Skip to main content
Log in

Increase of Drosophila melanogaster lifespan due to D-GADD45 overexpression in the nervous system

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

Abstract

The GADD45 protein family plays an important role in stress signaling and participates in the integration of cellular response to environmental and physiological factors. GADD45 proteins are involved in cell cycle control, DNA repair, apoptosis, cell survival and aging, and inflammatory response by complicated protein–protein interactions. In Drosophila melanogaster a single D-GADD45 ortholog (GG1086) has been described. Our data show that overexpression of the D-GADD45 gene in the nervous system leads to a significantly increase of Drosophila lifespan without a decrease in fecundity and locomotor activity. The lifespan extension effect is more pronounced in males than in females, which agrees with the sex-dependent expression of this gene. The longevity of D. melanogaster with D-GADD45 overexpression is apparently due to more efficient recognition and repair of DNA damage, as the DNA comet assay showed that the spontaneous DNA damage in the larva neuroblasts is reduced with statistical significance.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Amrit FR, Boehnisch CM, May RC (2010) Phenotypic covariance of longevity, immunity and stress resistance in the Caenorhabditis nematodes. PLoS ONE 5:e9978

    Article  PubMed  Google Scholar 

  • Ashburner M (1989) Drosophila: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y

    Google Scholar 

  • Barsyte D, Lovejoy DA, Lithgow GJ (2001) Longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of Caenorhabditis elegans. FASEB J 15:627–634

    Article  PubMed  CAS  Google Scholar 

  • Breslow N (1970) A generalized Kruskal-Wallis test for comparing K samples subject to unequal patterns of censorship. Biometrika 57:579–594

    Article  Google Scholar 

  • Brown-Borg HM (2006) Longevity in mice: is stress resistance a common factor? Age (Dordr) 28:145–162

    Article  CAS  Google Scholar 

  • Carrier F, Georgel PT, Pourquier P, Blake M, Kontny HU, Antinore MJ, Gariboldi M, Myers TG, Weinstein JN, Pommier Y, Fornace AJ Jr (1999) Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol Cell Biol 19:1673–1685

    PubMed  CAS  Google Scholar 

  • Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106

    Article  PubMed  CAS  Google Scholar 

  • Cortopassi GA, Shibata D, Soong NW, Arnheim N (1992) A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 89:7370–7374

    Article  PubMed  CAS  Google Scholar 

  • Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292:288–290

    Article  PubMed  CAS  Google Scholar 

  • Fleming TR, O’Fallon JR, O’Brien PC, Harrington DP (1980) Modified Kolmogorov-Smirnov test procedures with application to arbitrarily right-censored data. Biometrics 36:607–625

    Article  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  PubMed  CAS  Google Scholar 

  • Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118:75–86

    PubMed  CAS  Google Scholar 

  • Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N (2002) FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 277:26729–26732

    Article  PubMed  CAS  Google Scholar 

  • Gavrilov LA, Gavrilova NS (1991) The biology of life span: a quantitative approach. Harwood Academic Publishers, Chur, New York, Switzerland

    Google Scholar 

  • Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L (2004) Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305:361

    Article  PubMed  CAS  Google Scholar 

  • Giannakou ME, Goss M, Partridge L (2008) Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response. Aging Cell 7:187–198

    Article  PubMed  CAS  Google Scholar 

  • Gilad GM, Rabey JM, Tizabi Y, Gilad VH (1987) Age-dependent loss and compensatory changes of septohippocampal cholinergic neurons in two rat strains differing in longevity and response to stress. Brain Res 436:311–322

    Article  PubMed  CAS  Google Scholar 

  • Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408:255–262

    Article  PubMed  CAS  Google Scholar 

  • Gupta M, Gupta SK, Hoffman B, Liebermann DA (2006) Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. J Biol Chem 281:17552–17558

    Article  PubMed  CAS  Google Scholar 

  • Halaschek-Wiener J, Khattra JS, McKay S, Pouzyrev A, Stott JM, Yang GS, Holt RA, Jones SJ, Marra MA, Brooks-Wilson AR, Riddle DL (2005) Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. Genome Res 15:603–615

    Article  PubMed  CAS  Google Scholar 

  • Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS (1995) Characterisation of the interaction between PCNA and Gadd45. Oncogene 10:2427–2433

    PubMed  CAS  Google Scholar 

  • Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A (2001) Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 98:10469–10474

    Article  PubMed  CAS  Google Scholar 

  • Henis-Korenblit S, Zhang P, Hansen M, McCormick M, Lee SJ, Cary M, Kenyon C (2010) Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc Natl Acad Sci USA 107:9730–9735

