Abstract
An organism’s well-being is facilitated by numerous molecular and biochemical pathways that ensure homeostasis within cells and tissues. Aging causes a gradual let-down in the maintenance of homeostasis due to various endogenous and environmental challenges, leading to amassing of damages, functional deterioration of different tissues and vulnerability to ailments. Nutrient sensing pathways that maintain glucose homeostasis in body are involved in regulation of aging. Insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) pathway was the first nutrient sensing pathway discovered to affect the aging process. This pathway is highly conserved and the most studied among different organisms. Epigenetic machineries that include DNA and histone modifying enzymes and various non-coding RNAs have been identified as important contributors to nutrition-related longevity and aging control. In this report, we present the homology and differences in IIS pathway of various organisms including worm, fly, rodent and human. We also discuss how epigenome remodelling, chromatin based strategies, small and long non-coding RNA are involved to regulate multiple steps of aging or age-related insulin homeostasis. Enhanced study of the role of IIS pathway and epigenetic mechanisms that regulate aging may facilitate progressive prevention and treatment of human age-related diseases.
Similar content being viewed by others
References
Alic N et al (2011) Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling. Mol Syst Biol 7:502. doi:10.1038/msb.2011.36
Anisimov VN, Bartke A (2013) The key role of growth hormone-insulin-IGF-1 signaling in aging and cancer. Crit Rev Oncol Hematol 87:201–223. doi:10.1016/j.critrevonc.2013.01.005
Anselmi CV et al (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12:95–104. doi:10.1089/rej.2008.0827
Arantes-Oliveira N, Berman JR, Kenyon C (2003) Healthy animals with extreme longevity. Science 302:611. doi:10.1126/science.1089169
Aravin AA, Hannon GJ (2008) Small RNA silencing pathways in germ and stem cells. Cold Spring Harb Symp Quant Biol 73:283–290. doi:10.1101/sqb.2008.73.058
Armstrong VL, Rakoczy S, Rojanathammanee L, Brown-Borg HM (2014) Expression of DNA methyltransferases is influenced by growth hormone in the long-living Ames dwarf mouse in vivo and in vitro. J Gerontol A Biol Sci Med Sci 69:923–933. doi:10.1093/gerona/glt133
Bai H, Kang P, Tatar M (2012) Drosophila insulin-like peptide-6 (dilp6) expression from fat body extends lifespan and represses secretion of Drosophila insulin-like peptide-2 from the brain. Aging Cell 11:978–985. doi:10.1111/acel.12000
Bai H, Post S, Kang P, Tatar M (2015) Drosophila longevity assurance conferred by reduced insulin receptor substrate chico partially requires d4eBP. PLoS ONE 10:e0134415. doi:10.1371/journal.pone.0134415
Banerjee KK, Ayyub C, Ali SZ, Mandot V, Prasad NG, Kolthur-Seetharam U (2012a) dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner. Cell Rep 2:1485–1491. doi:10.1016/j.celrep.2012.11.013
Banerjee KK, Ayyub C, Sengupta S, Kolthur-Seetharam U (2012b) dSir2 deficiency in the fatbody, but not muscles, affects systemic insulin signaling, fat mobilization and starvation survival in flies. Aging 4:206–223
Barbieri M, Bonafe M, Franceschi C, Paolisso G (2003) Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 285:E1064–E1071. doi:10.1152/ajpendo.00296.2003
Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS (2001) Extending the lifespan of long-lived mice. Nature 414:412. doi:10.1038/35106646
Bartke A, Sun LY, Longo V (2013) Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev 93:571–598. doi:10.1152/physrev.00006.2012
Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61:1315–1322. doi:10.2337/db11-1300
Bates DJ et al (2010) MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging. Aging Cell 9:1–18. doi:10.1111/j.1474-9726.2009.00529.x
Batista PJ et al (2008) PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans. Mol Cell 31:67–78. doi:10.1016/j.molcel.2008.06.002
Baugh LR, Sternberg PW (2006) DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Curr Biol 16:780–785. doi:10.1016/j.cub.2006.03.021
Bellizzi D et al (2005) A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 85:258–263. doi:10.1016/j.ygeno.2004.11.003
