Skip to main content
SpringerLink
Log in

Mifepristone/RU486 acts in Drosophila melanogaster females to counteract the life span-shortening and pro-inflammatory effects of male Sex Peptide

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Males with null mutation of Sex Peptide (SP) gene were compared to wild-type males for the ability to cause physiological changes in females that could be reversed by mifepristone. Males from wild-type strains decreased median female life span by average −51%. Feeding mifepristone increased life span of these females by average +106%. In contrast, SP-null males did not decrease female life span, and mifepristone increased median life span of these females by average +14%, which was equivalent to the effect of mifepristone in virgin females (average +16%). Expression of innate immune response transgenic reporter (Drosocin-GFP) was increased in females mated to wild-type males, and this expression was reduced by mifepristone. In contrast, SP-null males did not increase Drosocin-GFP reporter expression in the female. Similarly, mating increased endogenous microbial load, and this effect was reduced or absent in females fed mifepristone and in females mated to SP-null males; no loss of intestinal barrier integrity was detected using dye-leakage assay. Reduction of microbial load by treating adult flies with doxycycline reduced the effects of both mating and mifepristone on life span. Finally, mifepristone blocked the negative effect on life span caused by transgenic expression of SP in virgin females. The data support the conclusion that the majority of the life span-shortening, immune-suppressive and pro-inflammatory effects of mating are due to male SP, and demonstrate that mifepristone acts in females to counteract these effects of male SP.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

SP:

Sex Peptide

SPR:

Sex Peptide receptor

SPN:

Sex Peptide null

AMP:

Anti-microbial peptide

GFP:

Green fluorescent protein

DOX:

Doxycycline

References

  • Aigaki T, Fleischmann I, Chen PS, Kubli E (1991) Ectopic expression of sex peptide alters reproductive behavior of female D. melanogaster. Neuron 7:557–563

    Article  CAS  PubMed  Google Scholar 

  • Ameku T, Niwa R (2016) Mating-induced increase in germline stem cells via the neuroendocrine system in female Drosophila. PLoS Genet 12:e1006123. doi:10.1371/journal.pgen.1006123

    Article  PubMed  PubMed Central  Google Scholar 

  • Apger-McGlaughon J, Wolfner MF (2013) Post-mating change in excretion by mated Drosophila melanogaster females is a long-term response that depends on sex peptide and sperm. J Insect Physiol 59:1024–1030. doi:10.1016/j.jinsphys.2013.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ardekani R, Huang YM, Sancheti P, Stanciauskas R, Tavare S, Tower J (2012) Using GFP video to track 3D movement and conditional gene expression in free-moving flies. PLoS ONE 7:e40506. doi:10.1371/journal.pone.0040506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baulieu EE (1997) RU 486 (mifepristone). A short overview of its mechanisms of action and clinical uses at the end of 1996. Ann N Y Acad Sci 828:47–58

    Article  CAS  PubMed  Google Scholar 

  • Belles X, Piulachs MD (2015) Ecdysone signalling and ovarian development in insects: from stem cells to ovarian follicle formation. Biochim Biophy Acta 1849:181–186. doi:10.1016/j.bbagrm.2014.05.025

    Article  CAS  Google Scholar 

  • Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118:401–415

    CAS  PubMed  Google Scholar 

  • Broderick NA, Lemaitre B (2012) Gut-associated microbes of Drosophila melanogaster. Gut Microbes 3:307–321. doi:10.4161/gmic.19896

    Article  PubMed  PubMed Central  Google Scholar 

  • Chapman T, Liddle LF, Kalb JM, Wolfner MF, Partridge L (1995) Cost of mating in Drosophila melanogaster females is mediated by male accessory gland products. Nature 373:241–244. doi:10.1038/373241a0

    Article  CAS  PubMed  Google Scholar 

  • Chapman T, Bangham J, Vinti G, Seifried B, Lung O, Wolfner MF, Smith HK, Partridge L (2003) The sex peptide of Drosophila melanogaster: female post-mating responses analyzed by using RNA interference. Proc Natl Acad Sci USA 100:9923–9928. doi:10.1073/pnas.1631635100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen PS, Stumm-Zollinger E, Aigaki T, Balmer J, Bienz M, Bohlen P (1988) A male accessory gland peptide that regulates reproductive behavior of female D. melanogaster. Cell 54:291–298

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Wang J, Shao J, Gao Y, Xu J, Yu S, Liu Z, Jia L (2014) The unique pharmacological characteristics of mifepristone (RU486): from terminating pregnancy to preventing cancer metastasis. Med Res Rev 34:979–1000. doi:10.1002/med.21311

