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The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster
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  • Journal title : BMB Reports
  • Volume 49, Issue 2,  2016, pp.81-92
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2016.49.2.261
 Title & Authors
The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster
Altintas, Ozlem; Park, Sangsoon; Lee, Seung-Jae V.;
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Insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway regulates aging in many organisms, ranging from simple invertebrates to mammals, including humans. Many seminal discoveries regarding the roles of IIS in aging and longevity have been made by using the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In this review, we describe the mechanisms by which various IIS components regulate aging in C. elegans and D. melanogaster. We also cover systemic and tissue-specific effects of the IIS components on the regulation of lifespan. We further discuss IIS-mediated physiological processes other than aging and their effects on human disease models focusing on C. elegans studies. As both C. elegans and D. melanogaster have been essential for key findings regarding the effects of IIS on organismal aging in general, these invertebrate models will continue to serve as workhorses to help our understanding of mammalian aging.
Aging;C. elegans;D. melanogaster;Insulin/IGF-1 signaling;Longevity;
 Cited by
Lee Y, An S, Artan M et al (2015) Genes and Pathways That Influence Longevity in Caenorhabditis elegans; in Aging Mechanisms, Mori N and Mook-Jung I (eds), 123-169, Springer Japan

Giannakou ME and Partridge L (2007) Role of insulin-like signalling in Drosophila lifespan. Trends Biochem Sci 32, 180-188 crossref(new window)

Fontana L, Partridge L and Longo VD (2010) Extending healthy life span--from yeast to humans. Science 328, 321-326 crossref(new window)

Kenyon CJ (2010) The genetics of ageing. Nature 464, 504-512 crossref(new window)

Morris JZ, Tissenbaum HA and Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536-539 crossref(new window)

Kimura KD, Tissenbaum HA, Liu Y and Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942-946 crossref(new window)

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

Kenyon C, Chang J, Gensch E, Rudner A and Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366, 461-464 crossref(new window)

Klass MR (1983) A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Ageing Dev 22, 279-286 crossref(new window)

Wolkow CA, Munoz MJ, Riddle DL and Ruvkun G (2002) Insulin receptor substrate and p55 orthologous adaptor proteins function in the Caenorhabditis elegans daf-2/insulin-like signaling pathway. J Biol Chem 277, 49591-49597 crossref(new window)

Zhou K, Pandol S, Bokoch G and Traynor-Kaplan AE (1998) Disruption of Dictyostelium PI3K genes reduces [32P]phosphatidylinositol 3,4 bisphosphate and [32P]phosphatidylinositol trisphosphate levels, alters F-actin distribution and impairs pinocytosis. J Cell Sci 111 (Pt 2), 283-294

Ogg S and Ruvkun G (1998) The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 2, 887-893 crossref(new window)

Gil EB, Malone Link E, Liu LX, Johnson CD and Lees JA (1999) Regulation of the insulin-like developmental pathway of Caenorhabditis elegans by a homolog of the PTEN tumor suppressor gene. Proc Natl Acad Sci U S A 96, 2925-2930 crossref(new window)

Mihaylova VT, Borland CZ, Manjarrez L, Stern MJ and Sun H (1999) The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci U S A 96, 7427-7432 crossref(new window)

Rouault JP, Kuwabara PE, Sinilnikova OM, Duret L, Thierry-Mieg D and Billaud M (1999) Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. Curr Biol 9, 329-332 crossref(new window)

Dorman JB, Albinder B, Shroyer T and Kenyon C (1995) The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141, 1399-1406

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

Gottlieb S and Ruvkun G (1994) daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. Genetics 137, 107-120

Solari F, Bourbon-Piffaut A, Masse I, Payrastre B, Chan AM and Billaud M (2005) The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans. Oncogene 24, 20-27 crossref(new window)

Paradis S, Ailion M, Toker A, Thomas JH and Ruvkun G (1999) A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev 13, 1438-1452 crossref(new window)

Paradis S and Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12, 2488-2498 crossref(new window)

Hertweck M, Gobel C and Baumeister R (2004) C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6, 577-588 crossref(new window)

Chen AT, Guo C, Dumas KJ, Ashrafi K and Hu PJ (2013) Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation. Aging Cell 12, 932-940 crossref(new window)