Ben-Avraham D, Muzumdar RH, Atzmon G (2012) Epigenetic genome-wide association methylation in aging and longevity. Epigenomics 4:503–509. doi:10.2217/epi.12.41
Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593–610. doi:10.1038/nrm4048
Bennett-Baker PE, Wilkowski J, Burke DT (2003) Age-associated activation of epigenetically repressed genes in the mouse. Genetics 165:2055–2062
Berdichevsky A, Viswanathan M, Horvitz HR, 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. doi:10.1016/j.cell.2006.04.036
Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12:1133–1138. doi:10.1038/nm1006-1133
Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574. doi:10.1126/science.1078223
Boehm M, Slack F (2005) A developmental timing microRNA and its target regulate life span in C. elegans. Science 310:1954–1957. doi:10.1126/science.1115596
Bonkowski MS, Rocha JS, Masternak MM, Al Regaiey KA, Bartke A (2006) Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc Natl Acad Sci USA 103:7901–7905. doi:10.1073/pnas.0600161103
Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E (2001) An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 11:213–221
Broughton S, Partridge L (2009) Insulin/IGF-like signalling, the central nervous system and aging. Biochem J 418:1–12. doi:10.1042/BJ20082102
Broughton SJ et al (2005) Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc Natl Acad Sci USA 102:3105–3110. doi:10.1073/pnas.0405775102
Broughton S et al (2008) Reduction of DILP2 in Drosophila triages a metabolic phenotype from lifespan revealing redundancy and compensation among DILPs. PLoS ONE 3:e3721. doi:10.1371/journal.pone.0003721
Brown-Borg HM (2009) Hormonal control of aging in rodents: the somatotropic axis. Mol Cell Endocrinol 299:64–71. doi:10.1016/j.mce.2008.07.001
Brunet A et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868
Brunet A et al (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015. doi:10.1126/science.1094637
Brunet C et al (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477:482–485. doi:10.1038/nature10296
Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288. doi:10.1038/onc.2008.21
Campisi J, di Fagagna FDA (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740. doi:10.1038/nrm2233
Carter ME, Brunet A (2007) FOXO transcription factors. Curr Biol 17:R113–R114. doi:10.1016/j.cub.2007.01.008
Casillas MA Jr, Lopatina N, Andrews LG, Tollefsbol TO (2003) Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 252:33–43
Cava E, Fontana L (2013) Will calorie restriction work in humans? Aging 5:507–514
Cedar H, Bergman Y (2012) Programming of DNA methylation patterns. Annu Rev Biochem 81:97–117. doi:10.1146/annurev-biochem-052610-091920
Chung WJ, Okamura K, Martin R, Lai EC (2008) Endogenous RNA interference provides a somatic defense against Drosophila transposons. Curr Biol 18:795–802. doi:10.1016/j.cub.2008.05.006
Claeys I, Simonet G, Poels J, Van Loy T, Vercammen L, De Loof A, Vanden Broeck J (2002) Insulin-related peptides and their conserved signal transduction pathway. Peptides 23:807–816
Clancy DJ et al (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106. doi:10.1126/science.1057991
Clayton RN (2003) Cardiovascular function in acromegaly. Endocr Rev 24:272–277. doi:10.1210/er.2003-0009
Cohen E et al (2009) Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139:1157–1169. doi:10.1016/j.cell.2009.11.014
Czech B et al (2008) An endogenous small interfering RNA pathway in Drosophila. Nature 453:798–802. doi:10.1038/nature07007
Davalos A et al (2011) miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA 108:9232–9237. doi:10.1073/pnas.1102281108
de Lencastre A, Pincus Z, Zhou K, Kato M, Lee SS, Slack FJ (2010) MicroRNAs both promote and antagonize longevity in C. elegans. Curr Biol 20:2159–2168. doi:10.1016/j.cub.2010.11.015
De Meyts P (2016) The insulin receptor and its signal transduction network. In: De Groot LJ, Chrousos G, Dungan K, et al., (eds) Endotext [Internet]. South Dartmouth (MA): MDText.com Inc, Available from: https://www.ncbi.nlm.nih.gov/books/NBK378978/
Demontis F, Perrimon N (2010) FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143:813–825. doi:10.1016/j.cell.2010.10.007
