Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes


Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes

Goldberg, Alexander A. and Richard, Vincent R. and Kyryakov, Pavlo and Bourque, Simon D. and Beach, Adam and Burstein, Michelle T. and Glebov, Anastasia and Koupaki, Olivia and Boukh-Viner, Tatiana and Gregg, Christopher and Juneau, Mylène and English, Ann M. and Thomas, David Y. and Titorenko, Vladimir I. (2010) Chemical genetic screen identifies lithocholic acid as an anti-aging compound that extends yeast chronological life span in a TOR-independent manner, by modulating housekeeping longevity assurance processes. Aging, 2 (7). 393-414 . ISSN 1945-4589

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In chronologically aging yeast, longevity can be extended by administering a caloric restriction (CR) diet or some small molecules. These life-extending interventions target the adaptable target of rapamycin (TOR) and cAMP/protein kinase A (cAMP/PKA) signaling pathways that are under the stringent control of calorie availability. We designed a chemical genetic screen for small molecules that increase the chronological life span of yeast under CR by targeting lipid metabolism and modulating housekeeping longevity pathways that regulate longevity irrespective of the number of available calories. Our screen identifies lithocholic acid (LCA) as one of such molecules. We reveal two mechanisms underlying the life-extending effect of LCA in chronologically aging yeast. One mechanism operates in a calorie availability-independent fashion and involves the LCA-governed modulation of housekeeping longevity assurance pathways that do not overlap with the adaptable TOR and cAMP/PKA pathways. The other mechanism extends yeast longevity under non-CR conditions and consists in LCA-driven unmasking of the previously unknown anti-aging potential of PKA. We provide evidence that LCA modulates housekeeping longevity assurance pathways by suppressing lipid-induced necrosis, attenuating mitochondrial fragmentation, altering oxidation-reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria-controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Article
Authors:Goldberg, Alexander A. and Richard, Vincent R. and Kyryakov, Pavlo and Bourque, Simon D. and Beach, Adam and Burstein, Michelle T. and Glebov, Anastasia and Koupaki, Olivia and Boukh-Viner, Tatiana and Gregg, Christopher and Juneau, Mylène and English, Ann M. and Thomas, David Y. and Titorenko, Vladimir I.
Journal or Publication:Aging
Date:July 2010
Keywords:Cellular aging, longevity, yeast, caloric restriction, chemical biology, anti-aging compounds
ID Code:6993
Deposited On:20 Dec 2010 10:49
Last Modified:20 Dec 2010 10:49
1.Guarente LP, Partridge L and Wallace DC. Molecular Biology of Aging. 2008; Cold Spring Harbor: Cold Spring Harbor Laboratory Press.

2.Greer EL, Brunet A. Signaling networks in aging. J Cell Sci. 2008; 121: 407-412.

3.Narasimhan SD, Yen K, Tissenbaum HA. Converging pathways in lifespan regulation. Curr Biol. 2009; 19: R657-R666.

4.Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol. 2009; 196: 65-80.

5.Fontana L, Partridge L, Longo VD. Extending healthy life span - from yeast to humans. Science 2010; 328: 321-326.

6.Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, Longo VD. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008; 4: e13.

7.Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci. 2009; 122: 3589-3594.

8.Finley LW, Haigis MC. The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Ageing Res Rev. 2009; 8: 173-188.

9.Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 2009; 23: 496-511.

10.Giorgio M, Trinei M, Migliaccio E, Pelicci PG. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol. 2007; 8: 722-728.

11.Lapointe J, Hekimi S. When a theory of aging ages badly. Cell Mol Life Sci. 2010; 67: 1-8.

12.Mair W, Dillin A. Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem. 2008; 77: 727-754.

13.Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325: 201-204.

14.Masoro EJ. Caloric Restriction: A Key to Understanding and Modulating Aging. 2002; Amsterdam: Elsevier.

15.>Min KJ, Flatt T, Kulaots I, Tatar M. Counting calories in Drosophila diet restriction. Exp Gerontol. 2007; 42: 247-251.

16.Weindruch R and Walford RL. The Retardation of Aging and Disease by Dietary Restriction. 1998; Springfield: Thomas.

17.Zimmerman JA, Malloy V, Krajcik R, Orentreich N. Nutritional control of aging. Exp Gerontol. 2003; 38: 47-52.

18.Piper MD, Mair W, Partridge L. Counting the calories: the role of specific nutrients in extension of life span by food restriction. J Gerontol A Biol Sci Med Sci. 2005; 60: 549-555.

19.Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 2006; 5: 2087-2102.

20.Blagosklonny MV. Aging: ROS or TOR. Cell Cycle 2008; 7: 3344-3354.

