#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

An Engineering Approach to Extending Lifespan in


We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add exogenous components. Here, we engineered longer lifespan by expressing genes from zebrafish encoding molecular functions not normally present in worms. Additionally, we extended lifespan by increasing the activity of four endogenous worm aging pathways. Next, we used a modular approach to extend lifespan by combining components. Finally, we used cell- and worm-based assays to analyze changes in cell physiology and as a rapid means to evaluate whether multi-component transgenic lines were likely to have extended longevity. Using engineering to add novel functions and to tune endogenous functions provides a new framework for lifespan extension that goes beyond the constraints of the worm genome.


Vyšlo v časopise: An Engineering Approach to Extending Lifespan in. PLoS Genet 8(6): e32767. doi:10.1371/journal.pgen.1002780
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002780

Souhrn

We have taken an engineering approach to extending the lifespan of Caenorhabditis elegans. Aging stands out as a complex trait, because events that occur in old animals are not under strong natural selection. As a result, lifespan can be lengthened rationally using bioengineering to modulate gene expression or to add exogenous components. Here, we engineered longer lifespan by expressing genes from zebrafish encoding molecular functions not normally present in worms. Additionally, we extended lifespan by increasing the activity of four endogenous worm aging pathways. Next, we used a modular approach to extend lifespan by combining components. Finally, we used cell- and worm-based assays to analyze changes in cell physiology and as a rapid means to evaluate whether multi-component transgenic lines were likely to have extended longevity. Using engineering to add novel functions and to tune endogenous functions provides a new framework for lifespan extension that goes beyond the constraints of the worm genome.


Zdroje

1. ElowitzMBLeiblerS 2000 A synthetic oscillatory network of transcriptional regulators. Nature 403 335 338

2. ChenMTWeissR 2005 Artificial cell-cell communication in yeast Saccharomyces cerevisiae using signaling elements from Arabidopsis thaliana. Nat Biotechnol 23 1551 1555

3. GibsonDGGlassJILartigueCNoskovVNChuangRY 2010 Creation of a bacterial cell controlled by a chemically synthesized genome. Science 329 52 56

4. KirkwoodTB 2005 Understanding the odd science of aging. Cell 120 437 447

5. BudovskayaYVWuKSouthworthLKJiangMTedescoP 2008 An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans. Cell 134 291 303

6. KenyonCJ 2010 The genetics of ageing. Nature 464 504 512

7. GeorgeJCBadaJZehJScottLBrownSE 1999 Age and growth estimates of bowhead whales (Balaena mysticetus) via aspartic acid racemization. Canadian Journal of Zoology 77 571 580

8. U.N. 2007 United Nations World Population Prospects: 2006 revision: United Nations, Department of Economic and Social Affairs, Population Division

9. RidgwayIDRichardsonCAAustadSN 2011 Maximum shell size, growth rate, and maturation age correlate with longevity in bivalve molluscs. J Gerontol A Biol Sci Med Sci 66 183 190

10. KirkwoodTBAustadSN 2000 Why do we age? Nature 408 233 238

11. Van VoorhiesWAFuchsJThomasS 2005 The longevity of Caenorhabditis elegans in soil. Biol Lett 1 247 249

12. HsuALMurphyCTKenyonC 2003 Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300 1142 1145

13. GreerELDowlatshahiDBankoMRVillenJHoangK 2007 An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17 1646 1656

14. DoonanRMcElweeJJMatthijssensFWalkerGAHouthoofdK 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 Dev 22 3236 3241

15. KwonESNarasimhanSDYenKTissenbaumHA 2010 A new DAF-16 isoform regulates longevity. Nature 466 498 502

16. PrahladVMorimotoRI 2009 Integrating the stress response: lessons for neurodegenerative diseases from C. elegans. Trends Cell Biol 19 52 61

17. KahnBBAlquierTCarlingDHardieDG 2005 AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1 15 25

18. PerryJJShinDSGetzoffEDTainerJA 2010 The structural biochemistry of the superoxide dismutases. Biochim Biophys Acta 1804 245 262

