Amino Acids

, Volume 48, Issue 7, pp 1707–1716 | Cite as

Determination of the safety of leucine supplementation in healthy elderly men

  • Betina Rasmussen
  • Erin Gilbert
  • Abrar Turki
  • Kenneth Madden
  • Rajavel ElangoEmail author
Original Article


Leucine, a branched-chain amino acid (BCAA), has been shown to stimulate muscle protein synthesis, and thus has been proposed to prevent age-related muscle atrophy (sarcopenia). Therefore, leucine supplementation may have potential benefits in elderly populations to preserve muscle mass. The tolerable upper intake level (UL) for leucine intake in young men has recently been determined to be 500 mg kg−1 day−1, and increases in blood ammonia concentrations were seen at intake levels above 500 mg kg−1 day−1; the UL for leucine in elderly is unknown. The objective of the current study was to determine the safety of leucine supplementation in healthy elderly men. Six healthy elderly men (72.2 ± 3.5 years) received graded stepwise increases in leucine intakes ranging from 50 to 750 mg kg−1 day−1, on eight separate study days. Plasma and urinary biochemical variables, including blood ammonia, and an oral primed-continuous protocol of L-1-13C-Leucine was performed. Blood ammonia concentrations above normal values (35 µmol/L) were observed at leucine intakes >550 mg kg−1 day−1. Leucine oxidation measured as a F13CO2 (rate of label tracer oxidation) increased with increasing leucine intakes and started to plateau after 450 mg kg−1 day−1. Two-phased linear regression analysis of the F13CO2 data revealed a breakpoint of 431 mg kg−1 day−1 (R 2 = 0.73), suggesting that the upper limit to oxidize leucine was reached at that point. Taking the data together the upper limit for leucine intake in healthy elderly could be set similar to young men at 500 mg kg−1 day−1 or ~35 g/day for an individual weighing 70 kg.


Leucine Upper limit Oxidation Elderly Ammonia 



This study was funded by the International Council of Amino Acid Science (ICAAS).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

726_2016_2241_MOESM1_ESM.docx (75 kb)
Supplementary material 1 (DOCX 75 kb)


