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Lifespan extension in Caenorhabditis elegans insulin/IGF-1 signalling mutants is supported by non-vertebrate physiological traits

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The insulin/IGF-1 signalling (IIS) pathway connects nutrient levels to metabolism, growth and lifespan in eukaryotes ranging from yeasts to humans, including nematodes such as the genetic model organism Caenorhabditis elegans. The link between ageing and the IIS pathway has been thoroughly studied in C. elegans; upon reduced IIS signalling, a genetic survival program is activated resulting in a drastic lifespan extension. One of the components of this program is the upregulation of antioxidant activity but experiments failed to show a clear causal relation to longevity. However, oxidative damage, such as protein carbonyls, accumulates at a slower pace in long-lived C. elegans mutants with reduced IIS. This is probably not achieved by increased macroautophagy, a process that sequesters cellular components to be eliminated as protein turnover rates are slowed down in IIS mutants. The IIS mutant daf-2, bearing a mutation in the insulin/IGF-1 receptor, recapitulates the dauer survival program, including accumulation of fat and glycogen. Fat can be converted into glucose and glycogen via the glyoxylate shunt, a pathway absent in vertebrates. These carbohydrates can be used as substrates for trehalose synthesis, also absent in mammals. Trehalose, a non-reducing homodimer of glucose, stabilises intracellular components and is responsible for almost half of the lifespan extension in IIS mutants. Hence, the molecular mechanisms by which lifespan is extended under reduced IIS may differ substantially between phyla that have an active glyoxylate cycle and trehalose synthesis, such as ecdysozoans and fungi, and vertebrate species such as mammals.

Affiliations: 1: Biology Department, Ghent University, Proeftuinstraat 86 N1, Ghent, Belgium

*Corresponding author, e-mail:

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1. Alpert P. (2006). "Constraints of tolerance: why are desiccation-tolerant organisms so small or rare?" Journal of Experimental Biology Vol 209, 1575-1584. DOI: [Crossref]
2. Brys K., Vanfleteren J.R., Braeckman B.P. (2007). "Testing the rate-of-living/oxidative damage theory of aging in the nematode model Caenorhabditis elegans". Experimental Gerontology Vol 42, 845-851. DOI: [Crossref]
3. Chakrabortee S., Boschetti C., Walton L.J., Sarkar S., Rubinsztein D.C., Tunnacliffe A. (2007). "Hydrophilic protein associated with desiccation tolerance exhibits broad protein stabilization function". Proceedings of the National Academy of Sciences of the United States of America Vol 104, 18073-18078. DOI: [Crossref]
4. Chen A.T., Guo C., Itani O.A., Budaitis B.G., Williams T.W., Hopkins C.E., Mceachin R.C., Pande M., Grant A.R., Yoshina S. , et al (2015). "Longevity genes revealed by integrative analysis of isoform-specific daf-16/FoxO mutants of Caenorhabditis elegans". Genetics Vol 201, 613-629. DOI: [Crossref]
5. Clayton P.E., Banerjee I., Murray P.G., Renehan A.G. (2011). "Growth hormone, the insulin-like growth factor axis, insulin and cancer risk". Nature Reviews Endocrinology Vol 7, 11-24. DOI: [Crossref]
6. Cornils A., Gloeck M., Chen Z., Zhang Y., Alcedo J. (2011). "Specific insulin-like peptides encode sensory information to regulate distinct developmental processes". Development Vol 138, 1183-1193. DOI: [Crossref]
