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The effect of dichloroacetate on health- and lifespan in C. elegans

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Abstract

Aging is associated with increased vulnerability to chronic, degenerative diseases and death. Strategies for promoting healthspan without necessarily affecting lifespan or aging rate have gained much interest. The mitochondrial free radical theory of aging suggests that mitochondria and, in particular, age-dependent mitochondrial decline play a central role in aging, making compounds that affect mitochondrial function a possible strategy for the modulation of healthspan and possibly the aging rate. Here we tested such a “metabolic tuning” approach in nematodes using the mitochondrial modulator dichloroacetate (DCA). We explored DCA as a proof-of-principle compound to alter mitochondrial parameters in wild-type animals and tested whether this approach is suitable for reducing reactive oxygen species (ROS) production and for improving organismal health- and lifespan. In parallel, we addressed the potential problem of operator bias by running both unblinded and blinded lifespan studies. We found that DCA treatment (1) increased ATP levels without elevating oxidative protein damage and (2) reduced ROS production in adult C. elegans. DCA treatment also significantly prolonged nematode health- and lifespan, but did not strongly impact mortality doubling time. Operator blinding resulted in considerably smaller lifespan-extending effects of DCA. Our data illustrate the promise of a “metabolic tuning” intervention strategy, emphasize the importance of mitochondria in nematode aging and highlight operator bias as a potential confounder in lifespan studies.

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References

  • Artal-Sanz M, Tavernarakis N (2009) Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans. Nature 461:793–797

    Article  PubMed  CAS  Google Scholar 

  • Barja G, Herrero A (2000) Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. FASEB J 14:312–318

    PubMed  CAS  Google Scholar 

  • Barrientos A, Casademont J, Cardellach F et al (1997) Reduced steady-state levels of mitochondrial RNA and increased mitochondrial DNA amount in human brain with aging. Brain Res Mol Brain Res 52:284–289

    Article  PubMed  CAS  Google Scholar 

  • Beckman KB, Ames BN (1998) The free radical theory of aging matures. Physiol Rev 78:547–581

    PubMed  CAS  Google Scholar 

  • Bonnet S, Archer SL, Allalunis-Turner J et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51

    Article  PubMed  CAS  Google Scholar 

  • Burdon KL, Stokes JC, Kimbrough CE (1942) Studies of the common aerobic spore-forming bacilli: I. Staining for fat with Sudan black B-safranin. J Bacteriol 43:717–724

    PubMed  CAS  Google Scholar 

  • Clay Montier LL, Deng JJ, Bai Y (2009) Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genomics 36:125–131

    Article  PubMed  Google Scholar 

  • Cordaro L, Ison JR (1963) Psychology of the scientist: X. Observer bias in classical conditioning of the planaria. Psychol Rep 13:787–789

    Google Scholar 

  • Crabb DW, Yount EA, Harris RA (1981) The metabolic effects of dichloroacetate. Metabolism 30:1024–1039

    Article  PubMed  CAS  Google Scholar 

  • D’Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824

    Article  PubMed  Google Scholar 

  • de Craen AJ, Roos PJ, Leonard dV et al (1996) Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness. BMJ 313:1624–1626

    PubMed  Google Scholar 

  • de Magalhaes JP, Church GM (2006) Cells discover fire: employing reactive oxygen species in development and consequences for aging. Exp Gerontol 41:1–10

    Article  PubMed  Google Scholar 

  • de Magalhaes JP, Toussaint O (2002) The evolution of mammalian aging. Exp Gerontol 37:769–775

    Article  PubMed  Google Scholar 

  • de Magalhaes JP, Cabral JA, Magalhaes D (2005) The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging. Genetics 169:265–274

    Article  PubMed  Google Scholar 

  • Durkot MJ, De Garavilla L, Caretti D et al (1995) The effects of dichloroacetate on lactate accumulation and endurance in an exercising rat model. Int J Sports Med 16:167–171

    Article  PubMed  CAS  Google Scholar 

  • Faragher RG, Sheerin AN, Ostler EL (2009) Can we intervene in human ageing? Expert Rev Mol Med 11:e27

    Article  PubMed  Google Scholar 

  • Finch CE (1990) Longevity, senescence and the genome. The University of Chicago Press, Chicago

    Google Scholar 

  • Finch CE, Pike MC, Witten M (1990) Slow mortality rate accelerations during aging in some animals approximate that of humans. Science 249:902–905

    Article  PubMed  CAS  Google Scholar 

  • Fong S, Gruber J, Halliwell B (2010) Measuring reactive oxygen species in C. elegans using DCFDA—a word of caution. Worm Breeder’s Gaz 18:11