Dong XC, Copps KD, Guo S, Li Y, Kollipara R, DePinho RA, White MF (2008) Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8:65–76. doi:10.1016/j.cmet.2008.06.006
Drummond MJ, McCarthy JJ, Sinha M, Spratt HM, Volpi E, Esser KA, Rasmussen BB (2011) Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol Genom 43:595–603. doi:10.1152/physiolgenomics.00148.2010
Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14:83–97. doi:10.1038/nrm3507
Eisenberg T et al (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11:1305–1314. doi:10.1038/ncb1975
Essers PB et al (2015) A long noncoding RNA on the ribosome is required for lifespan extension. Cell Rep. doi:10.1016/j.celrep.2014.12.029
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440. doi:10.1038/sj.onc.1205600
Ewald CY, Landis JN, Porter Abate J, Murphy CT, Blackwell TK (2015) Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. Nature 519:97–101. doi:10.1038/nature14021
Faraonio R et al (2012) A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts. Cell Death Differ 19:713–721. doi:10.1038/cdd.2011.143
Flachsbart F, Croucher PJ, Nikolaus S, Hampe J, Cordes C, Schreiber S, Nebel A (2006) Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol 41:98–102. doi:10.1016/j.exger.2005.09.008
Garcia AM et al (2008) Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. Mech Ageing Dev 129:528–533. doi:10.1016/j.mad.2008.04.013
Garelli A, Gontijo AM, Miguela V, Caparros E, Dominguez M (2012) Imaginal discs secrete insulin-like peptide 8 to mediate plasticity of growth and maturation. Science 336:579–582. doi:10.1126/science.1216735
Garofalo RS (2002) Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol Metab 13:156–162
Gems D et al (1998) Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 150:129–155
Ghildiyal M, Zamore PD (2009) Small silencing RNAs: an expanding universe. Nat Rev Genet 10:94–108. doi:10.1038/nrg2504
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. doi:10.1111/j.1474-9726.2007.00362.x
Grammatikakis I, Panda AC, Abdelmohsen K, Gorospe M (2014) Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging. Aging 6:992–1009. doi:10.18632/aging.100710
Greer EL, Brunet A (2008) Signaling networks in aging. J Cell Sci 121:407–412. doi:10.1242/jcs.021519
Greer EL, Brunet A (2009) Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8:113–127. doi:10.1111/j.1474-9726.2009.00459.x
Greer EL et al (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365–371. doi:10.1038/nature10572
Grillari J, Hackl M, Grillari-Voglauer R (2010) miR-17-92 cluster: ups and downs in cancer and aging. Biogerontology 11:501–506. doi:10.1007/s10522-010-9272-9
Gronke S, Clarke DF, Broughton S, Andrews TD, Partridge L (2010) Molecular evolution and functional characterization of Drosophila insulin-like peptides. PLoS Genet 6:e1000857. doi:10.1371/journal.pgen.1000857
Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408:255–262. doi:10.1038/35041700
Guevara-Aguirre J et al (2011) Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med 3:70ra13. doi:10.1126/scitranslmed.3001845
Hafen E (2004) Cancer, type 2 diabetes, and ageing: news from flies and worms. Swiss Med Wkly 134:711–719
Hamrick MW et al (2010) The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice. Biochem Biophys Res Commun 400:379–383. doi:10.1016/j.bbrc.2010.08.079
Han S, Brunet A (2012) Histone methylation makes its mark on longevity. Trends Cell Biol 22:42–49. doi:10.1016/j.tcb.2011.11.001
Hannum G et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367. doi:10.1016/j.molcel.2012.10.016
Harman D (1965) The free radical theory of aging: effect of age on serum copper levels. J Gerontol 20:151–153
Haselton A, Sharmin E, Schrader J, Sah M, Poon P, Fridell YW (2010) Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance. Cell Cycle 9:3063–3071. doi:10.4161/cc.9.15.12458
Hass BS, Hart RW, Lu MH, Lyn-Cook BD (1993) Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. Mutat Res 295:281–289
Holzenberger M et al (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187. doi:10.1038/nature01298
Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115. doi:10.1186/gb-2013-14-10-r115
Huang CW et al (2015) Tequila regulates insulin-like signaling and extends life span in Drosophila melanogaster. J Gerontol A Biol Sci Med Sci 70:1461–1469. doi:10.1093/gerona/glv094
Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562–566. doi:10.1038/nature02549
Hyun S et al (2009) Conserved microRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K. Cell 139:1096–1108. doi:10.1016/j.cell.2009.11.020
Ibanez-Ventoso C, Yang M, Guo S, Robins H, Padgett RW, Driscoll M (2006) Modulated microRNA expression during adult lifespan in Caenorhabditis elegans. Aging Cell 5:235–246. doi:10.1111/j.1474-9726.2006.00210.x
Ikeno Y et al (2009) Reduced incidence and delayed occurrence of fatal neoplastic diseases in growth hormone receptor/binding protein knockout mice. J Gerontol A Biol Sci Med Sci 64:522–529. doi:10.1093/gerona/glp017
Ikeya T, Galic M, Belawat P, Nairz K, Hafen E (2002) Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila. Curr Biol 12:1293–1300
Jain S, Thakkar N, Chhatai J, Bhadra MP, Bhadra U (2016) Long non-coding RNA: functional agent for disease traits. RNA Biol 1–14. doi: 10.1080/15476286.2016.1172756
Jin C et al (2011) Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab 14:161–172. doi:10.1016/j.cmet.2011.07.001
Johnson FB, Sinclair DA, Guarente L (1999) Molecular biology of aging. Cell 96:291–302
Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhaes JP (2012) The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation Res 15:483–494. doi:10.1089/rej.2012.1324
Jung M, Pfeifer GP (2015) Aging and DNA methylation. BMC Biol 13:7. doi:10.1186/s12915-015-0118-4
Kaletsky R, Lakhina V, Arey R, Williams A, Landis J, Ashraf J, Murphy CT (2016) The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Nature 529:92–96. doi:10.1038/nature16483
Karp X, Hammell M, Ow MC, Ambros V (2011) Effect of life history on microRNA expression during C. elegans development. Rna 17:639–651. doi:10.1261/rna.2310111
Karpac J, Jasper H (2009) Insulin and JNK: optimizing metabolic homeostasis and lifespan. Trends Endocrinol Metab 20:100–106. doi:10.1016/j.tem.2008.11.004
Kato M, Chen X, Inukai S, Zhao H, Slack FJ (2011) Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans. RNA 17:1804–1820. doi:10.1261/rna.2714411
Keniry A, Oxley D, Monnier P, Kyba M, Dandolo L, Smits G, Reik W (2012) The H19 lincRNA is a developmental reservoir of miR-675 that suppresses growth and Igf1r. Nat Cell Biol 14:659–665. doi:10.1038/ncb2521
Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120:449–460. doi:10.1016/j.cell.2005.02.002
Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512. doi:10.1038/nature08980
Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464. doi:10.1038/366461a0
Khanna A, Muthusamy S, Liang R, Sarojini H, Wang E (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging 3:223–236
Kim HS, Choi ES, Shin JA, Jang YK, Park SD (2004) Regulation of Swi6/HP1-dependent heterochromatin assembly by cooperation of components of the mitogen-activated protein kinase pathway and a histone deacetylase Clr6. J Biol Chem 279:42850–42859. doi:10.1074/jbc.M407259200
Kim DH et al (2015) The roles of FoxOs in modulation of aging by calorie restriction. Biogerontology 16:1–14. doi:10.1007/s10522-014-9519-y
Kim J, Kim KM, Noh JH, Yoon JH, Abdelmohsen K, Gorospe M (2016) Long noncoding RNAs in diseases of aging. Biochim Biophys Acta 1859:209–221. doi:10.1016/j.bbagrm.2015.06.013
Koubova J, Guarente L (2003) How does calorie restriction work? Genes Dev 17:313–321. doi:10.1101/gad.1052903
Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. doi:10.1016/j.cell.2007.02.005
Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:D68–D73. doi:10.1093/nar/gkt1181
Kucerova L, Kubrak OI, Bengtsson JM, Strnad H, Nylin S, Theopold U, Nassel DR (2016) Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster. BMC Genom 17:50. doi:10.1186/s12864-016-2383-1
Kume S et al (2010) Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Investig 120:1043–1055. doi:10.1172/JCI41376
Kuningas M, Putters M, Westendorp RG, Slagboom PE, van Heemst D (2007) SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J Gerontol A Biol Sci Med Sci 62:960–965
Lau NC, Seto AG, Kim J, Kuramochi-Miyagawa S, Nakano T, Bartel DP, Kingston RE (2006) Characterization of the piRNA complex from rat testes. Science 313:363–367. doi:10.1126/science.1130164
Lee C, Longo VD (2011) Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene 30:3305–3316. doi:10.1038/onc.2011.91
Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854
Lee HC, Chang SS, Choudhary S, Aalto AP, Maiti M, Bamford DH, Liu Y (2009) qiRNA is a new type of small interfering RNA induced by DNA damage. Nature 459:274–277. doi:10.1038/nature08041
Lescai F et al (2009) Human longevity and 11p15.5: a study in 1321 centenarians. Eur J Hum Genet 17:1515–1519. doi:10.1038/ejhg.2009.54
Li Y, Liu L, Tollefsbol TO (2010) Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 24:1442–1453. doi:10.1096/fj.09-149328
Li N, Bates DJ, An J, Terry DA, Wang E (2011a) Up-regulation of key microRNAs, and inverse down-regulation of their predicted oxidative phosphorylation target genes, during aging in mouse brain. Neurobiol Aging 32:944–955. doi:10.1016/j.neurobiolaging.2009.04.020
Li N, Muthusamy S, Liang R, Sarojini H, Wang E (2011b) Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1. Mech Ageing Dev 132:75–85. doi:10.1016/j.mad.2010.12.004
Li Y, Daniel M, Tollefsbol TO (2011c) Epigenetic regulation of caloric restriction in aging. BMC Med 9:98. doi:10.1186/1741-7015-9-98
Liang F, Kume S, Koya D (2009) SIRT1 and insulin resistance. Nat Rev Endocrinol 5:367–373. doi:10.1038/nrendo.2009.101
Liang R et al (2011) Post-transcriptional regulation of IGF1R by key microRNAs in long-lived mutant mice. Aging Cell 10:1080–1088. doi:10.1111/j.1474-9726.2011.00751.x
Lichtenberg FR (2011) The quality of medical care, behavioral risk factors, and longevity growth. Int J Health Care Finance Econ 11:1–34. doi:10.1007/s10754-010-9086-y
Lim DH et al (2011) The endogenous siRNA pathway in Drosophila impacts stress resistance and lifespan by regulating metabolic homeostasis. FEBS Lett 585:3079–3085. doi:10.1016/j.febslet.2011.08.034
Lin MJ, Tang LY, Reddy MN, Shen CK (2005) DNA methyltransferase gene dDnmt2 and longevity of Drosophila. J Biol Chem 280:861–864. doi:10.1074/jbc.C400477200
Liu L, van Groen T, Kadish I, Tollefsbol TO (2009) DNA methylation impacts on learning and memory in aging. Neurobiol Aging 30:549–560. doi:10.1016/j.neurobiolaging.2007.07.020
Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299:1342–1346. doi:10.1126/science.1077991
Maida Y et al (2009) An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461:230–235. doi:10.1038/nature08283
Mair W, Dillin A (2008) Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem 77:727–754. doi:10.1146/annurev.biochem.77.061206.171059
Malone CD, Brennecke J, Dus M, Stark A, McCombie WR, Sachidanandam R, Hannon GJ (2009) Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137:522–535. doi:10.1016/j.cell.2009.03.040
Marino G, Ugalde AP, Fernandez AF, Osorio FG, Fueyo A, Freije JM, Lopez-Otin C (2010) Insulin-like growth factor 1 treatment extends longevity in a mouse model of human premature aging by restoring somatotroph axis function. Proc Natl Acad Sci USA 107:16268–16273. doi:10.1073/pnas.1002696107
Martin GM, Oshima J (2000) Lessons from human progeroid syndromes. Nature 408:263–266. doi:10.1038/35041705
Martins R, Lithgow GJ, Link W (2015) Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. doi:10.1111/acel.12427
Maures TJ, Greer EL, Hauswirth AG, Brunet A (2011) The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell 10:980–990. doi:10.1111/j.1474-9726.2011.00738.x
McElwee JJ, Schuster E, Blanc E, Thomas JH, Gems D (2004) Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J Biol Chem 279:44533–44543. doi:10.1074/jbc.M406207200
Mercken EM et al (2013) Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 12:645–651. doi:10.1111/acel.12088
Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N (2014) Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13:769–771. doi:10.1111/acel.12213
Min KJ, Yamamoto R, Buch S, Pankratz M, Tatar M (2008) Drosophila lifespan control by dietary restriction independent of insulin-like signaling. Aging Cell 7:199–206. doi:10.1111/j.1474-9726.2008.00373.x
Mitteldorf J (2016) An epigenetic clock controls aging. Biogerontology 17:257–265. doi:10.1007/s10522-015-9617-5
Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539. doi:10.1038/382536a0
Morris BJ et al (2015a) Association analysis of FOXO3 longevity variants with blood pressure and essential hypertension. Am J Hypertens. doi:10.1093/ajh/hpv171