7. Depuydt G., Xie F., Petyuk V.A., Shanmugam N., Smolders A., Dhondt I., Brewer H.M., Camp D.G. 2nd, Smith R.D., Braeckman B.P. (2013). "Reduced insulin/insulin-like growth factor-1 signaling and dietary restriction inhibit translation but preserve muscle mass in Caenorhabditis elegans". Molecular and Cellular Proteomics Vol 12, 3624-3639. DOI: [Crossref]
8. Depuydt G., Xie F., Petyuk V.A., Smolders A., Brewer H.M., Camp D.G. 2nd, Smith R.D., Braeckman B.P. (2014). "LC-MS proteomics analysis of the insulin/IGF-1-deficient Caenorhabditis elegans daf-2(e1370) mutant reveals extensive restructuring of intermediary metabolism". Journal of Proteome Research Vol 13, 1938-1956. DOI: [Crossref]
9. Depuydt G., Shanmugam N., Rasulova M., Dhondt I., Braeckman B.P. (2016). "Increased protein stability and decreased protein turnover in the Caenorhabditis elegans Ins/IGF-1 daf-2 mutant". Journals of Gerontology. A: Biological Sciences and Medical Sciences Vol 71, 1553-1559. DOI: [Crossref]
10. Dhondt I., Petyuk V.A., Cai H., Vandemeulebroucke L., Vierstraete A., Smith R.D., Depuydt G., Braeckman B.P. (2016). "FOXO/DAF-16 activation slows down turnover of the majority of proteins in C. elegans". Cell Reports Vol 16, 3028-3040. DOI: [Crossref]
11. Dong M.Q., Venable J.D., Au N., Xu T., Park S.K., Cociorva D., Johnson J.R., Dillin A., Yates J.R. III (2007). "Quantitative mass spectrometry identifies insulin signaling targets in C. elegans". Science Vol 317, 660-663. DOI: [Crossref]
12. Doonan R., McElwee J.J., Matthijssens F., Walker G.A., Houthoofd K., Back P., Matscheski A., Vanfleteren J.R., Gems D. (2008). "Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans". Genes and Development Vol 22, 3236-3241. DOI: [Crossref]
13. Elbein A.D., Pan Y.T., Pastuszak I., Carroll D. (2003). "New insights on trehalose: a multifunctional molecule". Glycobiology Vol 13, 17R-27R. DOI: [Crossref]
14. Erkut C., Penkov S., Khesbak H., Vorkel D., Verbavatz J.M., Fahmy K., Kurzchalia T.V. (2011). "Trehalose renders the dauer larva of Caenorhabditis elegans resistant to extreme desiccation". Current Biology Vol 21, 1331-1336. DOI: [Crossref]
15. Erkut C., Gade V.R., Laxman S., Kurzchalia T.V. (2016). "The glyoxylate shunt is essential for desiccation tolerance in C. elegans and budding yeast". eLife Vol 5. DOI: [Crossref]
16. Erlanger M., Gershon D. (1970). "Studies on aging in nematodes. II. Studies of the activities of several enzymes as a function of age". Experimental Gerontology Vol 5, 13-19. DOI: [Crossref]
17. Frazier H.N. 3rd, Roth M.B. (2009). "Adaptive sugar provisioning controls survival of C. elegans embryos in adverse environments". Current Biology Vol 19, 859-863. DOI: [Crossref]
18. Friedman D.B., Johnson T.E. (1988). "A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility". Genetics Vol 118, 75-86.
19. Fuchs S., Bundy J.G., Davies S.K., Viney J.M., Swire J.S., Leroi A.M. (2010). "A metabolic signature of long life in Caenorhabditis elegans". BMC Biology Vol 8, 14. DOI: [Crossref]
20. Gafni A. (1990). "Altered protein metabolism in aging". Annual Reviews in Gerontology and Geriatrics Vol 10, 117-131. [Crossref]
21. Gershon D. (1970). "Studies on aging in nematodes. I. The nematode as a model organism for aging research". Experimental Gerontology Vol 5, 7-12. DOI: [Crossref]
22. Gershon H., Gershon D. (1970). "Detection of inactive enzyme molecules in ageing organisms". Nature Vol 227, 1214-1217. DOI: [Crossref]
23. Gladyshev V.N. (2014). "The free radical theory of aging is dead. Long live the damage theory!" Antioxidants and Redox Signaling Vol 20, 727-731. DOI: [Crossref]
24. Halaschek-Wiener J., Khattra J.S., McKay S., Pouzyrev A., Stott J.M., Yang G.S., Holt R.A., Jones S.J., Marra M.A., Brooks-Wilson A.R. , et al (2005). "Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression". Genome Research Vol 15, 603-615. DOI: [Crossref]
