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The Fruit Fly Drosophila melanogaster as a Model for Aging Research

  • Annely Brandt
  • Andreas Vilcinskas
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 135)

Abstract

Average human life expectancy is increasing and so is the impact on society of aging and age-related diseases. Here we highlight recent advances in the diverse and multidisciplinary field of aging research, focusing on the fruit fly Drosophila melanogaster, an excellent model system in which to dissect the genetic and molecular basis of the aging processes. The conservation of human disease genes in D. melanogaster allows the functional analysis of orthologues implicated in human aging and age-related diseases. D. melanogaster models have been developed for a variety of age-related processes and disorders, including stem cell decline, Alzheimer’s disease, and cardiovascular deterioration. Understanding the detailed molecular events involved in normal aging and age-related diseases could facilitate the development of strategies and treatments that reduce their impact, thus improving human health and increasing longevity.

Graphical Abstract

Keywords

Adult stem cells Age-related diseases Aging Dietary restriction Drosophila melanogaster Drug discovery Hutchinson–Gilford progeria syndrome 

Abbreviations

APH-1

Anterior pharynx-defective 1

aPKC

Atypical protein kinase C

APP

Amyloid precursor protein

Amyloid-β

BACE

β-site APP cleaving enzyme 1

bp

Base pairs

GFP

Green fluorescent protein

HGPS

Hutchinson–Gilford progeria syndrome

KCNQ

Potassium channel, KQT-like subfamily

LMNA

Lamin A gene

MHC

Myosin heavy chain

PDGF

Platelet-derived growth factor

PEN-2

Presenilin enhancer 2

PVF2

PDGF/VEGF-like factor 2

RNAi

RNA interference

UAS

Upstream activating sequence

VEGF

Vascular endothelial growth factor

ZMPSTE24

Zinc metalloproteinase homologous to yeast Ste24

Notes

Acknowledgments

We thank K. Grikscheit, and D. T. Brandt for critical reading of the manuscript. The authors acknowledge funding by the Hessian Ministry for Science and Art via the LOEWE research focus “Translational pharmaceutical research”.

