Accelerated Aging: Animal Models

Mev-1 (kn 1). A methyl viologen–sensitive mutant of the nematode Caenorhabditis elegans, named mev-1 (kn 1), was isolated after ethyl methanesulfonate mutagenesis. The herbicide methyl viologen, or paraquat, is a potent free-radical generator. The mutant C. elegans strain is about four times more sensitive to methyl viologen than the wild type (N2), and is also hypersensitive to oxygen. The mean life span of the mutant is remarkably reduced. The activity of superoxide dismutase, a scavenging enzyme for superoxide anion (O₂), is reduced in mev-1 (kn 1) by about half, compared to N2. (O₂is also a free-radical generator.) In 1998, Naoaki Ishii et al. reported that mev-1 encodes a subunit of the enzyme succinate dehydrogenase cytochrome b, which is a component of complex II of the mitochondrial respiratory chain, and that the ability of complex II to catalyze electron transport from succinate to ubiquinone is compromised in the mutant. This defect may cause an indirect increase in superoxide levels, which in turn leads to oxygen hypersensitivity and accelerated aging.

D. melanogaster cSODⁿ¹⁰⁸. The role of copper/zinc-containing superoxide dismutase (cSOD) in metabolic defense against O₂toxicity in the fruit fly, Drosophila melanogaster, has been examined through the properties of a mutant strain of D. melanogaster carrying cSOD-null mutation. The mutant, termed cSODⁿ¹⁰⁸confers recessive sensitivity to the paraquat. This indicates that the cSOD-null condition in fact leads to impaired O₂>metabolism. The mean adult life span of the mutant (11.8 days) is remarkably decreased compared to that of the control parental stocks (55.4–57.8 days). Furthermore, male mutants are completely sterile, and females are nearly so. Thus, the primary biological consequence of the reduced O₂dismutation capacity of cSODⁿ¹⁰⁸is infertility and a reduction in life span.

B10. F mice. A congenic line of mice, called B10. F, was produced by introducing a segment of chromosome 17 (H-2ⁿ) from the strain F/St on the background of the C57BL/10 of H-2^b by back-crossing. The congenic B10. F mice gray early, suffer severe weight loss, and have skin that becomes thin and fragile. The mean life span of the B10. F mice is reduced, with 90 percent of the mice dying within seventeen months. The survival curve also shows significantly accelerated aging in the B10. F mice. At twelve to fourteen months these mice have a capacity to produce plaques to red-blood cells of sheep (an antigen for immunization) that is 12 percent of the capacity at four months, as assessed as one aspect of the immune competence of the B10. F mice. Since the strain is a congenic line, the genetic difference (and possibly the basis for the degenerative signs and reduced life span) is amenable to analysis.

Klotho mice. The insertion of a mutated transgene in mice has been found to disrupt a new gene locus, termed klotho, resulting in the manifestation of various phenotypes resembling those in patients with premature-aging syndromes. Homozygous klotho mice show growth retardation and have a short life span—up to three to four weeks of age—and the mice grow normally but show growth retardation thereafter, gradually becoming inactive and marasmic (emaciated), and dying prematurely at eight to nine weeks of age. The average life span of klotho mice is 60.7 days. The pathological phenotypes are infertility, hypokinesis (decreased function of the left ventricle), atrophy of genital organs and the thymus, arteriosclerosis, ectopic calcification, osteoporosis, skin atrophy, emphysema, and abnormalities in the pituitary gland. The klotho gene encodes a membrane protein that shares a sequence similarity with the β-glucosidase enzymes and expresses mainly in kidney and brain. It is hoped that the study of klotho mice with a single gene mutation will help to clarify the molecular-genetic mechanisms of both premature aging and accelerated aging.