Links: this page
Small mice
Research index
Miller Lab home page
The goal of this set of projects is to learn about the mechanisms of aging by studies of mice that live longer (and presumably age more slowly) than the standard laboratory mouse stocks that are used for aging research. The lab makes use of several models: (a) Snell dwarf and other single-gene mutant mice; (b) mice given a low methionine diet; and (c) wild-derived mice and their hybrids. Our studies of cellular stress resistance, which focus on cells from long-lived mice, are described in more detail here.
To provide a test of the idea that the genes that regulate body size may also, as a side effect, influence the rate of aging and hence life expectancy, we collaborated with William Atchley at North Carolina State University. Dr. Atchley's laboratory has produced a series of 15 mouse stocks, all originating from a single genetically heterogeneous (but laboratory-derived) population. Three of the mouse lines were selected for slow rate of growth from birth to 10 days of age, and three others were selected for slow growth rate from 28 to 56 days of age. All six of these lines are rather small as adults. Six lines were produced by breeding for rapid growth, either from day 0 to 10 or from day 28 to 56; these lines produce large adults. Three unselected control lines were also available. Our longevity study showed that there was a strong correlation, among the 15 stocks, between small body size and longer life span. The correlation coefficient (R2 = 0.49) suggests that the genes that influence early life growth rate have a strong secondary effect on life expectancy.
Another group has reported that a diet that contains very low levels of the essential amino acid methionine leads to a 40% increase in the rat lifespan. Our own lab has shown that a diet low in methionine extends mean and maximum longevity of F1 hybrid mice as well [PubMed]. Analyses of mRNA levels show that the changes in liver gene expression induced by low methionine diets are very different from those induced by a calorically restricted diet. A second lifespan study, now nearing completion, has shown that a low methionine diet can extend lifespan even if begun when the mice are already 12 months of age. Cells from methionine restricted mice, like those of calorically restricted mice, do not show the in vitro stress resistance we have reported in cells from Snell and Ames dwarf mice, but both Meth-R and CR mice are resistant to the liver cell death induced by exposure to toxic doses of acetaminophen. Further work will be needed to see if the extended lifespan seen in Meth-R mice represents changes in DNA methylation patterns, glutathione levels, levels of hormones, alteration in mTOR pathways, or alteration in the rate of protein translation and degradation.
Most mice used in laboratory research have been developed by a long process of gradual adaptation to captive breeding conditions, followed by inbreeding. Because only a small proportion of wild mice will breed in captivity, the first few generations of mice produced by wild-captured animals will select, inadvertently, for genes that promote early reproduction and large litters. The selection pressure for large litters brings with it selection pressure for large body size and rapid growth early in life. Genetic alleles that slow down maturation, reduce litter size, and reduce body size will tend to be lost during this process. In many species, the genes that promote rapid growth and large body size also tend to produce short-lived breeds; large dogs, for example, have shorter lives than dogs from small breeds. Thus the selection for large body size in the production of domesticated laboratory mice may well have caused the elimination, from research mice, of genetic alleles that might retard the aging process - exactly the genes a gerontologist would want to learn more about.
To test this idea we collaborated with Steve Austad to develop a line of mice, called Id (Idaho-derived) from mice wild-trapped in Idaho. With the help of Robert Dysko, we foster nursed laboratory born offspring to create a specific-pathogen-free, non-inbred line for lifespan analysis, taking pains at each generation to include offspring from as many families as possible to minimize loss of genetic heterogeneity.
The first lifespan test showed that Id mice had an increase of 20% in both mean and maximal longevity compared to a genetically heterogeneous stock produced entirely from laboratory-adapted progenitors. A second, independent study replicated the original findings, and showed that F2 hybrids containing a 1:1 mixture of genes from Id mice and from a laboratory stock (B6) had intermediate lifespan, as well as intermediate rates of sexual maturation, weight, and IGF-I levels. A gene mapping study is now underway to map the genetic loci that cause the increased lifespan, slower maturation rate, and characteristic hormonal profile of the Id mouse stock. One of these mice is, we believe, may have set the record for longevity for non-mutant mice consuming a standard diet: click here to read the obituary of IdG1-030, as published on the SAGE-KE website.
4. Single gene mutants: Snell dwarf mice.
Our collaboration with Kevin Flurkey and David Harrison has shown that longevity can be extended by the Snell dwarf (dw/dw) mutation and by the little (lit/lit) mutation, both of which diminish signaling through the growth hormone (GH) and IGF-I pathways. This work also demonstrated that Snell dwarf mice show delayed aging both in T cell function and in collagen cross linking, supporting the conclusion that extended longevity in the Snell dwarf mice reflects authentic deceleration (or delay) in the rate of aging.
Next, to see if the long lifespan of the Snell dwarf mice depended on their small body size and prepubertal state, we injected a group of juvenile dwarf mice with daily doses of GH and T4 for a period of 11 weeks. Male mice treated in this way go through puberty, and mice of both sexes increased about 50% in body size compared to mock-treated dwarf mice (though not to the size of littermate controls). The hormone regimen, however, did not lead to any change in the long lifespan of the mutant mice. These results indicate that the exceptional lifespan of (male) dwarf mice does not represent the lack of sexual maturation, and suggests that longevity depends on hormonal deficits either during the pre-weaning period, or perhaps throughout adult life. In addition, we found that the dwarf mice, regardless of hormone exposure, showed lower levels of cataracts, kidney pathology, and neoplasia than control mice. This study also showed that when hormone-treated dwarf mice were, in addition, given thyroid hormone T4 in drinking water throughout their lifespan, they lost about half of their lifespan advantage over control mice, suggesting that the hypothyroid state of dw/dw mice contributes to their longevity.
5. New studies in progress include:
- Collaborations with Andrzej Bartke and John Kopchick on the Ames dwarf mouse and GHR-KO mice, and studies of the PAPPA-KO mouse of Cheryl Conover
- Studies of stress resistance of skin cells in situ after exposure to UV irradiation
- Work with James Harper on longevity extension by manipulation of nutrient status between birth and weaning
Collaborators: Kevin Flurkey, David Harrison, John Kopchick, Andrzej Bartke, Cheryl Conover, James Harper.
Technician: Maggie Lauderdale (Vergara)
Support: AG024824, AG023122
[Last update: December, 2007]
IdG1-030. world's oldest mouse, in "chew" mode
Plot of life span vs size for 15 Atchley mouse stocks
Methionine-restricted mouse (with chalk) and age-matched control
Dwarf mouse (on
the ground) and a normal sibling (on vehicle)