    Article  CAS  PubMed  Google Scholar 

  • Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, Rana A, Rera M, Pellegrini M, Ja WW, Walker DW (2015) Distinct shifts in microbiota composition during Drosophila aging impair intestinal function and drive mortality. Cell Rep 12:1656–1667. doi:10.1016/j.celrep.2015.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Erkosar B, Leulier F (2014) Transient adult microbiota, gut homeostasis and longevity: novel insights from the Drosophila model. FEBS Lett 588:4250–4257. doi:10.1016/j.febslet.2014.06.041

    Article  CAS  PubMed  Google Scholar 

  • Feng K, Palfreyman MT, Hasemeyer M, Talsma A, Dickson BJ (2014) Ascending SAG neurons control sexual receptivity of Drosophila females. Neuron 83:135–148. doi:10.1016/j.neuron.2014.05.017

    Article  CAS  PubMed  Google Scholar 

  • Finch CE (1990) Longevity, Senescence and the Genome. University of Chicago Press, Chicago

    Google Scholar 

  • Findlay GD, Sitnik JL, Wang W, Aquadro CF, Clark NL, Wolfner MF (2014) Evolutionary rate covariation identifies new members of a protein network required for Drosophila melanogaster female post-mating responses. PLoS Genet 10:e1004108. doi:10.1371/journal.pgen.1004108

    Article  PubMed  PubMed Central  Google Scholar 

  • Ford D, Hoe N, Landis GN, Tozer K, Luu A, Bhole D, Badrinath A, Tower J (2007) Alteration of Drosophila life span using conditional, tissue-specific expression of transgenes triggered by doxycyline or RU486/Mifepristone. Exp Gerontol 42:483–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fricke C, Green D, Smith D, Dalmay T, Chapman T (2014) MicroRNAs influence reproductive responses by females to male sex peptide in Drosophila melanogaster. Genetics 198:1603–1619. doi:10.1534/genetics.114.167320

    Article  PubMed  PubMed Central  Google Scholar 

  • Gavrilov LA, Gavrilova NS (1991) the biology of life span: a quantitative approach. Harwood Academic Publisher, New York

    Google Scholar 

  • Ghoumari AM, Piochon C, Tomkiewicz C, Eychenne B, Levenes C, Dusart I, Schumacher M, Baulieu EE (2006) Neuroprotective effect of mifepristone involves neuron depolarization. FASEB J 20:1377–1386. doi:10.1096/fj.05-5832com

    Article  CAS  PubMed  Google Scholar 

  • Haussmann IU, Hemani Y, Wijesekera T, Dauwalder B, Soller M (2013) Multiple pathways mediate the sex-peptide-regulated switch in female Drosophila reproductive behaviours. Proc Biol Sci 280:20131938. doi:10.1098/rspb.2013.1938

    Article  PubMed  PubMed Central  Google Scholar 

  • Heifetz Y, Vandenberg LN, Cohn HI, Wolfner MF (2005) Two cleavage products of the Drosophila accessory gland protein ovulin can independently induce ovulation. Proc Natl Acad Sci USA 102:743–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ja WW, Carvalho GB, Mak EM, de la Rosa NN, Fang AY, Liong JC, Brummel T, Benzer S (2007) Prandiology of Drosophila and the CAFE assay. Proc Natl Acad Sci USA 104:8253–8256. doi:10.1073/pnas.0702726104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Landis GN, Salomon MP, Keroles D, Brookes N, Sekimura T, Tower J (2015) The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila. Aging (Albany NY) 7:53–69

    Article  Google Scholar 

  • Liu H, Kubli E (2003) Sex-peptide is the molecular basis of the sperm effect in Drosophila melanogaster. Proc Natl Acad Sci USA 100:9929–9933. doi:10.1073/pnas.1631700100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakayama S, Kaiser K, Aigaki T (1997) Ectopic expression of sex-peptide in a variety of tissues in Drosophila females using the P[GAL4] enhancer-trap system. Mol Gener Genet 254:449–455

    Article  CAS  Google Scholar 

  • Ohhara Y, Shimada-Niwa Y, Niwa R, Kayashima Y, Hayashi Y, Akagi K, Ueda H, Yamakawa-Kobayashi K, Kobayashi S (2015) Autocrine regulation of ecdysone synthesis by beta3-octopamine receptor in the prothoracic gland is essential for Drosophila metamorphosis. Proc Natl Acad Sci USA 112:1452–1457. doi:10.1073/pnas.1414966112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng J, Zipperlen P, Kubli E (2005) Drosophila sex-peptide stimulates female innate immune system after mating via the Toll and Imd pathways. Curr Biol 15:1690–1694

