A screen for mutants that modulate lifespan upon nutritional changes in Drosophila

Pankaj Kapahi, Gil Carvalho, Seymour Benzer

Reduction of calories to 30-40% less than consumed ad libitum by rodents increases both maximum and mean lifespan by >50%. Dietary restriction (DR) has been shown to extend lifespan in various species, including C. elegans, D. melanogaster, S. cerevisiae, and Mus musculus. On the other hand, overnutrition in humans is linked with Type II diabetes, cardiovascular and neurodegenerative diseases, some cancers, and increased mortality rate. In order to understand the genetic factors that modulate lifespan, we undertook a screen for Drosophila mutants that are hypersensitive to a rich diet.

We found that reduction of the concentration of yeast extract in the fly food produces an effect on lifespan similar to that seen in rodents upon caloric restriction. We set up food with varied levels of yeast extract, keeping constant other diet components (5% sucrose, 0.5% agar, and 8% cornmeal). "Overnutrition" is defined as 5% or greater yeast extract (hiY), We find a dose-dependent increase in body size with increase in yeast extract. As in the mouse experiments, we also see an accompanying decrease in reproduction, measured by the number of eggs laid per female. These results agree with the hypothesis that there is a tradeoff between somatic maintenance and reproduction, which may arise due to competitive allocation of nutrients.

We discovered that, on hiY (but not on lowY), certain mutant fly strains failed to develop to adulthood. We have named these mutants creosote (ceo), after Mr. Creosote, a character in Monty Python's 'The Meaning of Life,' who explodes upon overeating. This provides a sensitive paradigm in which to screen for drugs and genes that suppress the toxic effects of overnutrition. Among P-element insertion lines, we have isolated five such strains, which fall into at least two complementation groups. To examine the effects on adult lifespan of these mutations, we raised ceo homozygotes to adulthood on 1% yeast extract food, then placed them on hiY. They suffered over 70% decrease in lifespan, whereas on 1% yeast extract food, their lifespans were only slightly less than the normal. Characterization of the genes involved is in progress.