21.Blagosklonny MV. TOR-driven aging: speeding car without brakes. Cell Cycle 2009; 8: 4055-4059.

22.Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005; 310: 1193-1196.

23.Meissner B, Boll M, Daniel H, Baumeister R. Deletion of the intestinal peptide transporter affects insulin and TOR signaling in Caenorhabditis elegans. J Biol Chem. 2004; 279: 36739-36745.

24.Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 2007; 6: 95-110.

25.Chen D, Guarente L. SIR2: a potential target for calorie restriction mimetics. Trends Mol Med. 2007; 13: 64-71.

26.Kaeberlein M, Powers RW 3rd. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res Rev. 2007; 6: 128-140.

27.Medvedik O, Lamming DW, Kim KD, Sinclair DA. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol. 2007; 5: e261.

28.Greer EL, Brunet A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 2009; 8: 113-127.

29.Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R. Calorie restriction mimetics: an emerging research field. Aging Cell 2006; 5: 97-108.

30.Lane MA, Roth GS, Ingram DK. Caloric restriction mimetics: a novel approach for biogerontology. Methods Mol Biol. 2007; 371: 143-149.

31.Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425: 191-196.

32.Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430: 686-689.

33.Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337-342.

34.Petrascheck M, Ye X, Buck LB. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature 2007; 450: 553-556.

35.Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS ONE 2010; 5: e8758.

36.McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem. 2008; 283: 350-357.

37.Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010; 11: 35-46.

38.Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature 2004; 429: 771-776.

39.Goldberg AA, Bourque SD, Kyryakov P, Gregg C, Boukh-Viner T, Beach A, Burstein MT, Machkalyan G, Richard V, Rampersad S, Cyr D, Milijevic S, Titorenko VI. Effect of calorie restriction on the metabolic history of chronologically aging yeast. Exp Gerontol. 2009; 44: 555-571.

40.Goldberg AA, Bourque SD, Kyryakov P, Boukh-Viner T, Gregg C, Beach A, Burstein MT, Machkalyan G, Richard V, Rampersad S, Titorenko VI. A novel function of lipid droplets in regulating longevity. Biochem Soc Trans. 2009; 37: 1050-1055.

41.Russell SJ, Kahn CR. Endocrine regulation of ageing. Nat Rev Mol Cell Biol. 2007; 8: 681-691.

42.Wang MC, O'Rourke EJ, Ruvkun G. Fat metabolism links germline stem cells and longevity in C. elegans. Science 2008; 322: 957-960.

43.Narbonne P, Roy R. Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 2009; 457: 210-214.

44.Grönke S, Mildner A, Fellert S, Tennagels N, Petry S, Müller G, Jäckle H, Kühnlein RP. Brummer lipase is an evolutionary conserved fat storage regulator in Drosophila. Cell Metab. 2005; 1: 323-330.

45.Blüher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003; 299: 572-574.

46.Chiu CH, Lin WD, Huang SY, Lee YH. Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. Genes Dev. 2004; 18: 1970-1975.

47.Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, Heldmaier G, Maier R, Theussl C, Eder S, Kratky D, Wagner EF, Klingenspor M et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006; 312: 734-737.

48.Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1α. EMBO J. 2007; 26: 1913-1923.

49.Léon S, Goodman JM, Subramani S. Uniqueness of the mechanism of protein import into the peroxisome matrix: transport of folded, co-factor-bound and oligomeric proteins by shuttling receptors. Biochim Biophys Acta 2006; 1763: 1552-1264.

50.Low CP, Liew LP, Pervaiz S, Yang H. Apoptosis and lipoapoptosis in the fission yeast Schizosaccharomyces pombe. FEMS Yeast Res. 2005; 5: 1199-1206.

51.Dirkx R, Vanhorebeek I, Martens K, Schad A, Grabenbauer M, Fahimi D, Declercq P, Van Veldhoven PP, Baes M. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities. Hepatology 2005; 41: 868-878.

52.D'Autréaux B, Toledano MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007; 8: 813-824.

53.Eisenberg T, Büttner S, Kroemer G, Madeo F. The mitochondrial pathway in yeast apoptosis. Apoptosis 2007; 12: 1011-1023.

54.Pereira C, Silva RD, Saraiva L, Johansson B, Sousa MJ, Côrte-Real M. Mitochondria-dependent apoptosis in yeast. Biochim Biophys Acta 2008; 1783: 1286-1302.

55.Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev. 2005; 126: 987-1002.

56.Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 2006; 20: 174-184.

57.Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008; 7: 678-693.

58.Wanke V, Cameroni E, Uotila A, Piccolis M, Urban J, Loewith R, De Virgilio C. Caffeine extends yeast lifespan by targeting TORC1. Mol Microbiol. 2008; 69: 277-285.