Xiao R, Zhang B, Dong Y et al (2013) A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Cell 152, 806-817 crossref(new window)

Henderson ST and Johnson TE (2001) daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr Biol 11, 1975-1980 crossref(new window)

Lee RY, Hench J and 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 crossref(new window)

Lin K, Hsin H, Libina N and Kenyon C (2001) Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28, 139-145 crossref(new window)

Cahill CM, Tzivion G, Nasrin N et al (2001) Phosphatidylinositol 3-kinase signaling inhibits DAF-16 DNA binding and function via 14-3-3-dependent and 14-3-3-independent pathways. J Biol Chem 276, 13402-13410 crossref(new window)

Ogg S, Paradis S, Gottlieb S et al (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994-999 crossref(new window)

Lin K, Dorman JB, Rodan A and Kenyon C (1997) daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319-1322 crossref(new window)

Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ and Tissenbaum HA (2005) JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci U S A 102, 4494-4499 crossref(new window)

Curtis R, O'Connor G and DiStefano PS (2006) Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119-126 crossref(new window)

Greer EL, Dowlatshahi D, Banko MR et al (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17, 1646-1656 crossref(new window)

Apfeld J, O'Connor G, McDonagh T, DiStefano PS and Curtis R (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18, 3004-3009 crossref(new window)

Lehtinen MK, Yuan Z, Boag PR et al (2006) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987-1001 crossref(new window)

Wolff S, Ma H, Burch D, Maciel GA, Hunter T and Dillin A (2006) SMK-1, an essential regulator of DAF-16-mediated longevity. Cell 124, 1039-1053 crossref(new window)

Seo M, Seo K, Hwang W et al (2015) RNA helicase HEL-1 promotes longevity by specifically activating DAF-16/FOXO transcription factor signaling in Caenorhabditis elegans. Proc Natl Acad Sci U S A 112, E4246-E4255 crossref(new window)

Chiang WC, Tishkoff DX, Yang B et al (2012) C. elegans SIRT6/7 homolog SIR-2.4 promotes DAF-16 relocalization and function during stress. PLoS Genet 8, e1002948 crossref(new window)

Hu PJ, Xu J and Ruvkun G (2006) Two membrane-associated tyrosine phosphatase homologs potentiate C. elegans AKT-1/PKB signaling. PLoS Genet 2, e99 crossref(new window)

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

Alam H, Williams TW, Dumas KJ et al (2010) EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity. Cell Metab 12, 30-41 crossref(new window)

Berdichevsky A, Viswanathan M, Horvitz HR and Guarente L (2006) C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125, 1165-1177 crossref(new window)

Li J, Tewari M, Vidal M and Lee SS (2007) The 14-3-3 protein FTT-2 regulates DAF-16 in Caenorhabditis elegans. Dev Biol 301, 82-91 crossref(new window)

Wang Y, Oh SW, Deplancke B, Luo J, Walhout AJ and Tissenbaum HA (2006) C. elegans 14-3-3 proteins regulate life span and interact with SIR-2.1 and DAF-16/FOXO. Mech Ageing Dev 127, 741-747 crossref(new window)

Lee SS, Kennedy S, Tolonen AC and Ruvkun G (2003) DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644-647 crossref(new window)

Ookuma S, Fukuda M and Nishida E (2003) Identification of a DAF-16 transcriptional target gene, scl-1, that regulates longevity and stress resistance in Caenorhabditis elegans. Curr Biol 13, 427-431 crossref(new window)

Murphy CT, McCarroll SA, Bargmann CI et al (2003) Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277-283 crossref(new window)

McElwee J, Bubb K and Thomas JH (2003) Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111-121 crossref(new window)

Golden TR and Melov S (2004) Microarray analysis of gene expression with age in individual nematodes. Aging Cell 3, 111-124 crossref(new window)

Halaschek-Wiener J, Khattra JS, McKay S et al (2005) Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. Genome Res 15, 603-615 crossref(new window)

Lee SJ, Murphy CT and Kenyon C (2009) Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab 10, 379-391 crossref(new window)

Tullet JM, Hertweck M, An JH et al (2008) Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132, 1025-1038 crossref(new window)