References

  1. 1.
    Oeppen J, Vaupel JW (2002) Demography. Broken limits to life expectancy. Science 296(5570):1029–1031CrossRefGoogle Scholar
  2. 2.
    Partridge L (2011) Some highlights of research on aging with invertebrates, 2010. Aging Cell 1:5–9CrossRefGoogle Scholar
  3. 3.
    Partridge L, Gems D (2002) The evolution of longevity. Curr Biol 16:R544–R546CrossRefGoogle Scholar
  4. 4.
    Eleftherianos I, Castillo JC (2012) Molecular mechanisms of aging and immune system regulation in Drosophila. Int J Mol Sci 13(8):9826–9844CrossRefGoogle Scholar
  5. 5.
    Manev H, Dimitrijevic N (2004) Drosophila model for in vivo pharmacological analgesia research. Eur J Pharmacol 491(2–3):207–208CrossRefGoogle Scholar
  6. 6.
    Arias AM (2008) Drosophila melanogaster and the development of biology in the twentieth century. Methods Mol Biol 420:1–25Google Scholar
  7. 7.
    Matthews KA, Kaufman TC, Gelbart WM (2005) Research resources for Drosophila: the expanding universe. Nat Rev Genet 3:179–193CrossRefGoogle Scholar
  8. 8.
    De Velasco B, Shen J, Go S, Hartenstein V (2004) Embryonic development of the Drosophila corpus cardiacum, a neuroendocrine gland with similarity to the vertebrate pituitary, is controlled by sine oculis and glass. Dev Biol 274(2):280–294CrossRefGoogle Scholar
  9. 9.
    Venken KJ, Bellen HJ (2005) Emerging technologies for gene manipulation in Drosophila melanogaster. Nat Rev Genet 3:167–178CrossRefGoogle Scholar
  10. 10.
    Matsushima Y, Adán C, Garesse R, Kaguni LS (2007) Functional analysis by inducible RNA interference in Drosophila melanogaster. Methods Mol Biol 372:207–217Google Scholar
  11. 11.
    Drysdale R (2008) FlyBase: a database for the Drosophila research community. FlyBase Consortium. Methods Mol Biol 420:45–59Google Scholar
  12. 12.
    Osterwalder T, Yoon KS, White BH, Keshishian H (2001) A conditional tissue-specific transgene expression system using inducible GAL4. Proc Natl Acad Sci USA 98(22):12596–12601CrossRefGoogle Scholar
  13. 13.
    Roman G, Davis RL (2002) Conditional expression of UAS-transgenes in the adult eye with a new gene-switch vector system. Genesis 34(1–2):127–131CrossRefGoogle Scholar
  14. 14.
    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 6:483–497CrossRefGoogle Scholar
  15. 15.
    Nicholson L, Singh GK, Osterwalder T, Roman GW, Davis RL, Keshishian H (2008) Spatial and temporal control of gene expression in Drosophila using the inducible GeneSwitch GAL4 system. I. Screen for larval nervous system drivers. Genetics 178:215–234CrossRefGoogle Scholar
  16. 16.
    Poirier L, Shane A, Zheng J, Seroude L (2008) Characterization of the Drosophila gene-switch system in aging studies: a cautionary tale. Aging Cell 7:758–770CrossRefGoogle Scholar
  17. 17.
    Brandt A, Krohne G, Grosshans J (2008) The farnesylated nuclear proteins KUGELKERN and LAMIN B promote aging-like phenotypes in Drosophila flies. Aging Cell 4:541–551CrossRefGoogle Scholar
  18. 18.
    Shen J, Curtis C, Tavaré S, Tower J (2009) A screen of apoptosis and senescence regulatory genes for life span effects when over-expressed in Drosophila. Aging 1(2):191–211Google Scholar
  19. 19.
    Takashima S, Hartenstein V (2012) Genetic control of intestinal stem cell specification and development: a comparative view. Stem Cell Rev 8(2):597–608CrossRefGoogle Scholar
  20. 20.
    Micchelli CA, Perrimon N (2006) Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439(7075):475–479CrossRefGoogle Scholar
  21. 21.
    Ohlstein B, Spradling A (2006) The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439(7075):470–474CrossRefGoogle Scholar
  22. 22.
    Van Zant G, Liang Y (2003) The role of stem cells in aging. Exp Hematol 8:659–672CrossRefGoogle Scholar
  23. 23.
    Choi NH, Kim JG, Yang DJ, Kim YS, Yoo MA (2008) Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor. Aging Cell 3:318–334CrossRefGoogle Scholar
  24. 24.
    Partridge L (2007) Some highlights of research on aging with invertebrates, 2006–2007. Aging Cell 6(5):595–598CrossRefGoogle Scholar
