Muscle Science for Senior Athletes

Courtney Stanley Courtney at 70

This Blog entry will contain a series of constantly updated articles and information relating to the Senior Athlete (Above 50). Sarcopenia is the degenerative loss of skeletal muscle mass, quality, and strength associated with aging. This should  be a real issue that concerns the well being and effectiveness of all Seniors, regardless of activity levels.  I am 74 and can attest that as a lifelong Athlete, the loss of muscle can have staggering consequences. After some down time from Pulmonary Embolism and a Heart Attack between 2016 and 2018 I was shocked to find out how weak I had become and the effects that weakness had on my daily life. I also looked puny…not great for the self esteem. In November of 2018 I decided to put the “Hammer Down” and resume my exercise routine and get real serious about Nutrition. As an accomplished Powerlifter-Runner- Skier and Swimmer,  I knew what to do about Muscle Building and whole body conditioning, but felt I was lacking in my understanding of the peculiarities of staying in shape as a Senior. Most of this ignorance resulted from a lack of understanding of the basic physiology/science of aging. I credit  Leonard Guarente and Dr. David Sinclair, both products of Harvard/MIT, for waking me up to the complexities of aging, and possible solutions. Each of the additions to this blog will be a bit heavy on the Science side, but if you really want to understand your bodily functions, a little science is necessary.

Anti-Aging Benefits of Creatine

While often viewed as a performance enhancement supplement for athletes, creatine continues to demonstrate exciting new anti-aging benefits for older adults, including fighting muscle loss, improving cognition, and modulating inflammation.

Scientifically reviewed by: Dr. Gary Gonzalez, MD, on January 2021. Written By Will Brink.

Creatine is a nutrient with a long list of potential medical, exercise-enhancing, and anti-aging applications. As discussed in the March 2003 issue of Life Extension, creatine may play a role in preventing and treating diseases such as muscular dystrophy that affect the neuromuscular system.1 Creatine has potential therapeutic applications in aging populations and against disorders such as wasting syndromes, muscle atrophy, fatigue, Parkinson’s disease, and Huntington’s disease, as well as mitochondrial disorders and brain pathologies. Another article in the September 2003 issue of Life Extension examined creatine’s potential role in increasing growth hormone levels, reducing homocysteine levels, and improving the symptoms of chronic fatigue syndrome.2

In this article, we will examine exciting new research on the use of creatine by older adults to fight age-related muscle loss (sarcopenia), improve function in both healthy and damaged brains, and perhaps modulate inflammation. Creatine is proving to be one of the most promising, well-researched, and safest supplements ever discovered for an exceptionally wide range of uses.

What is creatine? In a nutshell, creatine helps the body generate energy. Adenosine triphosphate (ATP), formed in the mitochondria, is often referred to as the body’s “universal energy molecule.” When ATP loses a high-energy phosphate molecule to become adenosine diphosphate (ADP), it must be converted back to ATP before it can be used again to produce energy. Creatine, stored in the body as creatine phosphate, can donate a phosphate group to ADP, thus recharging it to energy-producing ATP. By promoting faster and more efficient recycling of ATP, creatine helps provide the fuel our bodies need to accomplish physical and metabolic tasks.1

The Scourge of Aging: Sarcopenia

In literally dozens of studies, creatine has been shown to increase strength and muscle mass in young adults and to aid in rehabilitative strength training.3-13 Until recently, data concerning creatine’s effects on older adults was very limited. One of the greatest threats faced by aging adults is the steady loss of lean body mass (muscle) needed to maintain a healthy, functional lifestyle. The medical term for this loss of muscle tissue is sarcopenia, a condition that is only now getting the recognition it deserves by the medical and scientific community.