    Google Scholar 

  • Franco OH, Karnik K, Osborne G et al (2009) Changing course in ageing research: the healthy ageing phenotype. Maturitas 63:13–19

    Article  PubMed  Google Scholar 

  • Gadaleta MN, Rainaldi G, Lezza AM et al (1992) Mitochondrial DNA copy number and mitochondrial DNA deletion in adult and senescent rats. Mutat Res 275:181–193

    PubMed  CAS  Google Scholar 

  • Gandhi S, Santelli J, Mitchell DH et al (1980) A simple method for maintaining large, aging populations of Caenorhabditis elegans. Mech Ageing Dev 12:137–150

    Article  PubMed  CAS  Google Scholar 

  • Gardner MP, Gems D, Viney ME (2004) Aging in a very short-lived nematode. Exp Gerontol 39:1267–1276

    Article  PubMed  Google Scholar 

  • Gems D (2009) Ageing and oxidants in the nematode Caenorhabditis elegans. SEB Exp Biol Ser 62:31–56

    PubMed  CAS  Google Scholar 

  • Gems D, Partridge L (2001) Insulin/IGF signalling and ageing: seeing the bigger picture. Curr Opin Genet Dev 11:287–292

    Article  PubMed  CAS  Google Scholar 

  • Giustarini D, Dalle-Donne I, Tsikas D et al (2009) Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci 46:241–281

    Article  PubMed  CAS  Google Scholar 

  • Goldberg AA, Bourque SD, Kyryakov P et al (2009) A novel function of lipid droplets in regulating longevity. Biochem Soc Trans 37:1050–1055

    Article  PubMed  CAS  Google Scholar 

  • Grad LI, Lemire BD (2004) Mitochondrial complex I mutations in Caenorhabditis elegans produce cytochrome c oxidase deficiency, oxidative stress and vitamin-responsive lactic acidosis. Hum Mol Genet 13:303–314

    Article  PubMed  CAS  Google Scholar 

  • Gruber J, Schaffer S, Halliwell B (2008) The mitochondrial free radical theory of ageing—where do we stand? Front Biosci 13:6554–6579

    Article  PubMed  CAS  Google Scholar 

  • Gruber J, Ng LF, Poovathingal SK et al (2009) Deceptively simple but simply deceptive—Caenorhabditis elegans lifespan studies: considerations for aging and antioxidant effects. FEBS Lett 583:3377–3387

    Article  PubMed  CAS  Google Scholar 

  • Gruber J, Poovathingal SK, Schaffer S et al (2010) Caenorhabditis elegans life span studies: the challenge of maintaining synchronous cohorts. Rejuvenation Res 13:347–349

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B (1999) Establishing the significance and optimal intake of dietary antioxidants: the biomarker concept. Nutr Rev 57:104–113

    Article  PubMed  CAS  Google Scholar 

  • Halliwell B, Gutteridge JMC (2007) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  • Halliwell B, Whiteman M (2004) Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol 142:231–255

    Article  PubMed  CAS  Google Scholar 

  • Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300

    PubMed  CAS  Google Scholar 

  • Hassoun EA, Ray S (2003) The induction of oxidative stress and cellular death by the drinking water disinfection by-products, dichloroacetate and trichloroacetate in J774.A1 cells. Comp Biochem Physiol C 135:119–128

    Google Scholar 

  • Hayflick L (2000) The future of ageing. Nature 408:267–269

    Article  PubMed  CAS  Google Scholar 

  • Headlam HA, Davies MJ (2004) Markers of protein oxidation: different oxidants give rise to variable yields of bound and released carbonyl products. Free Radic Biol Med 36:1175–1184

    Article  PubMed  CAS  Google Scholar 

  • Herndon LA, Schmeissner PJ, Dudaronek JM et al (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419:808–814

    Article  PubMed  CAS  Google Scholar 

  • Hillyard SL, German JB (2009) Quantitative lipid analysis and life span of the fat-3 mutant of Caenorhabditis elegans. J Agric Food Chem 57:3389–3396

    Article  PubMed  CAS  Google Scholar 

  • Houthoofd K, Fidalgo MA, Hoogewijs D et al (2005) Metabolism, physiology and stress defense in three aging Ins/IGF-1 mutants of the nematode Caenorhabditis elegans. Aging Cell 4:87–95

    Article  PubMed  CAS  Google Scholar 

  • Houtkooper RH, Williams RW, Auwerx J (2010) Metabolic networks of longevity. Cell 142:9–14

