Mifepristone Increases Life Span of Virgin Female Drosophila on Regular and High-fat Diet Without Reducing Food Intake

Abstract

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.

Mifepristone Increases Life Span in Female Drosophila Without Detectable Antibacterial Activity

“…Mifepristone increased the life span of virgin females fed JH analog methoprene by +80%, while simultaneously doubling food intake (Landis et al, 2021a). Similarly, mifepristone can increase the life span of virgin females on both normal and high-fat diets while simultaneously increasing food intake (Landis et al, 2021b). Taken together, the data suggest that mifepristone reduces gut metabolism and midgut hypertrophy that would otherwise shorten life span.…”

“…Mating and male SP cause midgut hypertrophy in the mated female, and this hypertrophy was prevented by feeding the mated females mifepristone, for 3/3 genotypes tested (Landis et al, 2021b). Other studies have reported that the presence of bacteria stimulates midgut cell proliferation and increases midgut size relative to axenic flies (Broderick et al, 2014); however, the possible role of bacteria in mating-induced midgut hypertrophy is unclear.…”

“…JH and ecdysone induce intestinal stem cell (ISC) proliferation, midgut hypertrophy, and increased AA and lipid metabolism (Ahmed et al, 2020;Zipper et al, 2020;White et al, 2021), which supports increased egg production (Reiff et al, 2015;Sieber and Spradling, 2015). The midgut hypertrophy, increased AA metabolites and lipids, inflammation, and decreased life span caused by mating and SP can each be blocked by feeding the mated females mifepristone (Landis et al, 2015;Tower et al, 2017;Landis et al, 2021a;Landis et al, 2021b). Transcriptomics analysis indicated that mifepristone downregulates genes in the midgut that are negatively correlated with life span and upregulates genes in the nervous system that are positively correlated with life span (Landis et al, 2015;Landis et al, 2021a).…”

“…Transcriptomics analysis indicated that mifepristone downregulates genes in the midgut that are negatively correlated with life span and upregulates genes in the nervous system that are positively correlated with life span (Landis et al, 2015;Landis et al, 2021a). Metabolomics assays revealed that in both mated females and virgins, mifepristone reduces the levels of tryptophan metabolites (Landis et al, 2021b). Remarkably, mifepristone uncouples Drosophila life span from food intake.…”

Drosophila melanogaster flies better know than us the nutrients they need: Let them choose

“…In flies, as in humans, it could be possible to finely tune to nutritional needs at any time by modulating the proteins and carbohydrates intakes. However, adding live yeast at the surface of the medium does not allow, for instance, to study the effects of specific nutrients (e.g., Landis et al, 2021) or food intake (e.g., Lee et al, 2008), even if a food dye (e.g., Edgecomb et al, 1994;Wu et al, 2020b) in the live yeast could allow to know its very consumption. The capillary feeder system (CAFE: Ja et al, 2007, but see the pioneering study of David and Ramousse, 1970) readily provides the amount of ingested nutrients, but it can also decrease lifespan (e.g., Bruce et al, 2013).…”