19. MorimotoRI 2008 Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22 1427 1438

20. RubinszteinDCMarinoGKroemerG 2011 Autophagy and aging. Cell 146 682 695

21. AlavezSVantipalliMCZuckerDJKlangIMLithgowGJ 2011 Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472 226 229

22. ZhangCCuervoAM 2008 Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat Med 14 959 965

23. CuervoAM 2004 Autophagy: many paths to the same end. Mol Cell Biochem 263 55 72

24. SpenceRGerlachGLawrenceCSmithC 2008 The behaviour and ecology of the zebrafish, Danio rerio. Biol Rev Camb Philos Soc 83 13 34

25. BrandMD 2000 Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp Gerontol 35 811 820

26. FridellYWSanchez-BlancoASilviaBAHelfandSL 2005 Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 1 145 152

27. IserWBKimDBachmanEWolkowC 2005 Examination of the requirement for ucp-4, a putative homolog of mammalian uncoupling proteins, for stress tolerance and longevity in C. elegans. Mech Ageing Dev 126 1090 1096

28. PfeifferMKayserEBYangXAbramsonEKenastonMA 2011 Caenorhabditis elegans UCP4 controls complex II-mediated oxidative phosphorylation through succinate transport. J Biol Chem

29. GarsinDAVillanuevaJMBegunJKimDHSifriCD 2003 Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300 1921

30. Sánchez-BlancoAKimSK 2011 Variable Pathogenicity Determines Individual Lifespan in Caenorhabditis elegans. PLoS Genet 7 e1002047 doi:10.1371/journal.pgen.1002047

31. CallewaertLMichielsCW 2010 Lysozymes in the animal kingdom. J Biosci 35 127 160

32. MalloGVKurzCLCouillaultCPujolNGranjeaudS 2002 Inducible antibacterial defense system in C. elegans. Curr Biol 12 1209 1214

33. HouthoofdKBraeckmanBPDe VreeseAVan EygenSLenaertsI 2004 Caloric restriction, Ins/IGF-1 signalling and longevity in the nematode Caenorhabditis elegans. Belg J Zool 134 79 84

34. FontanaLPartridgeLLongoVD 2010 Extending healthy life span–from yeast to humans. Science 328 321 326

35. KraussSZhangCYLowellBB 2005 The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6 248 261

36. ChenKSunGLvZWangCJiangX 2010 Molecular cloning of amphioxus uncoupling protein and assessment of its uncoupling activity using a yeast heterologous expression system. Biochem Biophys Res Commun 400 701 706

37. MurphyCTMcCarrollSABargmannCIFraserAKamathRS 2003 Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424 277 283

38. GreerELOskouiPRBankoMRManiarJMGygiMP 2007 The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282 30107 30119

39. Arantes-OliveiraNBermanJRKenyonC 2003 Healthy animals with extreme longevity. Science 302 611

40. CabreiroFAckermanDDoonanRAraizCBackP 2011 Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med 51 1575 1582

41. WiesnerJVilcinskasA 2010 Antimicrobial peptides: the ancient arm of the human immune system. Virulence 1 440 464

42. WadaSHamadaMSatohN 2006 A genomewide analysis of genes for the heat shock protein 70 chaperone system in the ascidian Ciona intestinalis. Cell Stress Chaperones 11 23 33

43. SeoSBayeLMSchulzNPBeckJSZhangQ 2010 BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proc Natl Acad Sci U S A 107 1488 1493

44. BrennerS 1974 The genetics of Caenorhabditis elegans. Genetics 77 71 94

45. DupuyDLiQRDeplanckeBBoxemMHaoT 2004 A first version of the Caenorhabditis elegans Promoterome. Genome Res 14 2169 2175

46. LiuXLongFPengHAerniSJJiangM 2009 Analysis of cell fate from single-cell gene expression profiles in C. elegans. Cell 139 623 633

47. ApfeldJKenyonC 1999 Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 402 804 809

48. FisherALLithgowGJ 2006 The nuclear hormone receptor DAF-12 has opposing effects on Caenorhabditis elegans lifespan and regulates genes repressed in multiple long-lived worms. Aging Cell 5 127 138

49. ChenDThomasELKapahiP 2009 HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet 5 e1000486 doi:10.1371/journal.pgen.1000486

50. YangWLiJHekimiS 2007 A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 177 2063 2074

51. MahoneyTRLuoSNonetML 2006 Analysis of synaptic transmission in Caenorhabditis elegans using an aldicarb-sensitivity assay. Nat Protoc 1 1772 1777

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2012 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#