#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import


Aging is the greatest risk factor for many diseases, which together account for the majority of global deaths and healthcare costs. Here we show that the common drug ibuprofen increases the lifespan of yeast, worms and flies, indicative of conserved longevity effects. In budding yeast, an excellent model of cellular longevity mechanisms, ibuprofen's pro-longevity action is independent of its known anti-inflammatory role. We show that the critical function of ibuprofen in longevity is to inhibit the uptake of aromatic amino acids, by destabilizing the high-affinity tryptophan permease. We further show that ibuprofen alters cell cycle progression. Mirroring the effects of ibuprofen, we found that most yeast long-lived mutants were also similarly affected in cell cycle progression. These findings identify a safe drug that extends the lifespan of divergent organisms and reveal fundamental cellular properties associated with longevity.


Vyšlo v časopise: Enhanced Longevity by Ibuprofen, Conserved in Multiple Species, Occurs in Yeast through Inhibition of Tryptophan Import. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004860
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004860

Souhrn

Aging is the greatest risk factor for many diseases, which together account for the majority of global deaths and healthcare costs. Here we show that the common drug ibuprofen increases the lifespan of yeast, worms and flies, indicative of conserved longevity effects. In budding yeast, an excellent model of cellular longevity mechanisms, ibuprofen's pro-longevity action is independent of its known anti-inflammatory role. We show that the critical function of ibuprofen in longevity is to inhibit the uptake of aromatic amino acids, by destabilizing the high-affinity tryptophan permease. We further show that ibuprofen alters cell cycle progression. Mirroring the effects of ibuprofen, we found that most yeast long-lived mutants were also similarly affected in cell cycle progression. These findings identify a safe drug that extends the lifespan of divergent organisms and reveal fundamental cellular properties associated with longevity.


Zdroje

1. NiccoliT, PartridgeL (2012) Ageing as a risk factor for disease. Curr Biol 22: R741–752.

2. KennedyBK, PennypackerJK (2014) Drugs that modulate aging: the promising yet difficult path ahead. Transl Res 163: 456–465.

3. LucanicM, LithgowGJ, AlavezS (2013) Pharmacological lifespan extension of invertebrates. Ageing Res Rev 12: 445–458.

4. McCormickMA, KennedyBK (2012) Genome-scale studies of aging: challenges and opportunities. Curr Genomics 13: 500–507.

5. JohnsonSC, RabinovitchPS, KaeberleinM (2013) mTOR is a key modulator of ageing and age-related disease. Nature 493: 338–345.

6. McCormickMA, TsaiSY, KennedyBK (2011) TOR and ageing: a complex pathway for a complex process. Philos Trans R Soc Lond B Biol Sci 366: 17–27.

7. Martin-MontalvoA, MerckenEM, MitchellSJ, PalaciosHH, MotePL, et al. (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4: 2192.

8. BaurJA, UngvariZ, MinorRK, Le CouteurDG, de CaboR (2012) Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 11: 443–461.

9. HubbardBP, SinclairDA (2014) Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 35: 146–154.

10. Lopez-OtinC, BlascoMA, PartridgeL, SerranoM, KroemerG (2013) The hallmarks of aging. Cell 153: 1194–1217.

11. WaskoBM, KaeberleinM (2014) Yeast replicative aging: a paradigm for defining conserved longevity interventions. FEMS Yeast Research 14: 148–159.

12. LongoVD, ShadelGS, KaeberleinM, KennedyB (2012) Replicative and Chronological Aging in Saccharomyces cerevisiae. Cell Metab 16: 18–31.

13. Steffen KK, Kennedy BK, Kaeberlein M (2009) Measuring Replicative Life Span in the Budding Yeast. J Vis Exp: e1209.

14. SteinkrausKA, KaeberleinM, KennedyBK (2008) Replicative aging in yeast: the means to the end. Annu Rev Cell Dev Biol 24: 29–54.