An JH and Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17, 1882-1893 crossref(new window)

An JH, Vranas K, Lucke M et al (2005) Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. Proc Natl Acad Sci U S A 102, 16275-16280 crossref(new window)

Kahn NW, Rea SL, Moyle S, Kell A and Johnson TE (2008) Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidativestress response in Caenorhabditis elegans. Biochem J 409, 205-213 crossref(new window)

Oliveira RP, Porter Abate J, Dilks K et al (2009) Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf. Aging Cell 8, 524-541 crossref(new window)

Wang J, Robida-Stubbs S, Tullet JM, Rual JF, Vidal M and Blackwell TK (2010) RNAi screening implicates a SKN-1-dependent transcriptional response in stress resistance and longevity deriving from translation inhibition. PLoS Genet 6, e1001048 crossref(new window)

Staab TA, Griffen TC, Corcoran C, Evgrafov O, Knowles JA and Sieburth D (2013) The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. PLoS Genet 9, e1003354 crossref(new window)

Glover-Cutter KM, Lin S and Blackwell TK (2013) Integration of the unfolded protein and oxidative stress responses through SKN-1/Nrf. PLoS Genet 9, e1003701 crossref(new window)

Choe KP, Przybysz AJ and Strange K (2009) The WD40 repeat protein WDR-23 functions with the CUL4/DDB1 ubiquitin ligase to regulate nuclear abundance and activity of SKN-1 in Caenorhabditis elegans. Mol Cell Biol 29, 2704-2715 crossref(new window)

Park SK, Tedesco PM and Johnson TE (2009) Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging Cell 8, 258-269 crossref(new window)

Pang S, Lynn DA, Lo JY, Paek J and Curran SP (2014) SKN-1 and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation. Nat Commun 5, 5048 crossref(new window)

Kell A, Ventura N, Kahn N and Johnson TE (2007) Activation of SKN-1 by novel kinases in Caenorhabditis elegans. Free Radic Biol Med 43, 1560-1566 crossref(new window)

Li X, Matilainen O, Jin C, Glover-Cutter KM, Holmberg CI and Blackwell TK (2011) Specific SKN-1/Nrf stress responses to perturbations in translation elongation and proteasome activity. PLoS Genet 7, e1002119 crossref(new window)

Ewald CY, Landis JN, Porter Abate J, Murphy CT and Blackwell TK (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519, 97-101 crossref(new window)

Hsu AL, Murphy CT and Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142-1145 crossref(new window)

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

Cohen E, Bieschke J, Perciavalle RM, Kelly JW and Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313, 1604-1610 crossref(new window)

Chiang WC, Ching TT, Lee HC, Mousigian C and Hsu AL (2012) HSF-1 regulators DDL-1/2 link insulin-like signaling to heat-shock responses and modulation of longevity. Cell 148, 322-334 crossref(new window)

Seo K, Choi E, Lee D, Jeong DE, Jang SK and Lee SJ (2013) Heat shock factor 1 mediates the longevity conferred by inhibition of TOR and insulin/IGF-1 signaling pathways in C. elegans. Aging Cell 12, 1073-1081 crossref(new window)

Garigan D, Hsu AL, Fraser AG, Kamath RS, Ahringer J and Kenyon C (2002) Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101-1112

Douglas PM, Baird NA, Simic MS et al (2015) Heterotypic signals from neural HSF-1 separate thermotolerance from longevity. Cell Rep 12, 1196-1204 crossref(new window)

Baird NA, Douglas PM, Simic MS et al (2014) HSF-1-mediated cytoskeletal integrity determines thermotolerance and life span. Science 346, 360-363 crossref(new window)

Amin J, Ananthan J and Voellmy R (1988) Key features of heat shock regulatory elements. Mol Cell Biol 8, 3761-3769 crossref(new window)

Kay RJ, Boissy RJ, Russnak RH and Candido EP (1986) Efficient transcription of a Caenorhabditis elegans heat shock gene pair in mouse fibroblasts is dependent on multiple promoter elements which can function bidirectionally. Mol Cell Biol 6, 3134-3143 crossref(new window)

Russnak RH and Candido EP (1985) Locus encoding a family of small heat shock genes in Caenorhabditis elegans: two genes duplicated to form a 3.8-kilobase inverted repeat. Mol Cell Biol 5, 1268-1278 crossref(new window)