Sarcopenia can be defined as the age-related loss of muscle mass, strength, and function. For decades, the medical community has focused on the loss of bone mass (osteoporosis) in aging adults, but has paid little attention to the loss of muscle mass that occurs with aging. This loss of muscle mass can affect a person’s ability to be functional, perhaps even more so than a loss of bone mass. As with most medical conditions, it is easier, less expensive, and more effective to prevent or slow the progression of this condition than it is to treat it later in life. Sarcopenia generally appears in adults after the age of 40 and accelerates after the age of approximately 75.Although sarcopenia is mostly seen in physically inactive adults, it is not uncommon in people who remain physically active throughout their lives. Thus, while remaining physically active is essential to avoiding sarcopenia, physical inactivity is not the only contributing factor to its development. Like osteoporosis, sarcopenia is a multifactorial process whose contributing factors may include decreased hormone levels (particularly of growth hormone, insulin-like growth factor 1, and testosterone), lack of adequate protein and calories in the diet, oxidative stress, inflammatory processes, and loss of motor nerve cells.14-33

How Creatine Affects Older Adults

With aging and inactivity, muscle wasting or atrophy most often occurs in fast-twitch muscle fiber. These fibers, which are recruited during high-intensity, low-endurance movements such as weight lifting and sprinting, are the most profoundly affected by creatine.In a study examining creatine’s effect on isometric strength and body composition, 28 healthy men and women over the age of 65 received either five grams of creatine daily or a placebo.34 In this random, double-blind study, both the creatine and placebo groups were put on a resistance (weight) training regimen. Fourteen weeks of training resulted in significant increases in all measurements of strength, functional tasks, and muscle fiber area in both groups. However, the creatine group experienced significantly greater increases in fat-free muscle mass, isometric knee extension strength, isometric dorsiflexion (ankle) strength, and intramuscular creatine levels. The researchers concluded, “the addition of creatine supplementation to the exercise stimulus enhanced the increase in total and fat-free mass and gains in several indices of isometric muscle strength.”34An abundance of recent studies has found creatine to have beneficial effects in older adults, especially when combined with a resistance training protocol. One study examined the effects of creatine supplementation on muscular performance in older men over a brief time period.35 The study authors concluded, “. . . seven days of creatine supplementation is effective at increasing several indices of muscle performance, including functional tests in older men without adverse side effects. Creatine supplementation may be a useful therapeutic strategy for older adults to attenuate loss in muscle strength and performance of functional living tasks.”

athlete fixing shoes

One especially noteworthy study found that creatine’s positive effects on strength and lean tissue in older adults continued for at least 12 weeks after they stopped using it.36 According to the study authors, “withdrawal from creatine had no effect on the rate of strength, endurance, and loss of lean tissue mass with 12 weeks of reduced-volume training.” For most creatine users, however, optimal benefits occur with continuous use of creatine, which is both safe and well tolerated.

The Secret to Aging: Cellular Energy

What is one important difference between an older and a younger adult? The answer is cellular energy: each cell’s ability to produce energy, detoxify harmful compounds, and defend itself against free radical damage and other assaults. An increase in oxidative stress, coupled with a cell’s inability to produce essential energy molecules such as ATP, is a hallmark of aging and is present in many disease states.37-40 While a younger person’s cells can efficiently meet these challenges, an older person’s cells are poorly equipped to do so. Over time, damage accumulates in older cells, and cell death can occur. In younger healthy adults, healthy new cells rapidly repair or replace older cells, but this process slows with age.A decline in muscle mass with aging, or sarcopenia, may be related to a decline in mitochondrial function. Without optimal functioning of these energy generators that are found in every human cell, both the cell and the entire body experience a decline in function. Research has established that older adults tend to have lower tissue levels of creatine phosphate, ATP, and other essential high-energy molecules. Older adults are also less adept at replenishing these essential molecules after exercise.One study examined skeletal muscle mitochondrial function and lean body mass in healthy, exercising elderly adults.41 The study measured mitochondrial function and recovery time in 45 older adults (with an average age of 73) and 20 younger subjects (average age of 25) who were matched for body mass. The investigators then had the two groups exercise at different intensity levels. As other studies have found, the older adults had lower baseline creatine phosphate and ATP levels than did their younger counterparts, and they were slower to replenish tissue levels after exercise. As the researchers reported, “Our data suggest that mitochondrial function declines with age in healthy, exercising elderly adults and that the decline appears to be influenced by the level of physical activity.” Thus, the older subjects not only had lower levels of essential high-energy compounds to begin with, but those levels were further diminished with more intense exercise.As studies in older adults show, creatine in supplemental form can ameliorate some of the physiological decline that occurs with aging. Creatine may be one of the safest, most effective non-prescription compounds currently available to improve cellular energy.