    Article  CAS  PubMed  Google Scholar 

  • Platts AE, Land SJ, Chen L, Page GP, Rasouli P, Wang L, Lu X, Ruden DM (2009) Massively parallel resequencing of the isogenic Drosophila melanogaster strain w(1118); iso-2; iso-3 identifies hotspots for mutations in sensory perception genes. Fly (Austin) 3:192–203

    Article  Google Scholar 

  • Pletcher SD (1999) Model fitting and hypothesis testing for age-specific mortality data. J Evol Biol 12:430–439

    Article  Google Scholar 

  • Promislow DEL, Tatar M, Pletcher S, Carey JR (1999) Below-threshold mortality: implications for studies in evolution, ecology and demography. J Evol Biol 12:314–328

    Article  Google Scholar 

  • R Core Team (2009) R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria. http://www.R-project.org/

  • Rakotomamonjy J, Levenes C, Baulieu EE, Schumacher M, Ghoumari AM (2011) Novel protective effect of mifepristone on detrimental GABAA receptor activity to immature Purkinje neurons. FASEB J 25:3999–4010. doi:10.1096/fj.11-183384

    Article  CAS  PubMed  Google Scholar 

  • Ren C, Webster P, Finkel SE, Tower J (2007) Increased internal and external bacterial load during Drosophila aging without life-span trade-off. Cell Metab 6:144–152

    Article  CAS  PubMed  Google Scholar 

  • Ren C, Finkel SE, Tower J (2009) Conditional inhibition of autophagy genes in adult Drosophila impairs immunity without compromising longevity. Exp Gerontol 44:228–235

    Article  CAS  PubMed  Google Scholar 

  • Rera M, Bahadorani S, Cho J, Koehler CL, Ulgherait M, Hur JH, Ansari WS, Lo T Jr, Jones DL, Walker DW (2011) Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab 14:623–634. doi:10.1016/j.cmet.2011.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rera M, Clark RI, Walker DW (2012) Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci USA 109:21528–21533. doi:10.1073/pnas.1215849110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaval C, Pavlou HJ, Dornan AJ, Chan YB, Kravitz EA, Goodwin SF (2012) Neural circuitry underlying Drosophila female postmating behavioral responses. Curr Biol 22:1155–1165. doi:10.1016/j.cub.2012.04.062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rezaval C, Nojima T, Neville MC, Lin AC, Goodwin SF (2014) Sexually dimorphic octopaminergic neurons modulate female postmating behaviors in Drosophila. Curr Biol 24:725–730. doi:10.1016/j.cub.2013.12.051

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro C, Dickson BJ (2010) Sex peptide receptor and neuronal TOR/S6K signaling modulate nutrient balancing in Drosophila. Curr Biol 20:1000–1005. doi:10.1016/j.cub.2010.03.061

    Article  CAS  PubMed  Google Scholar 

  • Ryder E, Blows F, Ashburner M, Bautista-Llacer R, Coulson D, Drummond J, Webster J, Gubb D, Gunton N, Johnson G, O’Kane CJ, Huen D, Sharma P, Asztalos Z, Baisch H, Schulze J, Kube M, Kittlaus K, Reuter G, Maroy P, Szidonya J, Rasmuson-Lestander A, Ekstrom K, Dickson B, Hugentobler C, Stocker H, Hafen E, Lepesant JA, Pflugfelder G, Heisenberg M, Mechler B, Serras F, Corominas M, Schneuwly S, Preat T, Roote J, Russell S (2004) The DrosDel collection: a set of P-element insertions for generating custom chromosomal aberrations in Drosophila melanogaster. Genetics 167:797–813. doi:10.1534/genetics.104.026658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen J, Ford D, Landis GN, Tower J (2009) Identifying sexual differentiation genes that affect Drosophila life span. BMC Geriatr. 9:56

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen J, Landis GN, Tower J (2017) Multiple metazoan life-span interventions exhibit a sex-specific Strehler-Mildvan inverse relationship between initial mortality rate and age-dependent mortality rate acceleration. J Gerontol A Biol Sci Med Sci 72:44–53. doi:10.1093/gerona/glw005

    Article  PubMed  Google Scholar 

  • Short SM, Wolfner MF, Lazzaro BP (2012) Female Drosophila melanogaster suffer reduced defense against infection due to seminal fluid components. J Insect Physiol 58:1192–1201. doi:10.1016/j.jinsphys.2012.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sieber MH, Spradling AC (2015) Steroid Signaling Establishes a Female Metabolic State and Regulates SREBP to Control Oocyte Lipid Accumulation Curr Biol. 25:993–1004. doi:10.1016/j.cub.2015.02.019

    CAS  PubMed  Google Scholar 

  • Simon AF, Shih C, Mack A, Benzer S (2003) Steroid control of longevity in Drosophila melanogaster Science. 299:1407–1410