  25. 25.
    Wallenfang MR, Nayak R, DiNardo S (2006) Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell 4:297–304CrossRefGoogle Scholar
  26. 26.
    Goulas S, Conder R, Knoblich JA (2012) The par complex and integrins direct asymmetric cell division in adult intestinal stem cells. Cell Stem Cell 11(4):529–540CrossRefGoogle Scholar
  27. 27.
    Chippindale AK, Leroi AM, Kim SB, Rose MR (1993) Phenotypic plasticity and selection in Drosophila life-history evolution. I. Nutrition and the cost of reproduction. J Evol Biol 6:171–193CrossRefGoogle Scholar
  28. 28.
    Tatar M (2011) The plate half-full: status of research on the mechanisms of dietary restriction in Drosophila melanogaster. Exp Gerontol 46(5):363–368CrossRefGoogle Scholar
  29. 29.
    Wang P-Y, Neretti N, Whitaker R, Hosier S, Chang C, Lu D, Rogina B, Helfand SL (2009) Long-lived Indy and calorie restriction interact to extend life span. Proc Natl Acad Sci 106:9262–9267CrossRefGoogle Scholar
  30. 30.
    Staveley BE (2012) Successes of modelling parkinson disease in drosophila. In: Dushanova J (ed) Mechanism in Parkinson’s disease—models and treatments ISBN: 978-953-307-876-2, InTech p 233–248Google Scholar
  31. 31.
    Bernards A, Hariharan IK (2001) Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev 11(3):274–278CrossRefGoogle Scholar
  32. 32.
    Celniker SE, Rubin GM (2003) The Drosophila melanogaster genome. Annu Rev Genomics Hum Genet 4:89–117CrossRefGoogle Scholar
  33. 33.
    Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6(1):9–23CrossRefGoogle Scholar
  34. 34.
    Reiter LT, Potocki L, Chien S, Gribskov M, Bier E (2001) A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res 11(6):1114–1125CrossRefGoogle Scholar
  35. 35.
    Pandey UB, Nichols CD (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev 63(2):411–436CrossRefGoogle Scholar
  36. 36.
    Botas J (2007) Drosophila researchers focus on human disease. Nat Genet 39(5):589–591CrossRefGoogle Scholar
  37. 37.
    Doronkin S, Reiter LT (2008) Drosophila orthologues to human disease genes: an update on progress. Prog Nucleic Acid Res Mol Biol 82:1–32Google Scholar
  38. 38.
    Giacomotto J, Ségalat L (2010) High-throughput screening and small animal models, where are we? Br J Pharmacol 160(2):204–216CrossRefGoogle Scholar
  39. 39.
    Götz J, Matamales M, Götz NN, Ittner LM, Eckert A (2012) Alzheimer’s disease models and functional genomics—how many needles are there in the haystack? Front Physiol 3:320. doi: 10.3389/fphys.2012.00320 CrossRefGoogle Scholar
  40. 40.
    Shulman JM, Feany MB (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165(3):1233–1242Google Scholar
  41. 41.
    Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890CrossRefGoogle Scholar
  42. 42.
    Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5(5):486–488CrossRefGoogle Scholar
  43. 43.
    Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741CrossRefGoogle Scholar
  44. 44.
    Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M (2004) A model for studying Alzheimer’s Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26(3):365–375CrossRefGoogle Scholar
  45. 45.
    Greeve I, Kretzschmar D, Tschäpe JA, Beyn A, Brellinger C, Schweizer M, Nitsch RM, Reifegerste R (2004) Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila. J Neurosci 24(16):3899–3906CrossRefGoogle Scholar
  46. 46.
    Chung HM, Struhl G (2001) Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat Cell Biol 3(12):1129–1132CrossRefGoogle Scholar
  47. 47.
    Ye Y, Lukinova N, Fortini ME (1999) Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants. Nature 398(6727):525–529CrossRefGoogle Scholar
  48. 48.
    Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of notch in Drosophila. Nature 398:522–525CrossRefGoogle Scholar
  49. 49.
    Struhl G, Greenwald I (2001) Presenilin-mediated transmembrane cleavage is required for notch signal transduction in Drosophila. Proc Natl Acad Sci USA 98:229–234CrossRefGoogle Scholar
  50. 50.