couple cycling

Creatine’s Anti-Inflammatory Effects Creatine may also help to modulate inflammation, at least after exercise. One study examined creatine’s effect on inflammation and muscle soreness in experienced runners after a 30-kilometer race.42 The researchers looked at inflammatory and muscle soreness markers—creatine kinase, lactate dehydrogenase, prostaglandin E2, and tumor necrosis factor-alpha—in runners before and after the race. One group of runners supplemented for five days before the race with 20 grams of creatine and 15 grams of maltodextrine daily, while the control group received only the maltodextrine. Blood samples were collected before the race, immediately afterwards, and 24 hours after the race.As one would expect, the control group had large increases in all four markers: a fourfold increase in creatine kinase concentration, a 43% increase in lactate dehydrogenase, more than a sixfold increase in prostaglandin E2, and a doubling of tumor necrosis factor-alpha. All these markers indicate a high level of cell injury and inflammation in these athletes. In the creatine group, however, supplementation attenuated the exercise-induced changes observed for creatine kinase by 19%, for prostaglandin E2 by 61%, and for tumor necrosis factor-alpha by 34%, while entirely negating the increase in lactate dehydrogenase plasma concentration observed in the control group. Participants supplementing with creatine reported no side effects. The researchers concluded, “These results indicate that creatine supplementation reduced cell damage and inflammation after an exhaustive, intense race.”These findings underscore an important point. Regular exercise is an essential component of wellness for people who want to improve their health, minimize body fat, and retain essential muscle mass. Exercise, however, also has potentially negative effects that the body must manage, including increased free radical production. Creatine thus may be beneficial in helping to modulate the inflammatory stress generated by exercise.

Creatine Improves Brain Function

Perhaps the most compelling case for creatine supplementation is its ability to modulate brain function and metabolism. Previous articles in Life Extension have examined some of creatine’s applications in promoting muscle, brain, and heart health.1,2 Ongoing research indicates that creatine is an important nutrient for brain function and metabolism in both healthy people and those who suffer from brain damage or brain-related disease. Traumatic brain injuries affect thousands each year. Adding to this tragedy is that much of the damage is caused not by the immediate injury to the brain, but by cell death caused by ischemia (lack of blood flow and oxygen to tissues), free radical damage, and oxidative stress.

A cell’s ability to function is directly related to its mitochondrial health and ATP status. Even small changes in ATP supply can have profound effects on the tissues’ ability to function properly. Heart tissue, brain neurons, and other highly active tissues are very sensitive to diminished ATP levels. Creatine appears to be among the most effective nutritional supplements for maintaining or raising ATP levels.

exercise bike

Recent research indicates that creatine affords the human nervous system significant protection against ischemic and oxidative insults.43-56 A study published in the Annals of Neurology examined creatine’s effects on brain tissue damage following simulated traumatic brain injury in animals.57 Administration of creatine ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. The researchers noted that this protection may be tied to creatine-induced maintenance of mitochondrial bioenergetics. They concluded that creatine “. . . may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes.” This study suggests that creatine therapy should be initiated as soon as possible after traumatic brain injury. People who have already been using creatine regularly may be afforded considerable protection against additional brain damage following such an injury.

Research also indicates that creatine improves brain function in healthy adults. A recent double-blind, placebo-controlled crossover study examined how six weeks of creatine supplementation affected cognitive function in adult vegetarians.58 Subjects were given five grams of creatine daily. Following creatine supplementation, the study participants demonstrated improved scores on tests assessing intelligence and working memory. Creatine’s effects may be due to its ability to increase the cellular energy available to the brain. Although creatine supplementation may have a less dramatic effect on non-vegetarians who obtain some creatine from dietary sources such as meat, it is likely that creatine benefits brain function in meat eaters and vegetarians. Supplemental creatine thus appears to improve function and performance in healthy and injured brains alike.


Through its role in promoting an abundant pool of cellular energy, creatine helps support the healthy functioning of muscle, brain, and other body tissues. A substantial body of research demonstrates that creatine is a safe and effective tool for managing a wide range of pathologies, and may be a powerful anti-aging nutrient. Healthy adults may benefit from supplementing with two to three grams of creatine daily, while those seeking to address specific health concerns such as muscle loss or brain injury may benefit from five to ten grams of creatine daily.