    Article  PubMed  CAS  Google Scholar 

  • Holzenberger M (2009) IGF-1 receptors in the brain control longevity in mice. Med Sci (Paris) 25:371–376

    Article  Google Scholar 

  • Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Perin L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6:e254

    Article  PubMed  Google Scholar 

  • Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460

    Article  PubMed  CAS  Google Scholar 

  • Kojima S, Mayumi-Matsuda K, Suzuki H, Sakata T (1999) Molecular cloning of rat GADD45γ, gene induction and its role during neuronal cell death. FEBS Lett 446:313–317

    Article  PubMed  CAS  Google Scholar 

  • Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z (2009) Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296:H946–H956

    Article  PubMed  CAS  Google Scholar 

  • Landis GN, Bhole D, Tower J (2003) A search for doxycycline-dependent mutations that increase Drosophila melanogaster life span identifies the VhaSFD, Sugar baby, filamin, fwd and Cctl genes. Genome Biol 4:R8

    Article  PubMed  Google Scholar 

  • Larsen PL, Albert PS, Riddle DL (1995) Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139:1567–1583

    PubMed  CAS  Google Scholar 

  • Le Bourg E (2009) Hormesis, aging and longevity. Biochim Biophys Acta 1790:1030–1039

    PubMed  CAS  Google Scholar 

  • Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–297

    Article  PubMed  CAS  Google Scholar 

  • Lee RY, Hench J, Ruvkun G (2001) Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 11:1950–1957

    Article  PubMed  CAS  Google Scholar 

  • Li J, Ebata A, Dong Y, Rizki G, Iwata T, Lee SS (2008) Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol 6:e233

    Article  PubMed  Google Scholar 

  • Liebermann DA, Hoffman B (2008) Gadd45 in stress signaling. J Mol Signal 3:15

    Article  PubMed  Google Scholar 

  • Lin YJ, Seroude L, Benzer S (1998) Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282:943–946

    Article  PubMed  CAS  Google Scholar 

  • Lithgow GJ, White TM, Melov S, Johnson TE (1995) Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci USA 92:7540–7544

    Article  PubMed  CAS  Google Scholar 

  • Mantel N (1966) Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163–170

    PubMed  CAS  Google Scholar 

  • Masse I, Molin L, Mouchiroud L, Vanhems P, Palladino F, Billaud M, Solari F (2008) A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. PLoS ONE 3:e3354

    Article  PubMed  Google Scholar 

  • Meissner B, Boll M, Daniel H, Baumeister R (2004) Deletion of the intestinal peptide transporter affects insulin and TOR signaling in Caenorhabditis elegans. J Biol Chem 279:36739–36745

    Article  PubMed  CAS  Google Scholar 

  • Morley JF, Morimoto RI (2004) Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 15:657–664

    Article  PubMed  CAS  Google Scholar 

  • Morrow G, Samson M, Michaud S, Tanguay RM (2004) Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 18:598–599

    PubMed  CAS  Google Scholar 

  • Mukhopadhyay I, Chowdhuri DK, Bajpayee M, Dhawan A (2004) Evaluation of in vivo genotoxicity of cypermethrin in Drosophila melanogaster using the alkaline Comet assay. Mutagenesis 19:85–90

    Article  PubMed  CAS  Google Scholar 

  • Murakami S, Johnson TE (1996) A genetic pathway conferring life extension and resistance to UV stress in Caenorhabditis elegans. Genetics 143:1207–1218

    PubMed  CAS  Google Scholar 

  • Niedernhofer LJ, Robbins PD (2008) Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan. Int J Biochem Cell Biol 40:176–180

    Article  PubMed  CAS  Google Scholar 

  • Olive PL, Banath JP, Durand RE (1990) Heterogeneity in radiation-induced DNA damage and repair in tumor and normal cells measured using the “comet” assay. Radiat Res 122:86–94

    Article  PubMed  CAS  Google Scholar 

  • Papa S, Zazzeroni F, Fu YX, Bubici C, Alvarez K, Dean K, Christiansen PA, Anders RA, Franzoso G (2008) Gadd45β promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J Clin Invest 118:1911–1923

    Article  PubMed  CAS  Google Scholar 

  • Peretz G, Bakhrat A, Abdu U (2007) Expression of the Drosophila melanogaster GADD45 homolog (CG11086) affects egg asymmetric development that is mediated by the c-Jun N-terminal kinase pathway. Genetics 177:1691–1702