    Ocorr K, Akasaka T, Bodmer R (2007) Age-related cardiac disease model of Drosophila. Mech Ageing Dev 128(1):112–116CrossRefGoogle Scholar
  51. 51.
    Hidary G, Fortini ME (2001) Identification and characterization of the Drosophila tau homolog. Mech Dev 108:171–178CrossRefGoogle Scholar
  52. 52.
    Wittmann CW, Wszolek MF, Shulman JM et al (2001) Tauopathy in Drosophila 2001 neurodegeneration without neurofibrillary tangles. Science 293:711–714CrossRefGoogle Scholar
  53. 53.
    De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Levy N (2003) Lamin A truncation in Hutchinson-Gilford progeria. Science 300(5628):2055CrossRefGoogle Scholar
  54. 54.
    Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298CrossRefGoogle Scholar
  55. 55.
    Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, Collins FS (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci USA 101:8963–8968CrossRefGoogle Scholar
  56. 56.
    Hennekam RC (2006) Hutchinson-Gilford progeria syndrome: review of the phenotype. Am J Med Genet A 140(23):2603–2624CrossRefGoogle Scholar
  57. 57.
    McClintock D, Ratner D, Lokuge M, Owens DM, Gordon LB, Collins FS, Djabali K (2007) The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS One 2(12):e1269CrossRefGoogle Scholar
  58. 58.
    Olive M, Harten I, Mitchell R, Beers JK, Djabali K, Cao K, Erdos MR, Blair C, Funke B, Smoot L, Gerhard-Herman M, Machan JT, Kutys R, Virmani R, Collins FS, Wight TN, Nabel EG, Gordon LB (2010) Cardiovascular pathology in Hutchinson-Gilford progeria: correlation with the vascular pathology of aging. Arterioscler Thromb Vasc Biol 11:2301–2309CrossRefGoogle Scholar
  59. 59.
    Scaffidi P, Misteli T (2006) Lamin A-dependent nuclear defects in human Science 312:1059–1063Google Scholar
  60. 60.
    Scaffidi P, Misteli T (2005) Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med 11:440–445CrossRefGoogle Scholar
  61. 61.
    Capell BC, Collins FS (2006) Human laminopathies: nuclei gone genetically awry. Nat. Rev. Genet 7:940–952CrossRefGoogle Scholar
  62. 62.
    Brandt A, Krohne G, Grosshans J (2008) The farnesylated nuclear proteins KUGELKERN and LAMIN B promote aging-like phenotypes in Drosophila flies. Aging Cell 7(4):541–551CrossRefGoogle Scholar
  63. 63.
    Haithcock E, Dayani Y, Neufeld E, Zahand AJ, Feinstein N, Mattout A, Gruenbaum Y, Liu J (2005) Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci USA 102:16690–16695CrossRefGoogle Scholar
  64. 64.
    Kishi S, Bayliss PE, Uchiyama J, Koshimizu E, Qi J, Nanjappa P, Imamura S, Islam A, Neuberg D, Amsterdam A, Roberts TM (2008) The identification of zebrafish mutants showing alterations in senescence-associated biomarkers. PLoS Genet 4(8):e1000152CrossRefGoogle Scholar
  65. 65.
    Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J (2003) Aging and genome maintenance: lessons from the mouse? Science 299(5611):1355–1359CrossRefGoogle Scholar
  66. 66.
    Bauer JH, Goupil S, Garber GB, Helfand SL (2004) An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci USA 101(35):12980–12985CrossRefGoogle Scholar
  67. 67.
    Spindler SR, Li R, Dhahbi JM, Yamakawa A, Sauer F (2012) Novel protein kinase signaling systems regulating lifespan identified by small molecule library screening using Drosophila. PLoS One 7(2):e29782CrossRefGoogle Scholar
  68. 68.
    Prüfert K, Vogel A, Krohne G (2004) The lamin CxxM motif promotes nuclear membrane growth. J Cell Sci 117:6105–6116CrossRefGoogle Scholar
  69. 69.
    Brandt A, Papagiannouli F, Wagner N, Wilsch-Bräuninger M, Braun M, Furlong EE, Loserth S, Wenzl C, Pilot F, Vogt N, Lecuit T, Krohne G, Grosshans J (2006) Developmental control of nuclear size and shape by Kugelkern and Kurzkern. Curr Biol 16(6):543–552CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Department of BioresourcesFraunhofer Institute of Molecular Biology and Applied EcologyGiessenGermany
  2. 2.Institute of Phytopathology and Applied ZoologyJustus-Liebig-University of GiessenGiessenGermany

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