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The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila.

ABSTRACT: Mating causes decreased life span in female Drosophila. Here we report that mifepristone blocked this effect, yielding life span increases up to +68%. Drug was fed to females after mating, in the absence of males, demonstrating function in females. Mifepristone did not increase life span of virgin females or males. Mifepristone reduced progeny production but did not reduce food intake. High-throughput RNA sequencing was used to identify genes up-regulated or down-regulated upon mating, and where the change was reduced by mifepristone. Five candidate positive regulators of life span were identified, including dosage compensation regulator Unr and three X-linked genes: multi sex combs (PcG gene), Dopamine 2-like receptor and CG14215. The 37 candidate negative genes included neuropeptide CNMamide and several involved in protein mobilization and immune response. The results inform the interpretation of experiments involving mifepristone, and implicate steroid hormone signaling in regulating the trade-off between reproduction and life span.

SUBMITTER: Landis GN

PROVIDER: S-EPMC4350324 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila.

Landis Gary N GN Salomon Matthew P MP Keroles Daniel D Brookes Nicholas N Sekimura Troy T Tower John J

Aging 20150101 1

Mating causes decreased life span in female Drosophila. Here we report that mifepristone blocked this effect, yielding life span increases up to +68%. Drug was fed to females after mating, in the absence of males, demonstrating function in females. Mifepristone did not increase life span of virgin females or males. Mifepristone reduced progeny production but did not reduce food intake. High-throughput RNA sequencing was used to identify genes up-regulated or down-regulated upon mating, and where ...[more]

PMID: 25614682

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Project description:Mifepristone dramatically increases the life span of mated female Drosophila while reducing the expression of innate immune response genes. Previous results indicated that mifepristone also reduced the load of aero-tolerant bacteria in mated females. Experiments were conducted to further investigate the possible role of bacteria in mifepristone life span effects. Life span was assayed in flies grown from sterilized eggs on autoclaved media and in normally cultured controls in two independent assays. Sterilization increased mated female life span (+8.3% and +57%, respectively), and the effect of mifepristone was additive (+53% and +93%, respectively). High-throughput sequencing of 16S sequences revealed that sterilization reduced the abundance of multiple species and the classes Bacteroidia, Bacilli, Actinobacteria, and Cytophagia. By contrast, mifepristone caused no decreases and instead increased the abundance of three species. Five aero-tolerant bacterial species were cultured from extracts of mated female flies, including both Gram-positive and Gram-negative species (Acetobacter sicerae, Enterococcus faecalis, Lactobacillus plantarum, Serratia rubidea, and Paenibacillus glucanolyticus). There was no detectable effect of mifepristone on the growth of these bacteria in vitro, indicating that mifepristone does not have a direct antibiotic effect. To test if antibiotics could mimic the effects of mifepristone in vivo, mated female flies were treated throughout adult life span with high concentrations of the individual antibiotics doxycycline, ampicillin, kanamycin, and streptomycin, in replicate experiments. No significant effect on life span was observed for ampicillin, kanamycin, or streptomycin, and an inconsistent benefit was observed for doxycycline. Finally, supplementation of media with Enterococcus faecalis did not alter adult female life span in the presence or absence of mifepristone. Taken together, the results indicate the life span benefits of mifepristone are not due to an antibiotic effect.

Project description:Background: The synthetic steroid mifepristone is reported to have anti-obesity and anti-diabetic effects in mammals on normal and high-fat diets (HFD). We previously reported that mifepristone blocks the negative effect on life span caused by mating in female Drosophila melanogaster. Methods: Here we asked if mifepristone could protect virgin females from the life span-shortening effect of HFD. Mifepristone was assayed for effects on life span in virgin females, in repeated assays, on regular media and on media supplemented with coconut oil (HFD). The excrement quantification (EX-Q) assay was used to measure food intake of the flies after 12 days mifepristone treatment. In addition, experiments were conducted to compare the effects of mifepristone in virgin and mated females, and to identify candidate mifepristone targets and mechanisms. Results: Mifepristone increased life span of virgin females on regular media, as well as on media supplemented with either 2.5 or 5% coconut oil. Food intake was not reduced in any assay, and was significantly increased by mifepristone in half of the assays. To ask if mifepristone might rescue virgin females from all life span-shortening stresses, the oxidative stressor paraquat was tested, and mifepristone produced little to no rescue. Analysis of extant metabolomics and transcriptomics data suggested similarities between effects of mifepristone in virgin and mated females, including reduced tryptophan breakdown and similarities to dietary restriction. Bioinformatics analysis identified candidate mifepristone targets, including transcription factors Paired and Extra-extra. In addition to shortening life span, mating also causes midgut hypertrophy and activation of the lipid metabolism regulatory factor SREBP. Mifepristone blocked the increase in midgut size caused by mating, but did not detectably affect midgut size in virgins. Finally, mating increased activity of a SREBP reporter in abdominal tissues, as expected, but reporter activity was not detectably reduced by mifepristone in either mated or virgin females. Conclusion: Mifepristone increases life span of virgin females on regular and HFD without reducing food intake. Metabolomics and transcriptomics analyses suggest some similar effects of mifepristone between virgin and mated females, however reduced midgut size was observed only in mated females. The results are discussed regarding possible mifepristone mechanisms and targets.

Dataset Information

The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila.

Publications

The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila.

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