    Article  PubMed  CAS  Google Scholar 

  • Hulbert AJ (2005) On the importance of fatty acid composition of membranes for aging. J Theor Biol 234:277–288

    Article  PubMed  CAS  Google Scholar 

  • Izaks GJ, Westendorp RG (2003) Ill or just old? Towards a conceptual framework of the relation between ageing and disease. BMC Geriatr 3:7

    Article  PubMed  Google Scholar 

  • Jocelyn PC, Kamminga A (1970) Development of fluorescence between o-phthaldialdehyde and thiols. Anal Biochem 37:417–421

    Article  PubMed  CAS  Google Scholar 

  • Katayama Y, Welsh FA (1989) Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain. J Neurochem 52:1817–1822

    Article  PubMed  CAS  Google Scholar 

  • Kenyon CJ (2010) The genetics of ageing. Nature 464:504–512

    Article  PubMed  CAS  Google Scholar 

  • Kimura KD, Tissenbaum HA, Liu Y et al (1997) Daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946

    Article  PubMed  CAS  Google Scholar 

  • Kline JA, Maiorano PC, Schroeder JD et al (1997) Activation of pyruvate dehydrogenase improves heart function and metabolism after hemorrhagic shock. J Mol Cell Cardiol 29:2465–2474

    Article  PubMed  CAS  Google Scholar 

  • Ku HH, Brunk UT, Sohal RS (1993) Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med 15:621–627

    Article  PubMed  CAS  Google Scholar 

  • Lanza IR, Nair KS (2010) Mitochondrial function as a determinant of life span. Pflug Arch 459:277–289

    Article  CAS  Google Scholar 

  • Lao JI, Montoriol C, Morer I et al (2005) Genetic contribution to aging: deleterious and helpful genes define life expectancy. Ann N Y Acad Sci 1057:50–63

    Article  PubMed  CAS  Google Scholar 

  • Lapointe J, Hekimi S (2010) When a theory of aging ages badly. Cell Mol Life Sci 67:1–8

    Article  PubMed  CAS  Google Scholar 

  • Lee HC, Wei YH (2007) Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med 232:592–606

    CAS  Google Scholar 

  • Ludvik B, Mayer G, Stifter S et al (1993) Effects of dichloroacetate on exercise performance in healthy volunteers. Pflug Arch 423:251–254

    Article  CAS  Google Scholar 

  • Martinon F (2010) Signaling by ROS drives inflammasome activation. Eur J Immunol 40:616–619

    Article  PubMed  CAS  Google Scholar 

  • Miskin R, Tirosh O, Pardo M et al (2005) AlphaMUPA mice: a transgenic model for longevity induced by caloric restriction. Mech Ageing Dev 126:255–261

    Article  PubMed  CAS  Google Scholar 

  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13

    Article  PubMed  CAS  Google Scholar 

  • Nagendran J, Gurtu V, Fu DZ et al (2008) A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg 136:168–178

    Article  PubMed  Google Scholar 

  • Nakano K, Tarashima M, Tachikawa E et al (2005) Platelet mitochondrial evaluation during cytochrome c and dichloroacetate treatments of MELAS. Mitochondrion 5:426–433

    Article  PubMed  CAS  Google Scholar 

  • Olsen A, Vantipalli MC, Lithgow GJ (2006) Using Caenorhabditis elegans as a model for aging and age-related diseases. Ann N Y Acad Sci 1067:120–128

    Article  PubMed  CAS  Google Scholar 

  • Partridge L, Gems D (2007) Benchmarks for ageing studies. Nature 450:165–167

    Article  PubMed  CAS  Google Scholar 

  • Passos JF, von Zglinicki T, Kirkwood TB (2007) Mitochondria and ageing: winning and losing in the numbers game. Bioessays 29:908–917

    Article  PubMed  CAS  Google Scholar 

  • Pletcher SD, Khazaeli AA, Curtsinger JW (2000) Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters. J Gerontol A Biol Sci Med Sci 55:B381–B389

    PubMed  CAS  Google Scholar 

  • Poovathingal SK, Gruber J, Halliwell B et al (2009) Stochastic drift in mitochondrial DNA point mutations: a novel perspective ex silico. PLoS Comput Biol 5:e1000572

    Article  PubMed  Google Scholar 

  • Schneider SH, Komanicky PM, Goodman MN et al (1981) Dichloroacetate: effects on exercise endurance in untrained rats. Metabolism 30:590–595

    Article  PubMed  CAS  Google Scholar 

  • Schulz KF, Chalmers I, Altman DG et al (1995) The methodologic quality of randomization as assessed from reports of trials in specialist and general medical journals. Online J Curr Clin Trials Doc No 197:81