Yokoyama K, Fukumoto K, Murakami T et al (2002) Extended longevity of Caenorhabditis elegans by knocking in extra copies of hsp70F, a homolog of mot-2 (mortalin)/mthsp70/Grp75. FEBS Lett 516, 53-57 crossref(new window)

Walker GA and Lithgow GJ (2003) Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2, 131-139 crossref(new window)

Pierce SB, Costa M, Wisotzkey R et al (2001) Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev 15, 672-686 crossref(new window)

Li W, Kennedy SG and Ruvkun G (2003) daf-28 encodes a C. elegans insulin superfamily member that is regulated by environmental cues and acts in the DAF-2 signaling pathway. Genes Dev 17, 844-858 crossref(new window)

Chen Z, Hendricks M, Cornils A, Maier W, Alcedo J and Zhang Y (2013) Two insulin-like peptides antagonistically regulate aversive olfactory learning in C. elegans. Neuron 77, 572-585 crossref(new window)

Cornils A, Gloeck M, Chen Z, Zhang Y and Alcedo J (2011) Specific insulin-like peptides encode sensory information to regulate distinct developmental processes. Development 138, 1183-1193 crossref(new window)

Murphy CT, Lee SJ and Kenyon C (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci U S A 104, 19046-19050 crossref(new window)

Kawli T and Tan MW (2008) Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nat Immunol 9, 1415-1424 crossref(new window)

Malone EA, Inoue T and Thomas JH (1996) Genetic analysis of the roles of daf-28 and age-1 in regulating Caenorhabditis elegans dauer formation. Genetics 143, 1193-1205

Malone EA and Thomas JH (1994) A screen for nonconditional dauer-constitutive mutations in Caenorhabditis elegans. Genetics 136, 879-886

Fernandes de Abreu DA, Caballero A, Fardel P et al (2014) An insulin-to-insulin regulatory network orchestrates phenotypic specificity in development and physiology. PLoS Genet 10, e1004225 crossref(new window)

Ritter AD, Shen Y, Fuxman Bass J et al (2013) Complex expression dynamics and robustness in C. elegans insulin networks. Genome Res 23, 954-965 crossref(new window)

Hung WL, Wang Y, Chitturi J and Zhen M (2014) A Caenorhabditis elegans developmental decision requires insulin signaling-mediated neuron-intestine communication. Development 141, 1767-1779 crossref(new window)

Chen Y and Baugh LR (2014) Ins-4 and daf-28 function redundantly to regulate C. elegans L1 arrest. Dev Biol 394, 314-326 crossref(new window)

Duret L, Guex N, Peitsch MC and Bairoch A (1998) New insulin-like proteins with atypical disulfide bond pattern characterized in Caenorhabditis elegans by comparative sequence analysis and homology modeling. Genome Res 8, 348-353

Michaelson D, Korta DZ, Capua Y and Hubbard EJ (2010) Insulin signaling promotes germline proliferation in C. elegans. Development 137, 671-680 crossref(new window)

Leinwand SG and Chalasani SH (2013) Neuropeptide signaling remodels chemosensory circuit composition in Caenorhabditis elegans. Nat Neurosci 16, 1461-1467 crossref(new window)

Ohta A, Ujisawa T, Sonoda S and Kuhara A (2014) Light and pheromone-sensing neurons regulates cold habituation through insulin signalling in Caenorhabditis elegans. Nat Commun 5, 4412

Wolkow CA, Kimura KD, Lee MS and Ruvkun G (2000) Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147-150 crossref(new window)

Iser WB, Gami MS and Wolkow CA (2007) Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs. Dev Biol 303, 434-447 crossref(new window)

Hu PJ (2007) Dauer. WormBook: the online review of C. elegans biology, 1-19

Riddle DL and Albert PS (1997) Genetic and Environmental Regulation of Dauer Larva Development; in C. elegans II, Riddle DL, Blumenthal T, Meyer BJ et al (eds), Cold Spring Harbor Laboratory Press, Cold Spring Harbor (NY)

Libina N, Berman JR and Kenyon C (2003) Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 115, 489-502 crossref(new window)