Additional information on how creatine and other supplements may benefit athletes is available at


1. Available at: Accessed December 17, 2004.

2. Available at: Accessed December 17, 2004.

3. Racette SB. Creatine supplementation and athletic performance. J Orthop Sports PhysTher. 2003 Oct;33(10):615-21.

4. Hespel P, Op’t EB, Van Leemputte M, et al. Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans. J Physiol. 2001 Oct 15;536(Pt 2):625-33.

5. Jowko E, Ostaszewski P, Jank M, et al. Creatine and beta-hydroxy-beta-methylbutyrate (HMB) additively increase lean body mass and muscle strength during a weight-training program. Nutrition. 2001 Jul;17(7-8):558-66.

6. Tarnopolsky MA, Parise G, Yardley NJ, et al. Creatine-dextrose and protein-dextrose induce similar strength gains during training. Med Sci Sports Exerc. 2001 Dec;33(12):2044-52.

7. Becque MD, Lochmann JD, Melrose DR. Effects of oral creatine supplementation on muscular strength and body composition. Med Sci Sports Exerc. 2000 Mar;32(3):654-8.

8. Francaux M, Poortmans JR. Effects of training and creatine supplement on muscle strength and body mass. Eur J Appl Physiol Occup Physiol. 1999 Jul;80(2):165-8.

9. Clarkson PM, Rawson ES. Nutritional supplements to increase muscle mass. Crit Rev Food Sci Nutr. 1999 Jul;39(4):317-28.

10. Kreider RB, Ferreira M, Wilson M, et al. Effects of creatine supplementation on body composition, strength, and sprint performance. Med Sci Sports Exerc. 1998 Jan;30(1):73-82.

11. Vandenberghe K, Goris M, Van Hecke P, et al. Long-term creatine intake is beneficial to muscle performance during resistance training. J Appl Physiol. 1997 Dec;83(6):2055-63.

12. Balsom PD, Soderlund K, Sjodin B, Ekblom B. Skeletal muscle metabolism during short duration high-intensity exercise: influence of creatine supplementation. Acta Physiol Scand. 1995 Jul;154(3):303-10.

13. Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992 Sep;83(3):367-74.

14. Fulle S, Protasi F, Di Tano G, et al. The contribution of reactive oxygen species to sarcopenia and muscle ageing. Exp Gerontol. 2004 Jan;39(1):17-24.

15. Yarasheski KE. Exercise, aging, and muscle protein metabolism. J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):M918-22.

16. Semba RD, Blaum C, Guralnik JM, et al. Carotenoid and vitamin E status are associated with indicators of sarcopenia among older women living in the community. Aging Clin Exp Res. 2003 Dec;15(6):482-7.

17. Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR. Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr. 2003 Aug;78(2):250-8.

18. Doherty TJ. Invited review: Aging and sarcopenia. J Appl Physiol. 2003 Oct;95(4):1717-27.

19. Vanitallie TB. Frailty in the elderly: contributions of sarcopenia and visceral protein depletion. Metabolism. 2003 Oct;52(10 Suppl 2):22-6.

20. Kamel HK, Maas D, Duthie EH, Jr. Role of hormones in the pathogenesis and management of sarcopenia. Drugs Aging. 2002;19(11):865-77.

21. Lawler JM, Barnes WS, Wu G, Song W, Demaree S. Direct antioxidant properties of creatine. Biochem Biophys Res Commun. 2002 Jan 11;290(1):47-52.

22. Ji LL. Exercise-induced modulation of antioxidant defense. Ann NY Acad Sci. 2002 Apr;959:82-92.

23. Carmeli E, Coleman R, Reznick AZ. The biochemistry of aging muscle. Exp Gerontol. 2002 Apr;37(4):477-89.

24. Welle S. Cellular and molecular basis of age-related sarcopenia. Can J Appl Physiol. 2002 Feb;27(1):19-41.

25. Lio D, Scola L, Crivello A, et al. Allele frequencies of +874T: A single nucleotide polymorphism at the first intron of interferon-gamma gene in a group of Italian centenarians. Exp Gerontol. 2002 Jan;37(2-3):315-9.

26. Bonafe M, Olivieri F, Cavallone L, et al. A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol. 2001 Aug;31(8):2357-61.

27. Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol. 2001 May;8(3):131-6.

28. Marcell TJ, Harman SM, Urban RJ, et al. Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men. Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1159-E64.

29. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001 Jun;53(2):161-76.

30. Parise G, Mihic S, MacLennan D, Yarasheski KE, Tarnopolsky MA. Effects of acute creatine monohydrate supplementation on leucine kinetics and mixed-muscle protein synthesis. J Appl Physiol. 2001 Sep;91(3):1041-7.

31. Brod SA. Unregulated inflammation shortens human functional longevity. Inflamm Res. 2000 Nov;49(11):561-70.

32. Rogers MA, Evans WJ. Changes in skeletal muscle with aging: effects of exercise training. Exerc Sport Sci Rev. 1993;21:65-102.

33. Hutter E, Renner K, Pfister G, et al. Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J. 2004 Jun 15;380(Pt 3):919-28.

34. Brose A, Parise G, Tarnopolsky MA. Creatine supplementation enhances isometric strength and body composition improvements following strength exercise training in older adults. J Gerontol A Biol Sci Med Sci. 2003 Jan;58(1):11-9.

35. Gotshalk LA, Volek JS, Staron RS, et al. Creatine supplementation improves muscular performance in older men. Med Sci Sports Exerc. 2002 Mar;34(3):537-43.

36. Candow DG, Chilibeck PD, Chad KE, et al. Effect of ceasing creatine supplementation while maintaining resistance training in older men. J Aging Phys Act. 2004 Jul;12(3):219-31.

37. Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 2004 Jan;58(1):39-46.

38. Kang D, Hamasaki N. Mitochondrial oxidative stress and mitochondrial DNA. Clin Chem Lab Med. 2003 Oct;41(10):1281-8.

39. Szibor M and Holtz J. Mitochondrial ageing. Basic Res Cardiol. 2003 Jul;98(4):210-8.

40. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood.). 2002 Oct;227(9):671-82.

41. Waters DL, Brooks WM, Qualls CR, Baumgartner RN. Skeletal muscle mitochondrial function and lean body mass in healthy exercising elderly. Mech Ageing Dev. 2003 Mar;124(3):301-9.

42. Santos RV, Bassit RA, Caperuto EC, Costa Rosa LF. The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race. Life Sci. 2004 Sep 3;75(16):1917-24.

43. Klivenyi P, Calingasan NY, Starkov A, et al. Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiol Dis. 2004 Apr;15(3):610-7.

44. Zhu S, Li M, Figueroa BE, et al. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci. 2004 Jun 30;24(26):5909-12.

45. Dedeoglu A, Kubilus JK, Yang L, et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington’s disease transgenic mice. J Neurochem. 2003 Jun;85(6):1359-67.

46. Rabchevsky AG, Sullivan PG, Fugaccia I, Scheff SW. Creatine diet supplement for spinal cord injury: influences on functional recovery and tissue sparing in rats. J Neurotrauma. 2003 Jul;20(7):659-69.

47. Adcock KH, Nedelcu J, Loenneker T, et al. Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia. Dev Neurosci. 2002;24(5):382-8.

48. Hausmann ON, Fouad K, Wallimann T, Schwab ME. Protective effects of oral creatine supplementation on spinal cord injury in rats. Spinal Cord. 2002 Sep;40(9):449-56.

49. See D, Mason S, Roshan R. Increased tumor necrosis factor alpha (TNF-alpha) and natural killer cell (NK) function using an integrative approach in late stage cancers. Immunol Invest. 2002 May;31(2):137-53.

50. Andreassen OA, Dedeoglu A, Ferrante RJ, et al. Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis. 2001 Jun;8(3):479-91.

51. Tarnopolsky MA, Beal MF. Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol. 2001 May;49(5):561-74.

52. Walter MC, Lochmuller H, Reilich P, et al. Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study. Neurology. 2000 May 9;54(9):1848-50.

53. Tarnopolsky M, Martin J. Creatine monohydrate increases strength in patients with neuromuscular disease. Neurology. 1999 Mar 10;52(4):854-7.

54. Klivenyi P, Ferrante RJ, Matthews RT, et al. Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med. 1999 Mar;5(3):347-50.

55. Matthews RT, Ferrante RJ, Klivenyi P, et al. Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol. 1999 May;157(1):142-9.

56. Matthews RT, Yang L, Jenkins BG, et al. Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. J Neurosci. 1998 Jan 1;18(1):156-63.