15. SmithED, TsuchiyaM, FoxLA, DangN, HuD, et al. (2008) Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res 18: 564–570.

16. FureySA, WaksmanJA, DashBH (1992) Nonprescription ibuprofen: side effect profile. Pharmacotherapy 12: 403–407.

17. KellsteinDE, WaksmanJA, FureySA, BinstokG, CooperSA (1999) The safety profile of nonprescription ibuprofen in multiple-dose use: a meta-analysis. J Clin Pharmacol 39: 520–532.

18. DeArmondB, FranciscoCA, LinJS, HuangFY, HalladayS, et al. (1995) Safety profile of over-the-counter naproxen sodium. Clin Ther 17: 587–601 discussion 586.

19. RainsfordKD, RobertsSC, BrownS (1997) Ibuprofen and paracetamol: relative safety in non-prescription dosages. J Pharm Pharmacol 49: 345–376.

20. RomeLH, LandsWE (1975) Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Natl Acad Sci U S A 72: 4863–4865.

21. VladSC, MillerDR, KowallNW, FelsonDT (2008) Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70: 1672–1677.

22. GaoX, ChenH, SchwarzschildMA, AscherioA (2011) Use of ibuprofen and risk of Parkinson disease. Neurology 76: 863–869.

23. McSharryC (2011) Parkinson disease: Could over-the-counter treatment protect against Parkinson disease? Nat Rev Neurol 7: 244.

24. Cavalier-SmithT (2010) Kingdoms Protozoa and Chromista and the eozoan root of the eukaryotic tree. Biol Lett 6: 342–345.

25. SimmonsDL, BottingRM, HlaT (2004) Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev 56: 387–437.

26. MoritaM, OsodaK, YamazakiM, ShiraiF, MatsuokaN, et al. (2009) Effects of non-steroidal anti-inflammatory drugs on Abeta deposition in Abeta(1-42) transgenic C. elegans. Brain Res 1295: 186–191.

27. TootleTL, SpradlingAC (2008) Drosophila Pxt: a cyclooxygenase-like facilitator of follicle maturation. Development 135: 839–847.

28. VarvasK, KurgR, HansenK, JarvingR, JarvingI, et al. (2009) Direct evidence of the cyclooxygenase pathway of prostaglandin synthesis in arthropods: genetic and biochemical characterization of two crustacean cyclooxygenases. Insect Biochem Mol Biol 39: 851–860.

29. PagesM, RoselloJ, CasasJ, GelpiE, GualdeN, et al. (1986) Cyclooxygenase and lipoxygenase-like activity in Drosophila melanogaster. Prostaglandins 32: 729–740.

30. TuckerCL, FieldsS (2004) Quantitative genome-wide analysis of yeast deletion strain sensitivities to oxidative and chemical stress. Comp Funct Genomics 5: 216–224.

31. SchmidtA, HallMN, KollerA (1994) Two FK506 resistance-conferring genes in Saccharomyces cerevisiae, TAT1 and TAT2, encode amino acid permeases mediating tyrosine and tryptophan uptake. Mol Cell Biol 14: 6597–6606.

32. LjungdahlPO, Daignan-FornierB (2012) Regulation of amino acid, nucleotide, and phosphate metabolism in Saccharomyces cerevisiae. Genetics 190: 885–929.

33. RegenbergB, During-OlsenL, Kielland-BrandtMC, HolmbergS (1999) Substrate specificity and gene expression of the amino-acid permeases in Saccharomyces cerevisiae. Curr Genet 36: 317–328.

34. HeitmanJ, KollerA, KunzJ, HenriquezR, SchmidtA, et al. (1993) The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae. Mol Cell Biol 13: 5010–5019.

35. LoewithR, HallMN (2011) Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189: 1177–1201.

36. BeckT, SchmidtA, HallMN (1999) Starvation induces vacuolar targeting and degradation of the tryptophan permease in yeast. J Cell Biol 146: 1227–1238.

