Transgenes in the Analysis of Life Span and Fitness.

Abstract

Drosophila P element-mediated transformation can be used to determine whether and how a specific gene contributes to demographic components of fitness. Motivated by the problem of senescence, researchers have applied this approach to genes thought to affect survival through processes of somatic maintenance. Cu/Zn-superoxide dismutase and catalase reduce the flux of reactive oxygen molecules that are thought to be a central cause of aging. EF1α is a component of the protein synthesis machine; deterioration of this housekeeping function is a potential contributor to senescence. Molecular chaperones such as the heat shock protein hsp70 are multifunctional molecules that affect a cell's response to acute stress. In some models, senescence results from the cumulative effects of stress, and heat shock proteins may regulate the progress of this deterioration. Transformations with the candidate genes of these proteins were used in independent studies to measure the effect of overexpression on longevity; positive results were reported. Here, I discuss the robustness of these results. I use the studies of superoxide dismutase, catalase, and EF1α to illustrate how the mutagenic effects of inserts confound our interpretations. I present new data from a reported study of hsp70 overexpression to show how engineered constructs can be used to overcome mutagenic artifacts through the controlled excision of sequences or alleles. The data for hsp70 provide the first strong molecular evidence that somatic maintenance affects longevity. Finally, future potential uses of transformation with Drosophila are discussed. I consider how metabolic control theory predicts that overexpression of genes for enzymes of intermediary metabolism is not likely to produce analytically useful changes in components of fitness.