25. Harman D. (1956). "Aging: a theory based on free radical and radiation chemistry". Journal of Gerontology Vol 11, 298-300. [Crossref]
26. Harman D. (1972). "The biologic clock: the mitochondria?" Journal of the American Geriatric Society Vol 20, 145-147. [Crossref]
27. Hashimoto Y., Ookuma S., Nishida E. (2009). "Lifespan extension by suppression of autophagy genes in Caenorhabditis elegans". Genes to Cells Vol 14, 717-726. DOI: [Crossref]
28. Hertweck M., Gobel C., Baumeister R. (2004). "C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span". Developmental Cell Vol 6, 577-588. DOI: [Crossref]
29. Holt S.J., Riddle D.L. (2003). "SAGE surveys C. elegans carbohydrate metabolism: evidence for an anaerobic shift in the long-lived dauer larva". Mechanisms of Ageing and Development Vol 124, 779-800. DOI: [Crossref]
30. Honda Y., Tanaka M., Honda S. (2010). "Trehalose extends longevity in the nematode Caenorhabditis elegans". Aging Cell Vol 9, 558-569. DOI: [Crossref]
31. Houthoofd K., Braeckman B.P., Johnson T.E., Vanfleteren J.R. (2003). "Life extension via dietary restriction is independent of the Ins/IGF-1 signalling pathway in Caenorhabditis elegans". Experimental Gerontology Vol 38, 947-954. DOI: [Crossref]
32. Houthoofd K., Fidalgo M.A., Hoogewijs D., Braeckman B.P., Lenaerts I., Brys K., Matthijssens F., De Vreese A., Van Eygen S., Munoz M.J. , et al (2005). "Metabolism, physiology and stress defense in three aging Ins/IGF-1 mutants of the nematode Caenorhabditis elegans". Aging Cell Vol 4, 87-95. DOI: [Crossref]
33. Ishii N., Goto S., Hartman P.S. (2002). "Protein oxidation during aging of the nematode Caenorhabditis elegans". Free Radicals in Biology and Medicine Vol 33, 1021-1025. DOI: [Crossref]
34. Johnson T.E., Wood W.B. (1982). "Genetic analysis of life-span in Caenorhabditis elegans". Proceedings of the National Academy of Sciences of the United States of America Vol 79, 6603-6607. DOI: [Crossref]
35. Jones L.M., Staffa K., Perally S., Lacourse E.J., Brophy P.M., Hamilton J.V. (2010). "Proteomic analyses of Caenorhabditis elegans dauer larvae and long-lived daf-2 mutants implicates a shared detoxification system in longevity assurance". Journal of Proteome Research Vol 9, 2871-2881. DOI: [Crossref]
36. Kenyon C. (2011). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philosophical Transactions of the Royal Society of London, B: Biological Sciences Vol 366, 9-16. DOI: [Crossref]
37. Kenyon C., Chang J., Gensch E., Rudner A., Tabtiang R. (1993). "A C. elegans mutant that lives twice as long as wild type". Nature Vol 366, 461-464. DOI: [Crossref]
38. Kenyon C.J. (2010). "The genetics of ageing". Nature Vol 464, 504-512. DOI: [Crossref]
39. Kimura K.D., Tissenbaum H.A., Liu Y., Ruvkun G. (1997). "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans". Science Vol 277, 942-946. DOI: [Crossref]
40. Klass M., Hirsh D. (1976). "Non-ageing developmental variant of Caenorhabditis elegans". Nature Vol 260, 523-525. DOI: [Crossref]
41. Klass M.R. (1977). "Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span". Mechanisms of Ageing and Development Vol 6, 413-429. DOI: [Crossref]
42. Klass M.R. (1983). "A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results". Mechanisms of Ageing and Development Vol 22, 279-286. DOI: [Crossref]
43. Knoefler D., Thamsen M., Koniczek M., Niemuth N.J., Diederich A.K., Jakob U. (2012). "Quantitative in vivo redox sensors uncover oxidative stress as an early event in life". Molecular Cell Vol 47, 767-776. DOI: [Crossref]
