Lifespan varies among individuals, but the genetic factors that contribute to variation in lifespan are not completely understood. Drosophila melanogaster presents a powerful genetic model system to explore the genetic underpinnings of longevity, since its lifespan is limited and both the genetic background and environment can be controlled precisely. A previous study identified sequence variants associated with differences in lifespan between five long-lived lines originally selected for delayed reproduction (O lines) and their five unselected controls (B lines). Two single nucleotide polymorphisms in the promoter of the bellwether (blw) gene (A>G and G>T) were associated with differences in lifespan between the O and B lines. To assess whether associated polymorphisms in the blw promoter may contribute to differences in lifespan by modulating gene expression, we amplified 500 bp upstream promoter sequences containing all four possible haplotypes (AG, AT, GG, GT) and assessed promoter activity in an in vitro luciferase reporter system. Our results show that the AG haplotype characteristic of the B lines showed ~18% greater expression of luciferase than the GT haplotype, which is associated with the long-lived O lines. Current experiments are designed to assess to what extent alternative blw alleles modulate lifespan in a common genetic background. The blw gene codes for the alpha subunit of the mitochondrial ATP synthase, and thus may represent a possible molecular link between metabolic rate and lifespan.
Supported by NIH grant R01-AG043490..