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640 gm

350 gm

aFrom Turturrro et al. (1999).

aFrom Turturrro et al. (1999).

different parental alleles at many loci produces the pay-off of improved health. Tables 33.1 and 33.2 compare the median lifespan and the average maximum body weight of some of the inbred and hybrid mouse and rat strains included in the NIA's aged rodent colonies.

Genetically heterozygous (HET) mice are another alternative to inbred strains. HET mice are mixtures of four (F2 generation) or eight (F3 generation) strains of mice. They have more genetic diversity, with individuals in the population differing from each other at a portion of the loci. That genetic diversity makes the population more reflective of the human population than an inbred strain, but also necessitates use of larger sample sizes due to the differences between individuals. HET mice are a valuable resource for mapping and identifying genes that influence or modify traits, by exploiting differences in characteristics specific to the parental strains. For example, Lipman et al. (2004) identified genetic regions that influence the types and prevalence of pathologies present at death. HET mice were also used to identify QTLs that influence the severity of age-related cataracts (Wolf et al., 2004). Mice are a good model for age-related cataracts, as the timing and location of cataracts in mice are similar to what is observed in elderly humans. QTLs were identified on three chromosomes, and statistical analysis indicated that the effects of the three QTLs were additive—the more at-risk alleles a mouse had, the greater its risk for severe cataracts. Further description of HET mice can be found in Chapter 4 of this book and other references (Miller and Nadon, 2000; Miller and Chrisp, 2002).

Genetic Manipulations

The genetic makeup of rodents is easily manipulated by selective breeding and by genetic engineering. Table 33.3 summarizes types of rodent models produced by standard breeding protocols, selecting at each generation for chromosomal markers or phenotypic traits. They exploit strain-specific characteristics and are listed in descending order from the least amount of recombination between the strains to the most recombination between the strains. An example of the use of selective breeding models is found in Mountz et al. (2001), a review of recombinant inbred strains derived from a cross between C57BL/6 and DBA/2 mice that were used to identify genomic regions influencing immune response in young and aged mice.

Genetically engineered models have become an essential tool for identifying biochemical and genetic pathways involved in disease processes (summarized in Table 33.4). Transgenic mice are valuable for studying the effects of increased expression of a protein, expression of dominantnegative proteins, and replacement of defective proteins. Transgenic rats are also produced, but they have not caught on as well as mice as they are more costly and difficult to produce. Knockout mice are used to model diseases based on deficiency and to study the function of individual gene products in a pathway. A good review of both selective breeding models and genetically engineered models is provided in Brockmann and Bevova (2002). Genetic background is just as important when working with genetically engineered models as it is when working with inbred strains, because the phenotype of the genetic alteration can vary on different backgrounds. For example, the expression of an amyloid precursor protein transgene in FVB mice showed unexpected phenotypes, including premature death and seizures, not observed when the same transgene was expressed on other genetic backgrounds (Ashe, 2001).

Mutations, whether spontaneous or induced, have also contributed greatly to our understanding of aging. The Snell Dwarf mouse, first identified in the 1950s, was the first mutant to show an extended lifespan. There have been over 100 publications on the Snell Dwarf since then,

TABLE 33.3 Rodent models produced by selective breeding

Model

Description

Chromosome Substitution

Strain (CSS) Congenic strain

Recombinant Congenic Strain (RCS)

Recombinant Inbred Strain (RIS)

Advanced Intercross Lines (AIL)

An entire chromosome is moved to a different genetic background.

One region of one chromosome is moved onto a different genetic background by backcrossing an F1 hybrid to one parental strain to inbreed.

Large regions of chromosomes moved onto another background by backcrossing an F1 hybrid to one parental strain for a few generations and inbreeding by brother-sister matings.

Large number of smaller recombination units made by creating an F2 hybrid and inbreeding by brother-sister matings.

Multiple (F10 or more) intercrosses between two strains. They are not inbred, hence are heterozygous at many loci.

TABLE 33.4 Genetically engineered rodent models

Model

Inducible transgenic Knockout

Knock-in

Conditional Knockout

A genetic element is added through DNA injection into the embryo, resulting in a gain-of-function at the genome level.

Expression of a transgene is induced by exogenous compounds.

Expression of a genetic element is eliminated by homologous recombination with a construct that prevents transcription of intact mRNA.

Homologous recombination creates a change in the mouse genome, replacing the wild-type mouse sequence with a mutation, human gene sequence, etc.

Knockout of a genetic element is controlled in a temporal, developmental, or tissue-specific manner.

reporting on various aspects of aging in this mutant (reviewed in Bartke and Brown-Borg, 2004). It has been a key player in studies that demonstrate the importance of the insulin-signaling pathway in aging. The Ames Dwarf mouse is another spontaneous mutation with increased lifespan and a reduction in both total neoplastic load and total disease burden at death (Ikeno et al., 2003). An in-depth discussion of the dwarf mouse models is presented in Chapter 34 of this book.

Liang et al. (2003) review seven mouse models with extended lifespan, three mutations (Snell and Ames Dwarf mice and Little mice [Ghrhrlit/lit]), and four gene knockouts (GHR/BP p66shtW~ Igf1R+/~, and FIRKO). All of the models are loss-of-function changes at the genetic level. Six of the seven models (with the exception of p66shc~/~) share many characteristics in spite of involving different genes: growth retardation and reduced body weight, altered metabolism, and alterations in the insulin signaling pathway. This concordance of phenotypes speaks to the importance of metabolism and the insulin-signaling pathway in lifespan determination.

There is some difference of opinion on the value of mutations that shorten lifespan rather than extend it. There are now several mouse mutants that have shortened lifespans, many of them based on mutations identified in human diseases. Clearly it is important when using models that shorten lifespan to distinguish between those that cause premature death due to a specific disease, such as cancer, and those that accelerate many aspects of the aging phenotype. Hasty and Vijg (2004) provide a good discussion of the pros and cons of the mutant rodent models with accelerated aging.

Caloric Restriction

An exciting field in biogerontology research is the emphasis on finding interventions that delay the onset of aging phenotypes or slow the process of aging. While many compounds have some beneficial effects in lower organisms or cell culture, the only intervention proven to extend lifespan and health span in mammals is caloric restriction (CR). When rodents are fed a nutritionally complete diet limited to 60-70% of their ad libitum food intake, they generally live longer, have a reduced disease burden, and show delayed onset of many of the common phenotypes of aging (reviewed in Masoro, 2000). Understanding the mechanisms by which CR extends lifespan and health span will likely lead to new therapeutic interventions to delay the negative aspects of aging. The insulin-signaling pathway is clearly one candidate pathway, as CR reduces age-associated insulin resistance. The action of CR appears to be independent of body weight reduction, as mice subjected to every-other-day fasting did not reduce their total food intake or body weight, yet still experienced the beneficial effect on glucose

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