Across many species, including humans, one of the many consequences of aging is a reduction in fertility, particularly female fertility. Intriguingly some species can preserve fertility for longer than they otherwise would, under specific environmental conditions. For example, various species of Drosophila enter a state called adult reproductive diapause when they experience low temperatures and short day length. Under these conditions they can double their lifespan while maintaining fertility. Previous work has implicated a few genes in positive or negative regulation of adult reproductive diapause in Drosophila. For example, the insulin pathway negatively regulates diapause, suggesting mechanisms that are conserved with the regulation of metabolism, fertility, and lifespan in other species including C. elegans, mice, and humans. However, our mechanistic understanding of diapause is extremely limited, and how fertility is preserved is unknown. We have taken advantage of powerful genetic tools in Drosophila to carry out a genome-wide association study of diapause. This approach appears to be highly successful, as the few known genes emerged from the analysis, such as the insulin receptor. In addition, this screen revealed that the most highly enriched networks of genes associated with diapause include those involved in neuronal development and female reproduction. The neuronal development genes are striking, as they have not previously been associated with diapause and thus offer to provide new molecular and cellular insights. Here we propose to: 1) identify the genes controlling specific steps in the diapause program such as entry, maintenance, exit, preservation of fecundity, and lifespan; 2) test whether diapause genes are required during development to prepare the animals for diapause, or function specifically in adulthood; and 3) investigate the molecular mechanisms of germline stem cell preservation during diapause. We anticipate that just as studies of C. elegans dauer formation illuminated general pathways regulating metabolism, growth, reproduction and aging in animals ranging from worms to humans, studies of Drosophila diapause offer the exciting potential to uncover novel and general mechanisms of stem cell preservation, fertility maintenance, and lifespan extension.

Relevance to public health Some of the most important insights into lifespan and healthspan extension in humans have come from studying simple organisms that are amenable to large-scale genetic studies. We have used a powerful genetic approach in the fruit fly to identify hundreds of genes, most of which are closely related to genes in humans, that are good candidates for reversing the aging process and extending female fertility. Here we propose to uncover the precise cellular and molecular mechanisms by which these genes regulate fertility and longevity with the long-term goal of finding new genes that control these processes in people.