    CAS  PubMed  Google Scholar 

  • Strehler BL, Mildvan AS (1960) General theory of mortality and aging. Science 132:14–21

    Article  CAS  PubMed  Google Scholar 

  • Tarkhov AE, Menshikov LI, Fedichev PO (2017) Strehler-Mildvan correlation is a degenerate manifold of Gompertz fit. J Theor Biol 416:180–189. doi:10.1016/j.jtbi.2017.01.017

    Article  PubMed  Google Scholar 

  • Tower J, Landis G, Gao R, Luan A, Lee J, Sun Y (2014) Variegated expression of Hsp22 transgenic reporters indicates cell-specific patterns of aging in Drosophila oenocytes. J Gerontol A Biol Sci Med Sci 69:253–259. doi:10.1093/gerona/glt078

    Article  CAS  PubMed  Google Scholar 

  • Tricoire H, Battisti V, Trannoy S, Lasbleiz C, Pret AM, Monnier V (2009) The steroid hormone receptor EcR finely modulates Drosophila lifespan during adulthood in a sex-specific manner. Mech Ageing Dev 130:547–552. doi:10.1016/j.mad.2009.05.004

    Article  CAS  PubMed  Google Scholar 

  • Tsuda M, Aigaki T (2016) Evolution of sex-peptide in Drosophila. Fly (Austin) 10:172–177. doi:10.1080/19336934.2016.1193655

    Article  Google Scholar 

  • Tzou P, Ohresser S, Ferrandon D, Capovilla M, Reichhart JM, Lemaitre B, Hoffmann JA, Imler JL (2000) Tissue-specific inducible expression of antimicrobial peptide genes in Drosophila surface epithelia. Immunity 13:737–748

    Article  CAS  PubMed  Google Scholar 

  • Wigby S, Chapman T (2005) Sex peptide causes mating costs in female Drosophila melanogaster. Curr Biol 15:316–321. doi:10.1016/j.cub.2005.01.051

    Article  CAS  PubMed  Google Scholar 

  • Wolfner MF (2002) The gifts that keep on giving: physiological functions and evolutionary dynamics of male seminal proteins in Drosophila. Heredity 88:85–93

    Article  CAS  PubMed  Google Scholar 

  • Wolfner MF (2009) Battle and ballet: molecular interactions between the sexes in Drosophila. J Hered 100:399–410. doi:10.1093/jhered/esp013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada R, Deshpande SA, Keebaugh ES, Ehrlich MR, Soto Obando A, Ja WW (2017) Mifepristone reduces food palatability and affects Drosophila feeding and lifespan. J Gerontol A Biol Sci Med Sci 72:173–180. doi:10.1093/gerona/glw072

    Article  PubMed  Google Scholar 

  • Yang CH, Rumpf S, Xiang Y, Gordon MD, Song W, Jan LY, Jan YN (2009) Control of the postmating behavioral switch in Drosophila females by internal sensory neurons. Neuron 61:519–526. doi:10.1016/j.neuron.2008.12.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yapici N, Kim YJ, Ribeiro C, Dickson BJ (2008) A receptor that mediates the post-mating switch in Drosophila reproductive behaviour. Nature 451:33–37. doi:10.1038/nature06483

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Department of Health and Human Services Grants AG011833 and R56AG049629 (J. T), and pilot project funds from the Southern California Environmental Health Sciences Center grant 5P30ES007048 (J. T), Grant 31500970 from National Natural Science Foundation of China (J. S), the Project-sponsored by SRF for ROCS, SEM (J. S), and the Returned Overseas Chinese Scholars Research Merit Aid, Zhejiang [2014]115 (J. S).

Author information

Authors and Affiliations

  1. Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, 1050 Childs Way, RRI201, Los Angeles, CA, 90089-2910, USA

    John Tower, Gary N. Landis, Rachelle Choi, Yang Fan, Dasul Lee & Jaemin Song

  2. College of Life Information Science and Instrument Engineering, Hangzhou Dianzi University, Hangzhou, China

    Jie Shen

Authors
  1. John Tower
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gary N. Landis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rachelle Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yang Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dasul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jaemin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Tower.

Ethics declarations

Conflict of interest

None of the authors is aware of any conflict of interest regarding any aspect of the work reported here.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 507 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tower, J., Landis, G.N., Shen, J. et al. Mifepristone/RU486 acts in Drosophila melanogaster females to counteract the life span-shortening and pro-inflammatory effects of male Sex Peptide. Biogerontology 18, 413–427 (2017). https://doi.org/10.1007/s10522-017-9703-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-017-9703-y

Keywords

Search

Navigation