37. SchmidtA, BeckT, KollerA, KunzJ, HallMN (1998) The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease. EMBO J 17: 6924–6931.

38. GhaemmaghamiS, HuhWK, BowerK, HowsonRW, BelleA, et al. (2003) Global analysis of protein expression in yeast. Nature 425: 737–741.

39. BelleA, TanayA, BitinckaL, ShamirR, O'SheaEK (2006) Quantification of protein half-lives in the budding yeast proteome. Proc Natl Acad Sci U S A 103: 13004–13009.

40. MousleyCJ, YuanP, GaurNA, TrettinKD, NileAH, et al. (2012) A sterol-binding protein integrates endosomal lipid metabolism with TOR signaling and nitrogen sensing. Cell 148: 702–715.

41. ValenzuelaL, ArandaC, GonzalezA (2001) TOR modulates GCN4-dependent expression of genes turned on by nitrogen limitation. J Bacteriol 183: 2331–2334.

42. CherkasovaVA, HinnebuschAG (2003) Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. Genes Dev 17: 859–872.

43. HinnebuschAG (1985) A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. Mol Cell Biol 5: 2349–2360.

44. CrespoJL, HelliwellSB, WiederkehrC, DemouginP, FowlerB, et al. (2004) NPR1 kinase and RSP5-BUL1/2 ubiquitin ligase control GLN3-dependent transcription in Saccharomyces cerevisiae. J Biol Chem 279: 37512–37517.

45. TateJJ, CooperTG (2013) Five conditions commonly used to down-regulate tor complex 1 generate different physiological situations exhibiting distinct requirements and outcomes. J Biol Chem 288: 27243–27262.

46. KaeberleinM, PowersRW3rd, SteffenKK, WestmanEA, HuD, et al. (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310: 1193–1196.

47. HowellAS, LewDJ (2012) Morphogenesis and the cell cycle. Genetics 190: 51–77.

48. HooseSA, RawlingsJA, KellyMM, LeitchMC, AbabnehQO, et al. (2012) A systematic analysis of cell cycle regulators in yeast reveals that most factors act independently of cell size to control initiation of division. PLoS Genet 8: e1002590.

49. TruongSK, McCormickRF, PolymenisM (2013) Genetic Determinants of Cell Size at Birth and Their Impact on Cell Cycle Progression in Saccharomyces cerevisiae. G3 (Bethesda) 3: 1525–1530.

50. GiaeverG, ChuAM, NiL, ConnellyC, RilesL, et al. (2002) Functional profiling of the Saccharomyces cerevisiae genome. Nature 418: 387–391.

51. JorgensenP, NishikawaJL, BreitkreutzBJ, TyersM (2002) Systematic identification of pathways that couple cell growth and division in yeast. Science 297: 395–400.

52. Di TaliaS, SkotheimJM, BeanJM, SiggiaED, CrossFR (2007) The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature 448: 947–951.

53. TurnerJJ, EwaldJC, SkotheimJM (2012) Cell size control in yeast. Curr Biol 22: R350–359.

54. StrongR, MillerRA, AstleCM, FloydRA, FlurkeyK, et al. (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7: 641–650.

55. ChingTT, ChiangWC, ChenCS, HsuAL (2011) Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity. Aging Cell 10: 506–519.

56. JanssenGM, VenemaJF (1985) Ibuprofen: plasma concentrations in man. J Int Med Res 13: 68–73.

57. Mehlisch DR, Sykes J (2013) Ibuprofen blood plasma levels and onset of analgesia. Int J Clin Pract Suppl: 3–8.

58. BrausGH (1991) Aromatic amino acid biosynthesis in the yeast Saccharomyces cerevisiae: a model system for the regulation of a eukaryotic biosynthetic pathway. Microbiol Rev 55: 349–370.

59. De MarteML, EnescoHE (1986) Influence of low tryptophan diet on survival and organ growth in mice. Mech Ageing Dev 36: 161–171.

