Accelerated Aging: Animal Models

L line. High (H) and low (L) antibody responder lines of mice have been separated by selective breeding, presenting a maximal interline difference in antibody response to sheep red-blood cells, which was reached after fifteen successive generations of selective breeding. The life span of the H line and L line is 612 days and 346 days, respectively. Interpopulation correlation between life span and antibody response has shown that the life span is correlated positively with 2-mercaptoethanol (a reducing agent)– resistant agglutinin response and negatively with 2-mercaptoethanol-sensitive agglutinin response. Pathological examinations have revealed that chronic nephritis and malignant lymphoma are cardinal phenotypes observed at death in both the H and L lines. Mortality due to an early incidence of chronic nephritis, with a reducedsized kidney and an irregular scarring of the cortex contribute to the shorter life span of the L line. The L responder mice also show a significant increase in malignant lymphomas, compared to the H responder mice. Thus, chronic nephritis and malignant lymphomas should be considered as the two main diseases accounting for the reduced life span of the lower antibody responder L line.

Senescence-accelerated mouse. The senescence-accelerated mouse (SAM), which consists of fourteen senescence-prone inbred strains (SAMP) and four senescence-resistant inbred strains (SAMR), has been under development since 1970. The manifestation of senescence in SAMP does not occur in the developmental stage, but it occurs in an accelerated manner following normal development, though there is no evidence of growth retardation, malformation, limb palsy, or other neurological signs, such as tremors and convulsions. The life span of SAMP is about 40 percent shorter than that of SAMR. Thus, accelerated senescence is considered to be a characteristic feature common to all SAMP mice. Both SAMP and SAMR strains manifest various pathobiological phenotypes, which are often characteristic enough to differentiate the strains. These phenotypes include senile amyloidosis, impaired immune response, hyperinflation of the lungs, hearing impairment, deficits in learning and memory, cataracts, alveolar bone loss, degenerative joint disease, abnormality of circadian rhythms, emotional disorders, and brain atrophy.

Studies suggest that a hyperoxidative status due to mitochondrial dysfunction plays a pivotal role in the manifestation of accelerated senescence, as well as pathologic phenotypes, in SAMP. Genetic studies to identify the genes for accelerated senescence of SAMP mice and for pathological phenotypes such as senile osteoporosis of SAMP6 mice are underway.

S strain. By selection and inbreeding of Wistar rats (an ordinary strain of rats) for sensitivity to the cataractogenic effect of a galactose-rich diet, a sensitive (S) and a resistant (R) rat strain were developed. A heritable increase in cellular hexose uptake has been associated with an increased intracellular generation of hydroxy radicals, increased endogenous lipid peroxidation, mitochondrial dysfunction, numerous DNA rearrangements, and membrane fragility in the S rats. Age-related degenerative diseases such as emphysema, cataracts, myocardial alterations, spinal column deformations, and impaired retention of long-term memory also manifest in the S rats. The life span of S rats is more than 50 percent shorter than that of R rats. Because of high embryonic mortality, fertility is also lower in the S rats. It is reasonable to conclude that continuous oxidative damage results ultimately in premature aging and in early death of the S rats.