59.Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, Ring J, Schroeder S, Magnes C, Antonacci L, Fussi H, Deszcz L, Hartl R et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009; 11: 1305-1314.

60.Huber A, Bodenmiller B, Uotila A, Stahl M, Wanka S, Gerrits B, Aebersold R, Loewith R. Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis. Genes Dev. 2009; 23: 1929-1943.

61.Pan Y, Shadel GS. Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging 2009; 1: 131-145.

62.Smets B, Ghillebert R, De Snijder P, Binda M, Swinnen E, De Virgilio C, Winderickx J. Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae. Curr Genet. 2010; 56: 1-32.

63.Stephan JS, Yeh YY, Ramachandran V, Deminoff SJ, Herman PK. The Tor and PKA signaling pathways independently target the Atg1/Atg13 protein kinase complex to control autophagy. Proc Natl Acad Sci USA 2009; 106: 17049-17054.

64.Kamada Y, Yoshino K, Kondo C, Kawamata T, Oshiro N, Yonezawa K, Ohsumi Y. Tor directly controls the Atg1 kinase complex to regulate autophagy. Mol Cell Biol. 2010; 30: 1049-1058.

65.Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN et al. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 2007; 26: 663-674.

66.Yorimitsu T, Zaman S, Broach JR, Klionsky DJ. Protein kinase A and Sch9 cooperatively regulate induction of autophagy in Saccharomyces cerevisiae. Mol Biol Cell 2007; 18: 4180-4189.

67.Lee P, Cho BR, Joo HS, Hahn JS. Yeast Yak1 kinase, a bridge between PKA and stress-responsive transcription factors, Hsf1 and Msn2/Msn4. Mol Microbiol. 2008; 70: 882-895.

68.Ptacek J, Devgan G, Michaud G, Zhu H, Zhu X, Fasolo J, Guo H, Jona G, Breitkreutz A, Sopko R, McCartney RR, Schmidt MC, Rachidi N et al. Global analysis of protein phosphorylation in yeast. Nature 2005; 438: 679-684.

69.Fabrizio P, Longo VD. Chronological aging-induced apoptosis in yeast. Biochim Biophys Acta 2008; 1783: 1280-1285.

70.Hamann A, Brust D, Osiewacz HD. Apoptosis pathways in fungal growth, development and ageing. Trends Microbiol. 2008; 16: 276-283.

71.Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR et al. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta 2009; 1787: 437-461.

72.Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 2007; 6: 280-293.

73.Gems D, Partridge L. Stress-response hormesis and aging: "that which does not kill us makes us stronger". Cell Metab. 2008; 7: 200-203.

74.Pang CY, Ma YS, Wei YU. MtDNA mutations, functional decline and turnover of mitochondria in aging. Front Biosci. 2008; 13: 3661-3675.

75.Sinclair DA, Oberdoerffer P. The ageing epigenome: damaged beyond repair? Ageing Res Rev. 2009; 8: 189-198.

76.Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev. 2009; 89: 147-191.

77.Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res. 2009; 50: 1509-1520.

78.Vallim TQ, Edwards PA. Bile acids have the gall to function as hormones. Cell Metab. 2009; 10: 162-164.

79.Ramalho RM, Viana RJ, Low WC, Steer CJ, Rodrigues CM. Bile acids and apoptosis modulation: an emerging role in experimental Alzheimer's disease. Trends Mol. Med. 2008; 14: 54-62.

80.Amaral JD, Viana RJ, Ramalho RM, Steer CJ, Rodrigues CM. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J Lipid Res. 2009; 50: 1721-1734.

81.Amador-Noguez D, Yagi K, Venable S, Darlington G. Gene expression profile of long-lived Ames dwarf mice and Little mice. Aging Cell 2004; 3: 423-441.

82.Amador-Noguez D, Dean A, Huang W, Setchell K, Moore D, Darlington G. Alterations in xenobiotic metabolism in the long-lived Little mice. Aging Cell 2007; 6: 453-470.

83.Gems D. Long-lived dwarf mice: are bile acids a longevity signal? Aging Cell 2007; 6: 421-423.

84.Guo T, Gregg C, Boukh-Viner T, Kyryakov P, Goldberg A, Bourque S, Banu F, Haile S, Milijevic S, San KH, Solomon J, Wong V, Titorenko VI. A signal from inside the peroxisome initiates its division by promoting the remodeling of the peroxisomal membrane. J Cell Biol. 2007; 177: 289-303.

85.Bourque SD, Titorenko VI. A quantitative assessment of the yeast lipidome using electrospray ionization mass spectrometry. J Vis Exp. 2009; 30: doi: 10.3791/1513.
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