60. OxenkrugGF, NavrotskayaV, VoroboyvaL, SummergradP (2011) Extension of life span of Drosophila melanogaster by the inhibitors of tryptophan-kynurenine metabolism. Fly (Austin) 5: 307–309.

61. van der GootAT, NollenEA (2013) Tryptophan metabolism: entering the field of aging and age-related pathologies. Trends Mol Med 19: 336–344.

62. StoneTW, StoyN, DarlingtonLG (2013) An expanding range of targets for kynurenine metabolites of tryptophan. Trends Pharmacol Sci 34: 136–143.

63. BraidyN, GuilleminGJ, GrantR (2011) Effects of Kynurenine Pathway Inhibition on NAD Metabolism and Cell Viability in Human Primary Astrocytes and Neurons. Int J Tryptophan Res 4: 29–37.

64. HeitmanJ, MovvaNR, HallMN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253: 905–909.

65. HartwellLH, UngerMW (1977) Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division. J Cell Biol 75: 422–435.

66. JohnstonGC, PringleJR, HartwellLH (1977) Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res 105: 79–98.

67. BilinskiT, Zadrag-TeczaR, BartoszG (2012) Hypertrophy hypothesis as an alternative explanation of the phenomenon of replicative aging of yeast. FEMS Yeast Res 12: 97–101.

68. ZadragR, Kwolek-MirekM, BartoszG, BilinskiT (2006) Relationship between the replicative age and cell volume in Saccharomyces cerevisiae. Acta Biochimica Polonica 53: 747–751.

69. YangJ, DungrawalaH, HuaH, ManukyanA, AbrahamL, et al. (2011) Cell size and growth rate are major determinants of replicative lifespan. Cell Cycle 10: 144–155.

70. KaeberleinM (2012) Hypertrophy and senescence factors in yeast aging. A reply to Bilinski et al. FEMS Yeast Res 12: 269–270.

71. GanleyAR, BreitenbachM, KennedyBK, KobayashiT (2012) Yeast hypertrophy: cause or consequence of aging? Reply to Bilinski et al. FEMS Yeast Res 12: 267–268.

72. DelaneyJR, SutphinGL, DulkenB, SimS, KimJR, et al. (2011) Sir2 deletion prevents lifespan extension in 32 long-lived mutants. Aging Cell 10: 1089–1091.

73. DelaneyJR, MurakamiCJ, OlsenB, KennedyBK, KaeberleinM (2011) Quantitative evidence for early life fitness defects from 32 longevity-associated alleles in yeast. Cell Cycle 10: 156–165.

74. GemsD, PartridgeL (2008) Stress-response hormesis and aging: "that which does not kill us makes us stronger". Cell Metab 7: 200–203.

75. Kaiser C, Michaelis S, Mitchell A, Cold Spring Harbor Laboratory. (1994) Methods in yeast genetics: a Cold Spring Harbor Laboratory course manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press. vii, 234 p. p.

76. HeinriksonRL, MeredithSC (1984) Amino acid analysis by reverse-phase high-performance liquid chromatography: precolumn derivatization with phenylisothiocyanate. Anal Biochem 136: 65–74.

77. KushnirovVV (2000) Rapid and reliable protein extraction from yeast. Yeast 16: 857–860.

78. Sutphin GL, Kaeberlein M (2009) Measuring Caenorhabditis elegans Life Span on Solid Media. J Vis Exp: e1152.

79. BrejningJ, NorgaardS, ScholerL, MorthorstTH, JakobsenH, et al. (2014) Loss of NDG-4 extends lifespan and stress resistance in Caenorhabditis elegans. Aging Cell 13: 156–164.

80. Ashburner M (1989) Drosophila. A laboratory handbook.: Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1989. 1331 p.

81. WangC, LiQ, ReddenD, WeindruchR, AllisonD (2004) Statistical methods for testing effects on "maximum lifespan". Mech Ageing Dev 125: 629–632.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 12
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#