcerative dermatitis is low in young C57BL/6 mice, it increases with age. Andrews et al. analyzed 300 C57BL/6NNia mice that were barrier-raised and negative for ectoparasites and bacterial and fungal diseases. They found an incidence of ulcerative dermatitis of about 20% in the aged mice, with an average age of onset of 20 months. Males and females were affected approximately equally. It is important to take this condition into consideration when using C57BL/6 for aging studies because severe cases require euthanasia, and sample sizes must be large enough to allow for such losses. Aggression is another factor that can lead to losses in group-housed rodents, such as with BALB/c males where fighting leads to some losses in the population due to serious wounds requiring euthanasia.
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