    Article  PubMed  CAS  Google Scholar 

  • Perez VI, Buffenstein R, Masamsetti V, Leonard S, Salmon AB, Mele J, Andziak B, Yang T, Edrey Y, Friguet B, Ward W, Richardson A, Chaudhuri A (2009) Protein stability and resistance to oxidative stress are determinants of longevity in the longest-living rodent, the naked mole-rat. Proc Natl Acad Sci USA 106:3059–3064

    Article  PubMed  CAS  Google Scholar 

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

    Article  Google Scholar 

  • Poirier L, Shane A, Zheng J, Seroude L (2008) Characterization of the Drosophila Gene-Switch system in aging studies: a cautionary tale. Aging Cell 7:758–770

    Article  PubMed  CAS  Google Scholar 

  • Rattan SI (2005) Hormetic modulation of aging and longevity by mild heat stress. Dose Response 3:533–546

    Article  CAS  Google Scholar 

  • Ruan H, Tang XD, Chen ML, Joiner ML, Sun G, Brot N, Weissbach H, Heinemann SH, Iverson L, Wu CF, Hoshi T (2002) High-quality life extension by the enzyme peptide methionine sulfoxide reductase. Proc Natl Acad Sci USA 99:2748–2753

    Article  PubMed  CAS  Google Scholar 

  • Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ (2008) Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22:807–818

    Article  PubMed  CAS  Google Scholar 

  • Singh NP (2000) A simple method for accurate estimation of apoptotic cells. Exp Cell Res 256:328–337

    Article  PubMed  CAS  Google Scholar 

  • Slack C, Werz C, Wieser D, Alic N, Foley A, Stocker H, Withers DJ, Thornton JM, Hafen E, Partridge L (2010) Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. PLoS Genet 6:e1000881

    Article  PubMed  Google Scholar 

  • Sohal RS, Sohal BH, Brunk UT (1990) Relationship between antioxidant defenses and longevity in different mammalian species. Mech Ageing Dev 53:217–227

    Article  PubMed  CAS  Google Scholar 

  • Sun LY (2006) Hippocampal IGF-1 expression, neurogenesis and slowed aging: clues to longevity from mutant mice. Age (Dordr) 28:181–189

    Article  CAS  Google Scholar 

  • Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110

    Article  PubMed  CAS  Google Scholar 

  • Ungvari Z, Krasnikov BF, Csiszar A, Labinskyy N, Mukhopadhyay P, Pacher P, Cooper AJ, Podlutskaya N, Austad SN, Podlutsky A (2008) Testing hypotheses of aging in long-lived mice of the genus Peromyscus: association between longevity and mitochondrial stress resistance, ROS detoxification pathways, and DNA repair efficiency. Age (Dordr) 30:121–133

    Article  CAS  Google Scholar 

  • Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA (2000) Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. J Biol Chem 275:16810–16819

    Article  PubMed  CAS  Google Scholar 

  • Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, O’Connor PM, Fornace AJ Jr, Harris CC (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96:3706–3711

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Li Q, Redden DT, Weindruch R, Allison DB (2004) Statistical methods for testing effects on “maximum lifespan”. Mech Ageing Dev 125:629–632

    Article  PubMed  Google Scholar 

  • Yoo J, Ghiassi M, Jirmanova L, Balliet AG, Hoffman B, Fornace AJ Jr, Liebermann DA, Bottinger EP, Roberts AB (2003) Transforming growth factor-β-induced apoptosis is mediated by Smad-dependent expression of GADD45b through p38 activation. J Biol Chem 278:43001–43007

    Article  PubMed  CAS  Google Scholar 

  • Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ Jr (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18:2892–2900

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the Institute of Biology of Aging and the “Science for Life Extension” Foundation for financial support of the project. We are also grateful to Dr. Uri Abdu (Ben-Gurion University, Israel), Dr. Haig Keshishian (Yale University, New Haven, USA), and the Drosophila Stock Center (Indiana University, Bloomington, Indiana, USA) for providing the D. melanogaster laboratory strains. We thank postgraduate students I. Velegzhaninov, O. Malysheva, E. Romanova and students D. Chernyshova, V. Mezentseva and A. Danilov for their technical assistance, and V. Artyuchov for the help with manuscript translation into English.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. A. Moskalev.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Plyusnina, E.N., Shaposhnikov, M.V. & Moskalev, A.A. Increase of Drosophila melanogaster lifespan due to D-GADD45 overexpression in the nervous system. Biogerontology 12, 211–226 (2011). https://doi.org/10.1007/s10522-010-9311-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-010-9311-6

Keywords

Navigation