Comparing mutants,selective breeding,and transgenics in the dissection of aging processes ofCaenorhabditis elegans

The genetic analysis of aging processes has matured in the last ten years with reports that long-lived strains of both fruit flies and nematodes have been developed. Several attempts to identify mutants in the fruit fly with increased longevity have failed and the reasons for these failures are analyzed. A major problem in obligate sexual species, such as the fruit fly, is the presence of inbreeding depression that makes the analysis of life-history traits in homozygotes very difficult. Nevertheless, several successful genetic analyses of aging inDrosophila suggest that with careful design, fruitful analysis of induced mutants affecting life span is possible. In the nematodeCaenorhabditis elegans, mutations in theage-1 gene result in a life extension of some 70%; thusage-1 clearly specifies a process involved in organismic senescence. This gene maps to chromosome II, well separated from a locus (fer-15) which is responsible for a large fertility deficit in the original stocks. There is no trade-off between either rate of development or fertility versus life span associated with theage-1 mutation. Transgenic analyses confirm that the fertility deficit can be corrected by a wild-typefer-15 transformant (transgene); however, the life span of these transformed stocks is affected by the transgenic array in an unpredictable fashion. The molecular nature of theage-1 gene remains unknown and we continue in our efforts to clone the gene.