Morris BJ, Wilicoxa DC, Donlon TA, Willcox BJ (2015b) FOXO3: a major gene for human longevity—a mini-review. Gerontology 61:515–525. doi:10.1159/000375235
Mosammaparast N, Shi Y (2010) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem 79:155–179. doi:10.1146/annurev.biochem.78.070907.103946
Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE (2013) The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 12:661–684. doi:10.1016/j.arr.2012.02.001
Moskalev AA, Aliper AM, Smit-McBride Z, Buzdin A, Zhavoronkov A (2014) Genetics and epigenetics of aging and longevity. Cell Cycle 13:1063–1077. doi:10.4161/cc.28433
Mostoslavsky R et al (2006) Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124:315–329. doi:10.1016/j.cell.2005.11.044
Munoz-Najar U, Sedivy JM (2011) Epigenetic control of aging. Antioxid Redox Signal 14:241–259. doi:10.1089/ars.2010.3250
Murabito JM, Yuan R, Lunetta KL (2012) The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals. J Gerontol A Biol Sci Med Sci 67:470–479. doi:10.1093/gerona/gls089
Murphy CT, Lee SJ, Kenyon C (2007) Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans. Proc Natl Acad Sci USA 104:19046–19050. doi:10.1073/pnas.0709613104
Nakae J, Biggs WH 3rd, Kitamura T, Cavenee WK, Wright CV, Arden KC, Accili D (2002) Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32:245–253. doi:10.1038/ng890
Narasimhan SD, Yen K, Bansal A, Kwon ES, Padmanabhan S, Tissenbaum HA (2011) PDP-1 links the TGF-beta and IIS pathways to regulate longevity, development, and metabolism. PLoS Genet 7:e1001377. doi:10.1371/journal.pgen.1001377
Nassel DR, Liu Y, Luo J (2015) Insulin/IGF signaling and its regulation in Drosophila. Gen Comp Endocrinol 221:255–266. doi:10.1016/j.ygcen.2014.11.021
Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999. doi:10.1038/40194
Okamoto N, Yamanaka N, Yagi Y, Nishida Y, Kataoka H, O’Connor MB, Mizoguchi A (2009) A fat body-derived IGF-like peptide regulates postfeeding growth in Drosophila. Dev Cell 17:885–891. doi:10.1016/j.devcel.2009.10.008
Okamura K, Lai EC (2008) Endogenous small interfering RNAs in animals. Nat Rev Mol Cell Biol 9:673–678. doi:10.1038/nrm2479
Outeiro TF, Marques O, Kazantsev A (2008) Therapeutic role of sirtuins in neurodegenerative disease. Biochim Biophys Acta 1782:363–369. doi:10.1016/j.bbadis.2008.02.010
Paaby AB, Schmidt PS (2009) Dissecting the genetics of longevity in Drosophila melanogaster. Fly 3:29–38
Papanicolaou KN, Izumiya Y, Walsh K (2008) Forkhead transcription factors and cardiovascular biology. Circ Res 102:16–31. doi:10.1161/CIRCRESAHA.107.164186
Papatheodorou I, Petrovs R, Thornton JM (2014) Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing. Bioinformatics 30:2999–3003. doi:10.1093/bioinformatics/btu493
Partridge L, Harvey PH (1993) Gerontology. Methuselah among nematodes. Nature 366:404–405. doi:10.1038/366404a0
Partridge L, Alic N, Bjedov I, Piper MD (2011) Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Exp Gerontol 46:376–381. doi:10.1016/j.exger.2010.09.003
Patel NV et al (2005) Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000. doi:10.1016/j.neurobiolaging.2004.09.014
Pincus Z, Smith-Vikos T, Slack FJ (2011) MicroRNA predictors of longevity in Caenorhabditis elegans. PLoS Genet 7:e1002306. doi:10.1371/journal.pgen.1002306
Polito L, Kehoe PG, Forloni G, Albani D (2010) The molecular genetics of sirtuins: association with human longevity and age-related diseases. Int J Mol Epidemiol Genet 1:214–225
Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991. doi:10.1146/annurev.biochem.052308.114844
Proshkina EN, Shaposhnikov MV, Sadritdinova AF, Kudryavtseva AV, Moskalev AA (2015) Basic mechanisms of longevity: a case study of Drosophila pro-longevity genes. Ageing Res Rev 24:218–231. doi:10.1016/j.arr.2015.08.005
Pu M et al (2015) Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev 29:718–731. doi:10.1101/gad.254144.114
Puig O, Tjian R (2005) Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 19:2435–2446. doi:10.1101/gad.1340505
Puig O, Marr MT, Ruhf ML, Tjian R (2003) Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17:2006–2020. doi:10.1101/gad.1098703
Qin Z, Hubbard EJ (2015) Non-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells. Nat Commun 6:7107. doi:10.1038/ncomms8107
Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, Longo VD (2008) Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci USA 105:8215–8220. doi:10.1073/pnas.0708100105
Rajasethupathy P, Antonov I, Sheridan R, Frey S, Sander C, Tuschl T, Kandel ER (2012) A role for neuronal piRNAs in the epigenetic control of memory-related synaptic plasticity. Cell 149:693–707. doi:10.1016/j.cell.2012.02.057
Redman LM, Veldhuis JD, Rood J, Smith SR, Williamson D, Ravussin E, Pennington CT (2010) The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women. Aging Cell 9:32–39. doi:10.1111/j.1474-9726.2009.00530.x
Richard DS et al (2005) Insulin signaling is necessary for vitellogenesis in Drosophila melanogaster independent of the roles of juvenile hormone and ecdysteroids: female sterility of the chico1 insulin signaling mutation is autonomous to the ovary. J Insect Physiol 51:455–464. doi:10.1016/j.jinsphys.2004.12.013
Riedel CG et al (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nat Cell Biol 15:491–501. doi:10.1038/ncb2720
Russell SJ, Kahn CR (2007) Endocrine regulation of ageing. Nat Rev Mol Cell Biol 8:681–691. doi:10.1038/nrm2234
Salpea P et al (2012) Postnatal development- and age-related changes in DNA-methylation patterns in the human genome. Nucleic Acids Res 40:6477–6494. doi:10.1093/nar/gks312
Satoh A et al (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab 18:416–430. doi:10.1016/j.cmet.2013.07.013
Schenk S et al (2011) Sirt1 enhances skeletal muscle insulin sensitivity in mice during caloric restriction. J Clin Investig 121:4281–4288. doi:10.1172/JCI58554
Sen P et al (2015) H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev 29:1362–1376. doi:10.1101/gad.263707.115
Sharma S, Brosh RM Jr (2007) Human RECQ1 is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS ONE 2:e1297. doi:10.1371/journal.pone.0001297
Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513. doi:10.1016/j.coi.2010.05.003
Shimokawa I et al (2015) The life-extending effect of dietary restriction requires Foxo3 in mice. Aging Cell 14:707–709. doi:10.1111/acel.12340
Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ (2010) Polycomb repressive complex 2 and trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci USA 107:169–174. doi:10.1073/pnas.0907739107
Singh A, Kumar N, Matai L, Jain V, Garg A, Mukhopadhyay A (2016) A chromatin modifier integrates insulin/IGF-1 signalling and dietary restriction to regulate longevity. Aging Cell. doi:10.1111/acel.12477
Soerensen M, Nygaard M, Dato S, Stevnsner T, Bohr VA, Christensen K, Christiansen L (2015) Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals. Aging Cell 14:60–66. doi:10.1111/acel.12295
Steuerman R, Shevah O, Laron Z (2011) Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol 164:485–489. doi:10.1530/EJE-10-0859
Suh Y et al (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci USA 105:3438–3442. doi:10.1073/pnas.0705467105
Sun L et al (2015) FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: a case–control study and meta-analysis. Sci Rep 5:9852. doi:10.1038/srep09852
Taguchi A, Wartschow LM, White MF (2007) Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317:369–372. doi:10.1126/science.1142179
Tait IS, Li Y, Lu J (2015) Effects of PTEN on the longevity of cultured human umbilical vein endothelial cells: the role of antioxidants. Int J Mol Med 35:277–284. doi:10.3892/ijmm.2014.1999
Talens RP et al (2012) Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell 11:694–703. doi:10.1111/j.1474-9726.2012.00835.x
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. doi:10.1126/science.1057987
Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299:1346–1351. doi:10.1126/science.1081447
Thompson RF, Atzmon G, Gheorghe C, Liang HQ, Lowes C, Greally JM, Barzilai N (2010) Tissue-specific dysregulation of DNA methylation in aging. Aging Cell 9:506–518. doi:10.1111/j.1474-9726.2010.00577.x
Toiber D et al (2013) SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell 51:454–468. doi:10.1016/j.molcel.2013.06.018
Tra J, Kondo T, Lu Q, Kuick R, Hanash S, Richardson B (2002) Infrequent occurrence of age-dependent changes in CpG island methylation as detected by restriction landmark genome scanning. Mech Ageing Dev 123:1487–1503