57. Sullivan PG, Geiger JD, Mattson MP, Scheff SW. Dietary supplement creatine protects against traumatic brain injury. Ann Neurol. 2000 Nov;48(5):723-9.

58. Rae C, Digney AL, McEwan SR, Bates TC. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial. Proc R Soc Lond B Biol Sci. 2003 Oct 22;270(1529):2147-50.

59. Marshall K. Therapeutic applications of whey protein. Altern Med Rev. 2004 Jun;9(2):136-56.

60. Bounous G. Whey protein concentrate (WPC) and glutathione modulation in cancer treatment. Anticancer Res. 2000 Nov;20(6C):4785-92.

61. Bounous G, Gold P. The biological activity of undenatured dietary whey proteins: role of glutathione. Clin Invest Med. 1991 Aug;14(4):296-309.

62. Tsai WY, Chang WH, Chen CH, Lu FJ. Enchancing effect of patented whey protein isolate (Immunocal) on cytotoxicity of an anticancer drug. Nutr Cancer. 2000;38(2):200-8.

63. Baruchel S, Viau G. In vitro selective modulation of cellular glutathione by a humanized native milk protein isolate in normal cells and rat mammary carcinoma model. Anticancer Res. 1996 May;16(3A):1095-99.

64. McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers GW. Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats. J Nutr. 1995 Apr;125(4):809-16.

65. Stumvoll M, Perriello G, Meyer C, Gerich J. Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int. 1999 Mar;55(3):778-92.

66. Walsh NP, Blannin AK, Robson PJ, Gleeson M. Glutamine, exercise and immune function. Links and possible mechanisms. Sports Med. 1998 Sep;26(3):177-91.

67. De Bandt JP, Cynober LA. Amino acids with anabolic properties. Curr Opin Clin Nutr Metab Care. 1998 May;1(3):263-72.

68. Balzola FA, Boggio-Bertinet D. The metabolic role of glutamine. Minerva Gastroenterol Dietol. 1996 Mar;42(1):17-26.

69. Roth E, Spittler A, Oehler R. Glutamine: effects on the immune system, protein balance and intestinal functions. Wien Klin Wochenschr. 1996;108(21):669-76.

70. Furst P, Albers S, Stehle P. Evidence for a nutritional need for glutamine in catabolic patients. Kidney Int Suppl. 1989 Nov;27:S287-92.

71. Available at: Accessed December 17, 2004.



Leucine is one of the branched chain amino acids, sometimes referred to as the main BCAA. It is the most potent inducer of muscle protein synthesis on a molecular level, and is ketogenic (produced ketones when metabolized)


Leucine is metabolized into one of several metabolites which may contribute to the effects of leucine. Of these, two of them are standalone supplements (HMB and HICA)

Mechanism of Action

TOR, or mammalian TOR (mTOR) is a protein complex that serves a pivotal role in regulating cellular signalling. Leucine is able to activate one of the two complexes it makes up, known as mTORc1 (c1 standing for ‘complex one’). When mTOR is mentioned in this article, it is shorthand for mTORc1 unless otherwise specified

Leucine and/or its metabolites appear to increase intracellular calcium, similar to muscle contractions, and the increase in calcium will activate proteins such as mTOR which then induce muscle protein synthesis. Unlike muscle contraction, however, leucine likely does this in all cells rather than localized to skeletal muscle

In other words: SHP-2 (currently the furthest far back in the chain) -> calcium mobilization -> hVPS34 binding to calmodulin -> mTORc1 activation (possibly via Rheb) -> S6K1 activation -> muscle protein synthesis


Hyper(aminoacid)emia is a term used to refer to an excess (hyper-) of amino acids in the blood (-emia), and similar to that hyperleucinemia refers to an excess of leucine in particular. In older men, leucine has been found to increase muscle protein synthesis independent of hyperaminoacidemia suggesting it itself is an independent predictor of muscle protein synthesis.[20]


Sirtuin proteins (SIRT being an acronym for Silent Information Regulator Transcript) are NAD+ dependent enzymes that are sensitive to a cellular NAD+/NADH ratio and thus energy status of a cell.[21] Of these, SIRT1 is a histone deacetylase that can modify signalling of the nuclear proteins p53, NF-κB and FOXO[22][23] and can induce the mitochondrial biogenesis factor PGC-1α.[24] Activation of SIRT1 (the molecule most commonly said to do this is resveratrol) is thought to be a pro-longevity mechanism.

