Sci. Aging Knowl. Environ., 3 October 2001
GENETICALLY ALTERED MICE
Ames Dwarf Mice
The df mutation, which causes the Ames dwarf mouse phenotype, is found in the prop-1 gene, which encodes a transcription factor required for the proper development of the anterior pituitary gland. The mutation in prop-1 leads to an underdevelopment of the pituitary gland, which renders the Ames mice deficient in GH, TSH, and PRL. Experimental evidence suggests that the life-span-extending effect results mostly from the GH deficiency, because overexpression of GH leads to the reduction of life-span, and the Little dwarf mouse (which was produced by knocking out the gene encoding the GH receptor) also shows increased longevity [albeit life-span extention in the Little dwarf mouse (lit/lit) is not quite as extensive as with the Snell or Ames dwarf mice, and in the Little mouse extension of life-span is dependent on a low-fat diet].
The Ames mutation was the first mutation reported to increase the average as well as the maximum life-span of a mammalian organism. The extension in average life-span is ~50%, and the extension in maximal life-span is ~40%. Just as with wild-type lab mice, in Ames mice, caloric restriction further increases life-span. Because the effects on life-span brought on by caloric restriction and the Ames mutation are additive, one can conclude that the pituitary hormones are most likely not involved in the life-extending effect brought on by caloric restriction. At present, it is unclear what mechanisms underlie the increased longevity seen in the Ames mice; however, the existing evidence suggests the involvement of the GH/IGF-1 axis. However, in Little mice, which are deficient only in GH (not in TSH or PRL), the extension in maximum life-span is only 15% (versus about 40% in the Ames mice). This may be related to the absence of the TSH deficiency in Little mice; it has been reported that artificially induced hypothyroidism does indeed increase life-span in rats. However, it is premature to speculate on this matter. The results regarding the lit/lit animals should be regarded as somewhat preliminary because of the small sample size used for the longevity studies.
It is possible that the increased longevity in Ames mice is brought about by a decrease in metabolic rate. Core body temperature is decreased by around 1.5°C in Ames mice as compared with wild-type mice. Paradoxically, mass-adjusted food intake is greater in Ames mice than in wild-type mice. It has also been suggested that elevation in antioxidants may cause the increased longevity in Ames mice. Indeed, Cu,Zn superoxide dismutase (SOD) and catalase are modestly elevated in Ames mice. However, it is unlikely that overxpression of Cu,Zn SOD is responsible for increased longevity in Ames mice, because (i) full knockout of Cu,Zn SOD in mice has no effect on life-span, and (ii) overexpression of Cu,Zn SOD has no effect on life-span.
October 3, 2001
Science of Aging Knowledge Environment. ISSN 1539-6150