  • Shroads AL, Guo X, Dixit V et al (2008) Age-dependent kinetics and metabolism of dichloroacetate: possible relevance to toxicity. J Pharmacol Exp Ther 324:1163–1171

    Article  PubMed  CAS  Google Scholar 

  • Sinclair DA, Oberdoerffer P (2009) The ageing epigenome: damaged beyond repair? Ageing Res Rev 8:189–198

    Article  PubMed  CAS  Google Scholar 

  • Sohal RS, Mockett RJ, Orr WC (2002) Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 33:575–586

    Article  PubMed  CAS  Google Scholar 

  • Soukas AA, Kane EA, Carr CE et al (2009) Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev 23:496–511

    Article  PubMed  CAS  Google Scholar 

  • Stacpoole PW (1989) The pharmacology of dichloroacetate. Metabolism 38:1124–1144

    Article  PubMed  CAS  Google Scholar 

  • Stacpoole PW, Wright EC, Baumgartner TG et al (1992) A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group. N Engl J Med 327:1564–1569

    Article  PubMed  CAS  Google Scholar 

  • Stiernagle T (2006) Maintenance of C. elegans. WormBook 1–11

  • Sun RC, Fadia M, Dahlstrom JE et al (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260

    Article  PubMed  CAS  Google Scholar 

  • Sutphin GL, Kaeberlein M (2008) Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes. Exp Gerontol 43:130–135

    Article  PubMed  CAS  Google Scholar 

  • Taniguchi M, Wilson C, Hunter CA et al (2001) Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak. Am J Physiol Heart Circ Physiol 280:H1762–H1769

    PubMed  CAS  Google Scholar 

  • Tatar M (2009) Can we develop genetically tractable models to assess healthspan (rather than life span) in animal models? J Gerontol A Biol Sci Med Sci 64:161–163

    Article  PubMed  Google Scholar 

  • Trifunovic A, Hansson A, Wredenberg A et al (2005) Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 102:17993–17998

    Article  PubMed  CAS  Google Scholar 

  • Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    Article  PubMed  CAS  Google Scholar 

  • Van Raamsdonk JM, Hekimi S (2009) Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 5:e1000361

    Article  PubMed  Google Scholar 

  • Wang MC, O’Rourke EJ, Ruvkun G (2008) Fat metabolism links germline stem cells and longevity in C. elegans. Science 322:957–960

    Article  PubMed  CAS  Google Scholar 

  • Wiesner RJ, Ruegg JC, Morano I (1992) Counting target molecules by exponential polymerase chain reaction: copy number of mitochondrial DNA in rat tissues. Biochem Biophys Res Commun 183:553–559

    Article  PubMed  CAS  Google Scholar 

  • World Health Organization (2005) Dichloroacetic acid in drinking-water. WHO document WHO/SDE/WSH/05.08/121

  • Wu D, Rea SL, Yashin AI et al (2006) Visualizing hidden heterogeneity in isogenic populations of C. elegans. Exp Gerontol 41:261–270

    Article  PubMed  CAS  Google Scholar 

  • Yan LJ, Sohal RS (1998) Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA 95:12896–12901

    Article  PubMed  CAS  Google Scholar 

  • Yen K, Mobbs CV (2010) Evidence for only two independent pathways for decreasing senescence in Caenorhabditis elegans. Age 32:39–49

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the Caenorhabditis Genetic Center (University of Minnesota) for the provision of the worm strain. This work was supported by the Biomedical Research Council (BMRC) of Singapore (Grant No.: 07/1/21/19/524).

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  1. S. Y. Tang

    Present address: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, BRB 2/3, 421 Curie Blvd, Philadelphia, PA, 19104, USA

Authors and Affiliations

  1. Department of Biochemistry, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore

    S. Schaffer, J. Gruber, L. F. Ng, Y. T. Wong, S. Y. Tang & B. Halliwell

  2. University Scholars Programme, National University of Singapore, Singapore, 119077, Singapore

    S. Fong

  3. National University of Singapore, University Hall, Lee Kong Chian Wing, UHL #05-02G, 21 Lower Kent Ridge Road, Singapore, 119077, Singapore

    B. Halliwell

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  1. S. Schaffer
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Correspondence to B. Halliwell.

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S. Schaffer and J. Gruber contributed equally to this study.

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Schaffer, S., Gruber, J., Ng, L.F. et al. The effect of dichloroacetate on health- and lifespan in C. elegans . Biogerontology 12, 195–209 (2011). https://doi.org/10.1007/s10522-010-9310-7

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