44. Kwon E.S., Narasimhan S.D., Yen K., Tissenbaum H.A. (2010). "A new DAF-16 isoform regulates longevity". Nature Vol 466, 498-502. DOI: [Crossref]
45. Lamacchia J.C., Frazier H.N. 3rd, Roth M.B. (2015). "Glycogen fuels survival during hyposmotic-anoxic stress in Caenorhabditis elegans". Genetics Vol 201, 65-74. DOI: [Crossref]
46. Lapierre L.R., De Magalhaes Filho C.D., Mcquary P.R., Chu C.C., Visvikis O., Chang J.T., Gelino S., Ong B., Davis A.E., Irazoqui J.E. , et al (2013). "The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans". Nature Communications Vol 4, 2267. DOI:
47. Larsen P.L. (1993). "Aging and resistance to oxidative damage in Caenorhabditis elegans". Proceedings of the National Academy of Sciences of the United States of America Vol 90, 8905-8909. DOI: [Crossref]
48. Lin K., Dorman J.B., Rodan A., Kenyon C. (1997). "daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans". Science Vol 278, 1319-1322. DOI: [Crossref]
49. Liu F., Thatcher J.D., Barral J.M., Epstein H.F. (1995). "Bifunctional glyoxylate cycle protein of Caenorhabditis elegans: a developmentally regulated protein of intestine and muscle". Developmental Biology Vol 169, 399-414. DOI: [Crossref]
50. Martins R., Lithgow G.J., Link W. (2016). "Long live FOXO: unraveling the role of FOXO proteins in aging and longevity". Aging Cell Vol 15, 196-207. DOI: [Crossref]
51. McElwee J., Bubb K., Thomas J.H. (2003). "Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16". Aging Cell Vol 2, 111-121. DOI: [Crossref]
52. McElwee J.J., Schuster E., Blanc E., Thomas J.H., Gems D. (2004). "Shared transcriptional signature in Caenorhabditis elegans Dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance". Journal of Biological Chemistry Vol 279, 44533-44543. DOI: [Crossref]
53. McElwee J.J., Schuster E., Blanc E., Thornton J., Gems D. (2006). "Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans". Mechanisms of Ageing and Development Vol 127, 458-472. DOI: [Crossref]
54. McGaugh S.E., Bronikowski A.M., Kuo C.H., Reding D.M., Addis E.A., Flagel L.E., Janzen F.J., Schwartz T.S. (2015). "Rapid molecular evolution across amniotes of the IIS/TOR network". Proceedings of the National Academy of Sciences of the United States of America Vol 112, 7055-7060. DOI: [Crossref]
55. Melendez A., Talloczy Z., Seaman M., Eskelinen E.L., Hall D.H., Levine B. (2003). "Autophagy genes are essential for dauer development and life-span extension in C. elegans". Science Vol 301, 1387-1391. DOI: [Crossref]
56. Morris J.Z., Tissenbaum H.A., Ruvkun G. (1996). "A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans". Nature Vol 382, 536-539. DOI: [Crossref]
57. Murphy C.T., McCarroll S.A., Bargmann C.I., Fraser A., Kamath R.S., Ahringer J., Li H., Kenyon C. (2003). "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans". Nature Vol 424, 277-283. DOI: [Crossref]
58. Narbonne P., Roy R. (2009). "Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival". Nature Vol 457, 210-214. DOI: [Crossref]
59. Ogg S., Ruvkun G. (1998). "The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway". Molecular Cell Vol 2, 887-893. DOI: [Crossref]
60. Ogg S., Paradis S., Gottlieb S., Patterson G.I., Lee L., Tissenbaum H.A., Ruvkun G. (1997). "The fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans". Nature Vol 389, 994-999. DOI: [Crossref]
61. Oh S.W., Mukhopadhyay A., Dixit B.L., Raha T., Green M.R., Tissenbaum H.A. (2006). "Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation". Nature Genetics Vol 38, 251-257. DOI: [Crossref]
62. Papatheodorou I., Petrovs R., Thornton J.M. (2014). "Comparison of the mammalian insulin signalling pathway to invertebrates in the context of FOXO-mediated ageing". Bioinformatics Vol 30, 2999-3003. DOI: [Crossref]