van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450. doi:10.1038/nrm2190
van Heemst D (2010) Insulin, IGF-1 and longevity. Aging Dis 1:147–157
van Heemst D et al (2005) Reduced insulin/IGF-1 signalling and human longevity. Aging Cell 4:79–85. doi:10.1111/j.1474-9728.2005.00148.x
Victoria B, Dhahbi JM, Nunez Lopez YO, Spinel L, Atamna H, Spindler SR, Masternak MM (2015) Circulating microRNA signature of genotype-by-age interactions in the long-lived Ames dwarf mouse. Aging Cell 14:1055–1066. doi:10.1111/acel.12373
Vitale G et al (2012) Low circulating IGF-I bioactivity is associated with human longevity: findings in centenarians’ offspring. Aging 4:580–589
Waki T, Tamura G, Sato M, Motoyama T (2003) Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene 22:4128–4133. doi:10.1038/sj.onc.1206651
Waly M et al (2004) Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry 9:358–370. doi:10.1038/sj.mp.4001476
Wang G, Reinke V (2008) A C. elegans Piwi, PRG-1, regulates 21U-RNAs during spermatogenesis. Curr Biol 18:861–867. doi:10.1016/j.cub.2008.05.009
Wang MC, Bohmann D, Jasper H (2005) JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121:115–125. doi:10.1016/j.cell.2005.02.030
Webb AE, Brunet A (2014) FOXO transcription factors: key regulators of cellular quality control. Trends Biochem Sci 39:159–169. doi:10.1016/j.tibs.2014.02.003
Weidner CI et al (2014) Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol 15:R24. doi:10.1186/gb-2014-15-2-r24
Weinkove D, Leevers SJ (2000) The genetic control of organ growth: insights from Drosophila. Curr Opin Genet Dev 10:75–80
Westbrook R, Bonkowski MS, Arum O, Strader AD, Bartke A (2014) Metabolic alterations due to caloric restriction and every other day feeding in normal and growth hormone receptor knockout mice. J Gerontol A Biol Sci Med Sci 69:25–33. doi:10.1093/gerona/glt080
Willcox BJ et al (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105:13987–13992. doi:10.1073/pnas.0801030105
Wolkow CA, Kimura KD, Lee MS, Ruvkun G (2000) Regulation of C. elegans life-span by insulin like signaling in the nervous system. Science 290:147–150
Wolkow CA, Munoz MJ, Riddle DL, 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. doi:10.1074/jbc.M207866200
Xiao C et al (2010) SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J Biol Chem 285:36776–36784. doi:10.1074/jbc.M110.168039
Yang Q, Sun M, Ramchandran R, Raj JU (2015) IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: role of epigenetic regulation. Vasc Pharmacol 73:20–31. doi:10.1016/j.vph.2015.04.005
Yu XY, Geng YJ, Liang JL, Lin QX, Lin SG, Zhang S, Li Y (2010) High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor. Exp Cell Res 316:2903–2909. doi:10.1016/j.yexcr.2010.07.004
Zeng Y et al (2015) Interaction between FOXO1A-209 genotype and tea drinking is significantly associated with reduced mortality at advanced ages. Rejuvenation Res. doi:10.1089/rej.2015.1737
Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813:1978–1986. doi:10.1016/j.bbamcr.2011.03.010
Zhao T, Li J, Chen AF (2010) MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab 299:E110–E116. doi:10.1152/ajpendo.00192.2010
Zhao G, Guo S, Somel M, Khaitovich P (2014) Evolution of human longevity uncoupled from caloric restriction mechanisms. PLoS ONE 9:e84117. doi:10.1371/journal.pone.0084117
Zhong L et al (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140:280–293. doi:10.1016/j.cell.2009.12.041
Zhou B et al (2012) Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 55:2032–2043. doi:10.1007/s00125-012-2539-8
Authors’ contribution
RM contributed the initial write up and drawing of the figures. UB and MPB finalized the write up, corrected and provided the concept of the review.
Acknowledgements
The work was supported by the CSIR network project of India to UB (B.S.C 0121) and DBT Drosophila project to M.P.B (GAP 0632). We thank members of our lab for critical review of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Mathew, R., Pal Bhadra, M. & Bhadra, U. Insulin/insulin-like growth factor-1 signalling (IIS) based regulation of lifespan across species. Biogerontology 18, 35–53 (2017). https://doi.org/10.1007/s10522-016-9670-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-016-9670-8