Genetics of Stress Resistance and Aging in Mice
This pilot study will test the hypothesis that cellular stress resistance is a predictor of individual longevity and of delayed aging in segregating populations of mice. The strategy is based on evidence that single gene mutations extending life span are associated with stress resistance in worms, flies, and mice, and on evidence that cells from long-lived species are resistant in culture to multiple forms of stress. The protocol involves 400 mice from an F2 population generated from C57BL/6 mice and mice of the long-lived, wild-derived stock Id. Each of the mice will be tested, at ages 6 and 18 months, for stress resistance using a method in which skin-derived short term fibroblast cultures are exposed to three stresses (UV light, H2O2, and the toxic heavy metal cadmium), and the dose needed to kill 50% of the cells recorded as an index of stress resistance. Each mouse will also be assessed for life span, cause of death, incidence of neoplastic and non-neoplastic lesions, and for several late-life age-sensitive traits, including T cell subset pattern, spontaneous activity level, inflammatory mediators, and severity of cataract. Developmental variables, including weight gain trajectory and rate of sexual maturation, will also be evaluated for each individual. The data set will support tests of several hypotheses: (i) high resistance to stress at each age will predict life span; (ii) stress resistance will predict the extent of age-dependent change in multiple physiological systems; (iii) mice with slow growth and maturation rates will age slowly and live a long time; and (iv) resistance to each form of cytotoxic stress will be associated to resistance to all forms tested, and at both ages tested. In addition, DNA from the mice will be genotyped by the Consortium's Genomics Core, and the results used to map quantitative trait l oci that influence stress resistance, life span, and age-sensitive traits in this cohort.
The results of this study, if positive, should provide a strong rationale and validated methodology for mapping cellular stress resistance genes in mice and humans, and help develop a list of candidate genes that influence cellular stress resistance pathways and deserve detailed consideration in studies of the genetic basis for human life span and resistance to late-life disease and disability.