63. Paradis S., Ruvkun G. (1998). "Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor". Genes and Development Vol 12, 2488-2498. DOI: [Crossref]
64. Paradis S., Ailion M., Toker A., Thomas J.H., Ruvkun G. (1999). "A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans". Genes and Development Vol 13, 1438-1452. DOI: [Crossref]
65. Perry R.N., Wharton D.A. (Eds) (2011). Molecular and physiological basis of nematode survival. Wallingford, UK, CAB International. DOI:
66. Pierce S.B., Costa M., Wisotzkey R., Devadhar S., Homburger S.A., Buchman A.R., Ferguson K.C., Heller J., Platt D.M., Pasquinelli A.A. , 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 and Development Vol 15, 672-686. DOI: [Crossref]
67. Possik E., Ajisebutu A., Manteghi S., Gingras M.C., Vijayaraghavan T., Flamand M., Coull B., Schmeisser K., Duchaine T., Van Steensel M. , et al (2015). "FLCN and AMPK confer resistance to hyperosmotic stress via remodeling of glycogen stores". PLoS Genetics Vol 11, e1005520. DOI: [Crossref]
68. Ryazanov A.G., Nefsky B.S. (2002). "Protein turnover plays a key role in aging". Mechanisms of Ageing and Development Vol 123, 207-213. DOI: [Crossref]
69. Schuster E., McElwee J.J., Tullet J.M., Doonan R., Matthijssens F., Reece-Hoyes J.S., Hope I.A., Vanfleteren J.R., Thornton J.M., Gems D. (2010). "DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO". Molecular Systems Biology Vol 6, 399. DOI: [Crossref]
70. Shen E.Z., Song C.Q., Lin Y., Zhang W.H., Su P.F., Liu W.Y., Zhang P., Xu J., Lin N., Zhan C. , et al (2014). "Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans". Nature Vol 508, 128-132. DOI: [Crossref]
71. Stout G.J., Stigter E.C., Essers P.B., Mulder K.W., Kolkman A., Snijders D.S., Van Den Broek N.J., Betist M.C., Korswagen H.C., MacInnes A.W. , et al (2013). "Insulin/IGF-1-mediated longevity is marked by reduced protein metabolism". Molecular Systems Biology Vol 9, 679. DOI:
72. Tavernarakis N., Driscoll M. (2002). "Caloric restriction and lifespan: a role for protein turnover?" Mechanisms of Ageing and Development Vol 123, 215-229. DOI: [Crossref]
73. Van Raamsdonk J.M., Hekimi S. (2012). "Superoxide dismutase is dispensable for normal animal lifespan". Proceedings of the National Academy of Sciences of the United States of America Vol 109, 5785-5790. DOI: [Crossref]
74. Vanfleteren J.R. (1993). "Oxidative stress and ageing in Caenorhabditis elegans". Biochemical Journal Vol 292, 605-608. DOI: [Crossref]
75. Visscher M., De Henau S., Wildschut M.H., Van Es R.M., Dhondt I., Michels H., Kemmeren P., Nollen E.A., Braeckman B.P., Burgering B.M. , et al (2016). "Proteome-wide changes in protein turnover rates in C. elegans models of longevity and age-related disease". Cell Reports Vol 16, 3041-3051. DOI: [Crossref]
76. Walther D.M., Kasturi P., Zheng M., Pinkert S., Vecchi G., Ciryam P., Morimoto R.I., Dobson C.M., Vendruscolo M., Mann M. , et al (2015). "Widespread proteome remodeling and aggregation in aging C. elegans". Cell Vol 161, 919-932. DOI: [Crossref]
77. Wang J., Kim S.K. (2003). "Global analysis of dauer gene expression in Caenorhabditis elegans". Development Vol 130, 1621-1634. DOI: [Crossref]
78. Wolkow C.A., Muñoz M.J., Riddle D.L., Ruvkun G. (2002). "Insulin receptor substrate and p55 orthologous adaptor proteins function in the Caenorhabditis elegans daf-2/insulin-like signaling pathway". Journal of Biological Chemistry Vol 277, 49591-49597. DOI: [Crossref]
79. Yilmaz L.S., Walhout A.J. (2016). "A Caenorhabditis elegans genome-scale metabolic network model". Cell Systems Vol 2, 297-311. DOI: [Crossref]

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