Abstract
The supplementation of creatine has shown a marked neuroprotective effect in mouse models of neurodegenerative diseases (Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis). This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic and anti-oxidant properties of creatine. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral creatine supplementation on aging in 162 aged wild-type C57Bl/6J mice. The median healthy life span of creatine-fed mice was 9% higher than in their control littermates, and they performed significantly better in neurobehavioral tests. In brains of creatine-treated mice, there was a trend toward a reduction of reactive oxygen species and significantly lower accumulation of the “aging pigment” lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data showed that creatine improves health and longevity in mice. Creatine may, therefore, be a promising food supplement to promote healthy human aging. However, the strong neuroprotective effects in animal studies of creatine have not been reproduced in human clinical trials (that have been conducted in Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis). The reasons for this translational gap are discussed. One obvious cause seems to be that all previous human studies may have been underpowered. Large phase III trials over long time periods are currently being conducted for Parkinson’s disease and Huntington’s disease, and will possibly solve this issue.
Similar content being viewed by others
References
Andreassen OA, Dedeoglu A, Ferrante RJ, Jenkins BG, Ferrante KL, Thomas M, Friedlich A, Browne SE, Schilling G, Borchelt DR, Hersch SM, Ross CA, Beal MF (2001a) Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 8:479–491
Andreassen OA, Jenkins BG, Dedeoglu A, Ferrante KL, Bogdanov MB, Kaddurah-Daouk R, Beal MF (2001b) Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem 77:383–390
Beal MF (2005) Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 58:495–505
Benatar M (2007) Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis 26:1–13
Bender A, Auer DP, Merl T, Reilmann R, Saemann P, Yassouridis A, Bender J, Weindl A, Dose M, Gasser T, Klopstock T (2005) Creatine supplementation lowers brain glutamate levels in Huntington’s disease. J Neurol 252:36–41
Bender A, Koch W, Elstner M, Schombacher Y, Bender J, Moeschl M, Gekeler F, Müller-Myhsok B, Gasser T, Tatsch K, Klopstock T (2006a) Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial. Neurology 67:1262–1264
Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM (2006b) High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet 38:515–517
Bender A, Beckers J, Schneider I, Hölter SM, Haack T, Ruthsatz T, Vogt-Weisenhorn DM, Becker L, Genius J, Rujescu D, Irmler M, Mijalski T, Mader M, Quintanilla-Martinez L, Fuchs H, Gailus-Durner V, de Angelis MH, Wurst W, Schmidt J, Klopstock T (2008a) Creatine improves health and survival of mice. Neurobiol Aging 29:1404–1411
Bender A, Samtleben W, Elstner M, Klopstock T (2008b) Long-term creatine supplementation is safe in aged patients with Parkinson disease. Nutr Res 28:172–178
Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297:842–857
Burger JM, Promislow DE (2004) Sex-specific effects of interventions that extend fly life span. Sci Aging Knowl Environ (pe30)
Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF, Ferrante RJ (2003) Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem 85:1359–1367
Duan W, Guo Z, Mattson MP (2001) Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice. J Neurochem 76:619–626
Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF (2000) Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20:4389–4397
Gordon PH, Cheung YK, Levin B, Andrews H, Doorish C, Macarthur RB, Montes J, Bednarz K, Florence J, Rowin J, Boylan K, Mozaffar T, Tandan R, Mitsumoto H, Kelvin EA, Chapin J, Bedlack R, Rivner M, McCluskey LF, Pestronk A, Graves M, Sorenson EJ, Barohn RJ, Belsh JM, Lou JS, Levine T, Saperstein D, Miller RG, Scelsa SN, Group CombinationDrugSelectionTrialStudy (2008) A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph Lateral Scler 9:212–222
Groeneveld GJ, Veldink JH, van der Tweel I, Kalmijn S, Beijer C, de Visser M, Wokke JH, Franssen H, van den Berg LH (2003) A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol 53:437–445
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775
Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147
Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2’dG. Neurology 66:250–252
Hervias I, Beal MF, Manfredi G (2006) Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve 33:598–608
Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5:347–350
Klivenyi P, Gardian G, Calingasan NY, Yang L, Beal MF (2003) Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. J Mol Neurosci 21:191–198
Klivenyi P, Kiaei M, Gardian G, Calingasan NY, Beal MF (2004) Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 88:576–582
Kreider RB (2003) Species-specific responses to creatine supplementation. Am J Physiol Regul Integr Comp Physiol 285:R725–R726
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V (1996) Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347:1425–1431
Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52
Lee CK, Pugh TD, Klopp RG, Edwards J, Allison DB, Weindruch R, Prolla TA (2004) The impact of alpha-lipoic acid, coenzyme Q10 and caloric restriction on life span and gene expression patterns in mice. Free Radic Biol Med 36:1043–1057
Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF (2003) Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res 123:87–100
Matthews RT, Yang L, Jenkins BG, Ferrante RJ, Rosen BR, Kaddurah-Daouk R, Beal MF (1998) Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci 18:156–163
Matthews RT, Ferrante RJ, Klivenyi P, Yang L, Klein AM, Mueller G, Kaddurah-Daouk R, Beal MF (1999) Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol 157:142–149
Mattson MP, Chan SL, Duan W (2002) Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior. Physiol Rev 82:637–672
Mazzini L, Balzarini C, Colombo R, Mora G, Pastore I, De Ambrogio R, Caligari M (2001) Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci 191:139–144
Nadon NL (2006) Of mice and monkeys: National Institute on Aging resources supporting the use of animal models in biogerontology research. J Gerontol A Biol Sci Med Sci 61:813–815
NINDS NET-PD Investigators (2006) A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 66:664–671
O’Gorman E, Beutner G, Dolder M, Koretsky AP, Brdiczka D, Wallimann T (1997) The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett 414:253–257
Pastula DM, Moore DH, Bedlack RS (2010) Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 6:CD005225
Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 101:15998–16003
Rosenfeld J, King RM, Jackson CE, Bedlack RS, Barohn RJ, Dick A, Phillips LH, Chapin J, Gelinas DF, Lou JS (2008) Creatine monohydrate in ALS: effects on strength, fatigue, respiratory status and ALSFRS. Amyotroph Later Scler 9:266–272
Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol 7:97–109
Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS (2005) Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308:1909–1911
Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA (2008) Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Later Scler 9:4–15
Shaw PJ (2005) Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry 76:1046–1057
Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, Urbinelli L, Qureshi M, Zhang H, Pestronk A, Caress J, Donofrio P, Sorenson E, Bradley W, Lomen-Hoerth C, Pioro E, Rezania K, Ross M, Pascuzzi R, Heiman-Patterson T, Tandan R, Mitsumoto H, Rothstein J, Smith-Palmer T, MacDonald D, Burke D, Consortium NEALS (2004) A clinical trial of creatine in ALS. Neurology 63:1656–1661
Snow RJ, Turnbull J, da Silva S, Jiang F, Tarnopolsky MA (2003) Creatine supplementation and riluzole treatment provide similar beneficial effects in copper, zinc superoxide dismutase (G93A) transgenic mice. Neuroscience 119:661–667
Sullivan PG, Geiger JD, Mattson MP, Scheff SW (2000) Dietary supplement creatine protects against traumatic brain injury. Ann Neurol 48:723–729
Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT (2003) Creatine therapy for Huntington’s disease: clinical and MRS findings in a 1-year pilot study. Neurology 61:141–142
Tabrizi SJ, Blamire AM, Manners DN, Rajagopalan B, Styles P, Schapira AH, Warner TT (2005) High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Neurology 64:1655–1656
Tarnopolsky MA, Bourgeois JM, Snow R, Keys S, Roy BD, Kwiecien JM, Turnbull J (2003) Histological assessment of intermediate- and long-term creatine monohydrate supplementation in mice and rats. Am J Physiol Regul Integr Comp Physiol 285:R762–R769
Turner BJ, Talbot K (2008) Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 85:94–134
Verbessem P, Lemiere J, Eijnde BO, Swinnen S, Vanhees L, Van Leemputte M, Hespel P, Dom R (2003) Creatine supplementation in Huntington’s disease: a placebo-controlled pilot trial. Neurology 61:925–930
Weindruch R (1996) Caloric restriction and aging. Sci Am 274:46–52
Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116
Xu CJ, Klunk WE, Kanfer JN, Xiong Q, Miller G, Pettegrew JW (1996) Phosphocreatine-dependent glutamate uptake by synaptic vesicles. A comparison with atp-dependent glutamate uptake. J Biol Chem 271:13435–13440
Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, Beal MF (2009) Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson’s and Huntington’s diseases. J Neurochem 109:1427–1439
Zhang W, Narayanan M, Friedlander RM (2003) Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS. Ann Neurol 53:267–270
Zhu S, Li M, Figueroa BE, Liu A, Stavrovskaya IG, Pasinelli P, Beal MF, Brown RH, Kristal BS, Ferrante RJ, Friedlander RM (2004) Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci 24:5909–5912
Conflict of interest
T. Klopstock received free creatine supplements for the described mouse studies and human trials as well as a travel grant from the creatine manufacturer AlzChem Trostberg GmbH.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Klopstock, T., Elstner, M. & Bender, A. Creatine in mouse models of neurodegeneration and aging. Amino Acids 40, 1297–1303 (2011). https://doi.org/10.1007/s00726-011-0850-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-011-0850-1