Leucine is thought to underlie the health benefits of dairy proteins on lifespan[25][26] which have independently been shown to promote health and reduce the risk of premature death in rats.[27] Serum taken from patients consuming a dairy-rich diet has been shown in vitro to stimulte SIRT1 activity by 13% (adipose) and 43% (muscle tissue), suggesting biological plausibility.[25]

Both leucine metabolites (α-Ketoisocaproic acid and HMB) are activators of SIRT1 in the range of 30-100%, which is a comparable potency to resveratrol (2-10μM) but requires a higher concentration (0.5mM).[25] Mitochondrial biogenesis has been noted with leucine incubation in both fat and muscle cells, and abolishing SIRT1 attenuates (but does not eliminate) leucine-induced mitochondrial biogenesis.[28]

Leucine metabolites are able to stimulate SIRT1 activity, which is a mechanism thought to underlie mitochondrial biogenesis. It is actually moderately potent at doing so

Glucose Uptake

Leucine appears to initially promote glucose uptake into muscle cells for about 45 minutes, and then cuts itself off which reduces overall effects somewhat. The ‘cut off’ is a negative feedback that normally occurs after mTOR activation. Isoleucine is better than leucine at promoting glucose uptake due to less activation of mTOR

Insulin Secretion

Leucine is known to stimulate insulin secretion from the pancreas, and appears to be the most potent BCAA at doing this. On a equimolar basis (same concentration of the molecule within a cell), leucine is approximately as potent as yohimbine but about two-thirds as potent as glucose itself

Leucine works via two pathways to stimulate insulin secretion from pancreatic beta-cells, but the major pathway appears to be due to reducing the influence of a negative regulator (α2A receptors). Reducing a negative regulator’s influence causes a refractory increase in activity

Skeletal Muscle and Physical Performance

Protein Synthesis

Leucine is able to stimulate mTOR activity and its subsequent protein synthesis signalling. Although Akt/PKB positively influences mTOR activity (so when Akt is activated, it activates mTOR) leucine appears to work via a different pathway and activate mTOR without affecting Akt. Regardless, anything that activates mTOR will then activate p70S6K and then promote muscle protein synthesis


Leucine is known to promote muscle protein synthesis at low concentrations in vitro while requiring higher concentrations to attenuate atrophy, despite synthesis rates plateuing.[75] This muscle preserving effect has been noted in disease states characterized by muscular wasting such as cancer[76] as well as sepsis, burns, and trauma.[77] In these scenarios the benefits appear to be dose-dependent.


Hyperaminoacidemia is a term used to refer to an excess (hyper-) of amino acids in the blood (-emia), and similar to that hyperleucinemia refers to an excess of leucine in particular.

In older men, leucine has been found to increase muscle protein synthesis independent of hyperaminoacidemia.[20]


Sarcopenia is characterized by a decrease in skeletal muscle mass protein content and an increase in skeletal muscle fat content that occurs with aging. One of the reasons as to why sarcopenia may occur is due to a decrease in the metabolic response to L-Leucine’s muscle preserving effects that occurs with cellular aging[79]. This effect can be negated in part by the addition of L-Leucine to protein containing foods.[80][81][82]

Nutrient-Nutrient Interactions


Leucine appears to be synergistic with dietary carbohydrate in promoting insulin secretion from the pancreas, and appears to be synergistic with insulin in promoting muscle protein synthesis


Resveratrol and leucine both appear to positively influence mitochondrial biogenesis via SIRT1 activation, and they both appear synergistic in doing so when incubated or ingested together


Citrulline may positively mediate leucine’s signalling through mTOR, which theoretically suggests that they are synergistic. The application of the combination towards weight lifters has not yet been investigated, so the synergism is currently just a hypothesis rather than a demonstrated fact

Safety and Toxicity

In a small study in 5 healthy men given graded leucine intake up to 1,250mg/kg (25-fold the estimated average requirement) noted that oral doses of 500-1,250 caused increases in serum ammonia and due to this the upper limited was said to be established at 500mg/kg (for a 150lb human, 34g).[93]

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