  1. Aftring RP, Block KP, Buse MG (1986) Leucine and isoleucine activate skeletal muscle branched-chain alpha-keto acid dehydrogenase in vivo. Am J Physiol 250:E599–E604PubMedGoogle Scholar
  2. Baker DH (2005) Tolerance for branched-chain amino acids in experimental animals and humans. J Nutr 135:1585S–1590SPubMedGoogle Scholar
  3. Balage M, Dardevet D (2010) Long-term effects of leucine supplementation on body composition. Curr Opin Clin Nutr Metab Care 13:265–270CrossRefPubMedGoogle Scholar
  4. Casperson SL, Sheffield-Moore M, Hewlings SJ, Paddon-Jones D (2012) Leucine supplementation chronically improves muscle protein synthesis in older adults consuming the RDA for protein. Clin Nutr 31:512–519CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M (2010) European Working Group on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 39:412–423CrossRefPubMedPubMedCentralGoogle Scholar
  6. Cynober L (2006) Introduction to the 5th Amino Acid Assessment Workshop. J Nutr 136:1633S–1635SPubMedGoogle Scholar
  7. Cynober L, Bier DM, Kadowaki M, Morris SM Jr, Renwick AG (2012) A proposal for an upper limit of leucine safe intake in healthy adults. J Nutr 142:2249S–2250SCrossRefPubMedGoogle Scholar
  8. Dillon EL (2013) Nutritionally essential amino acids and metabolic signaling in aging. Amino Acids 45:431–441CrossRefPubMedGoogle Scholar
  9. Elango R, Chapman K, Rafii M, Ball RO, Pencharz PB (2012) Determination of the tolerable upper intake level of leucine in acute dietary studies in young men. Am J Clin Nutr 96:759–767CrossRefPubMedGoogle Scholar
  10. Etchells E, Darzins P, Silberfeld M, Singer PA, McKenny J, Naglie G, Katz M, Guyatt GH, Molloy DW, Strang D (1999) Assessment of patient capacity to consent to treatment. J Gen Intern Med 14:27–34CrossRefPubMedPubMedCentralGoogle Scholar
  11. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMedGoogle Scholar
  12. Fukagawa NK (2013) Protein and amino acid supplementation in older humans. Amino Acids 44:1493–1509CrossRefPubMedGoogle Scholar
  13. Grubbs FE (1969) Procedures for detecting outlying observations in samples. Technometrics 11:1–21CrossRefGoogle Scholar
  14. Harper AE, Miller RH, Block KP (1984) Branched-chain amino acid metabolism. Annu Rev Nutr 4:409–454CrossRefPubMedGoogle Scholar
  15. Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB (2010) Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem 285:11348–11356CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hoerr RA, Yu YM, Wagner DA, Burke JF, Young VR (1989) Recovery of 13C in breath from NaH13CO3 infused by gut and vein: effect of feeding. Am J Physiol 257:E426–E438PubMedGoogle Scholar
  17. Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A, Wolfe RR (2006) A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291:E381–E387CrossRefPubMedGoogle Scholar
  18. Komar B, Schwingshackl L, Hoffmann G (2015) Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. J Nutr Health Aging 19:437–446CrossRefPubMedGoogle Scholar
  19. Koopman R, Verdijk L, Manders RJ, Gijsen AP, Gorselink M, Pijpers E, Wagenmakers AJ, van Loon LJ (2006) Co-ingestion of protein and leucine stimulates muscle protein synthesis rates to the same extent in young and elderly lean men. Am J Clin Nutr 84:623–632PubMedGoogle Scholar
  20. Le Boucher J, Charret C, Coudray-Lucas C, Giboudeau J, Cynober L (1997) Amino acid determination in biological fluids by automated ion-exchange chromatography: performance of Hitachi L-8500A. Clin Chem 43:1421–1428PubMedGoogle Scholar
  21. Leenders M, van Loon LJ (2011) Leucine as a pharmaconutrient to prevent and treat sarcopenia and type 2 diabetes. Nutr Rev 69:675–689CrossRefPubMedGoogle Scholar
  22. Littell R, Milliken G, Stroup W, Wolfinger R (1996) SAS system for mixed models. SAS Institute, CaryGoogle Scholar
  23. Newgard CB (2012) Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 15:606–614CrossRefPubMedPubMedCentralGoogle Scholar
  24. Ohtani M, Kawada S, Seki T, Okamoto Y (2012) Amino acid and vitamin supplementation improved health conditions in elderly participants. J Clin Biochem Nutr 50:162–168CrossRefPubMedGoogle Scholar
  25. Paddon-Jones D, Sheffield-Moore M, Zhang XJ, Volpi E, Wolf SE, Aarsland A, Ferrando AA, Wolfe RR (2004) Amino acid ingestion improves muscle protein synthesis in the young and elderly. Am J Physiol Endocrinol Metab 286:E321–E328CrossRefPubMedGoogle Scholar
  26. Pencharz PB, Elango R, Ball RO (2008) An approach to defining the upper safe limits of amino acid intake. J Nutr 138:1996S–2002SPubMedGoogle Scholar
  27. Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keränen H, Suomalainen A, Götz A, Suortti T, Yki-Järvinen H, Oresic M, Kaprio J, Peltonen L (2008) Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med 5:e51CrossRefPubMedPubMedCentralGoogle Scholar
  28. Roubenoff R, Baumgartner RN, Harris TB, Dallal GE, Hannan MT, Economos CD, Stauber PM, Wilson PW, Kiel DP (1997) Application of bioelectrical impedance analysis to elderly populations. J Gerontol A Biol Sci Med Sci 52:M129–M136CrossRefPubMedGoogle Scholar
  29. Sakai R, Miura M, Amao M, Kodama R, Toue S, Noguchi Y, Kimura T (2004) Potential approaches to the assessment of amino acid adequacy in rats: a progress report. J Nutr 134:1651S–1655SPubMedGoogle Scholar
  30. Seber GAF (1977) Linear regression analysis. Wiley, New YorkGoogle Scholar
  31. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab 293:E1552–E1563CrossRefPubMedPubMedCentralGoogle Scholar
  32. Tsikas D, Wolf A, Frölich JC (2004) Simplified HPLC method for urinary and circulating creatinine. Clin Chem 50:201–203CrossRefPubMedGoogle Scholar
  33. Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR (2003) Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr 78:250–258PubMedPubMedCentralGoogle Scholar
  34. Xu ZR, Tan ZJ, Zhang Q, Gui QF, Yang YM (2015) The effectiveness of leucine on muscle protein synthesis, lean body mass and leg lean mass accretion in older people: a systematic review and meta-analysis. Br J Nutr 113:25–34CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Betina Rasmussen
    • 1
  • Erin Gilbert
    • 1
  • Abrar Turki
    • 1
  • Kenneth Madden
    • 4
  • Rajavel Elango
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of PediatricsUniversity of British ColumbiaVancouverCanada
  2. 2.Child and Family Research Institute, BC Children’s HospitalVancouverCanada
  3. 3.School of Population and Public HealthUniversity of British ColumbiaVancouverCanada
  4. 4.Division of Geriatric Medicine, Department of Medicine, Vancouver General HospitalUniversity of British ColumbiaVancouverCanada

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