Life Extension Magazine September 2006
Why Aging Humans Need More Carnitine
By Julius G. Goepp, MD
Propionyl-L-Carnitine Enhances Muscle Energy
Another advanced carnitine formulation, known as propionyl-L-carnitine, is gaining increasing recognition for its role in increasing muscle energy.
Evidence of Targeted Cardiovascular Effects
Because of carnitine’s impact on both muscle and energy utilization, it is an ideal supplement to improve one of the body’s most important muscles—the heart.
Scientists have looked at numerous applications of propionyl-L-carnitine for cardiac health. Scientists believe that propionyl-L-carnitine appears to work by protecting heart muscle cells from damage caused by lack of blood flow (ischemia) and the subsequent free radical damage that can occur following restoration of blood flow (reperfusion).39-43 Propionyl-L-carnitine quickly penetrates into heart muscle cells,43 an effect thought to account for its superiority in supporting heart muscle recovery following a heart attack (myocardial infarction).3,44 In animal models of heart attack, propionyl-L-carnitine not only prevented tissue damage related to lack of blood flow (ischemia), but also prevented further progression of existing damage.45 Propionyl-L-carnitine’s antioxidant effects46 have been shown to protect animal tissues from damage related to hypertension, another source of danger to the cardiovascular system.47
This impressive animal data prompted researchers to explore propionyl-L-carnitine’s potential benefits in managing heart disease in humans.48 An early study demonstrated that intravenous administration of propionyl-L-carnitine in a small group of patients with chronic ischemic heart disease improved the heart’s left ventricular function by enhancing cardiac muscle efficiency.49 In a separate study, propionyl-L-carnitine greatly improved exercise tolerance in those with stable chest pain, without contributing to changes in heart rate or blood pressure.50
Because of the increased vulnerability of diabetics’ hearts to injury, researchers in 2005 examined the effects of propionyl-L-carnitine on chemical markers of heart muscle blood flow during coronary surgery.51 The study authors concluded that propionyl-L-carnitine improved multiple aspects of heart function during surgery, through mechanisms affecting metabolism and blood vessel function. These findings have important implications for protecting heart health in at-risk groups, such as people who have diabetes or require cardiac surgery.
Beneficial Actions in Skeletal Muscle
Propionyl-L-carnitine has important effects on skeletal as well as cardiac muscle. As early as 1990, a human study demonstrated that propionyl-L-carnitine could combat the destructive effects of low oxygen status and muscle fatigue.52 By 1997, propionyl-L-carnitine was found to contribute to the body’s ability to increase muscle glycogen stores.53 Since glycogen is the body’s most immediately available form of glucose energy storage, this observation likely explains propionyl-L-carnitine’s fatigue-reducing effects.
In peripheral arterial disease, plaque-filled arteries reduce blood flow to the muscles, resulting in pain and cramping in the legs with activity. However, very recent studies of propionyl-L-carnitine in this context have shed new light on the phenomenon of peripheral arterial disease. An article published in 2004 points out that the pain of peripheral arterial disease can also be caused by alterations in skeletal muscle metabolism.54 The authors note that propionyl-L-carnitine helped increase treadmill walking distance and may improve the metabolic performance of the skeletal muscles in these patients.
Success in Fighting Sexual Dysfunction
Both propionyl-L-carnitine and acetyl-L-carnitine can help men with sexual dysfunction. In one study, scientists looked at a group of diabetic men suffering from erectile dysfunction. They found that men who took propionyl-L-carnitine plus Viagra® showed significant measurable improvements compared to men who took only Viagra®.55
In a related study of sexual dysfunction in aging males, researchers gave patients testosterone, a combination of acetyl-L-carnitine and propionyl-L-carnitine, or placebo.While both testosterone and the carnitine combination notably improved penile blood flow and night-time erections, as well as the International Index of Erectile Dysfunction, depression, and fatigue scores, the carnitine combination outperformed testosterone on measures of erectile function.56 The authors concluded that the carnitine combination was especially useful in managing sexual dysfunction as well as other symptoms associated with male aging.
One of the most dreaded aspects of prostate surgery is the potential side effect of erectile dysfunction. The same investigators mentioned above also examined the effects of propionyl-L-carnitine and acetyl-L-carnitine in restoring sexual function after radical prostate surgery. They concluded that the combination of propionyl-L-carnitine and acetyl-L-carnitine safely and reliably augmented Viagra®’s effectiveness in restoring sexual function following prostate surgery.57
Acetyl-L-Carnitine Arginate May Halt Brain Aging
Acetyl-L-carnitine arginate—which is simply acetyl-L-carnitine with an additional molecule of arginine attached—may be the most important of all forms of carnitine in preventing age-related disease. This addition of arginine appears to give the molecule privileged access to nerve cells, priming them for the effects of nerve growth factor and other factors important in the development and function of nerve cells.58,59
Acetyl-L-carnitine alone is known to be neuroprotective, reducing the rate of nerve cell death in cultured cells exposed to some of the neurotoxic agents that are important in the development of Alzheimer’s disease.16 The observation that acetyl-L-carnitine makes cultured nerve cells much more sensitive to the effects of nerve growth factor,60,61 thereby rescuing them from the effects of aging, led scientists to seek out other compounds with this remarkable capability. What they found was that acetyl-L-carnitine arginate produced rapid differentiation of early brain cells into mature neurons, while increasing the cells’ content of GABA, an important neurotransmitter.62
A subsequent study demonstrated that acetyl-L-carnitine arginate increased the availability of crucial calcium channels in nerve cells by a factor of more than four—even more than the increase produced by nerve growth factor itself.59 This means that acetyl-L-carnitine arginate not only enhances the growth of nerve cells, but also increases their ability to respond to calcium ions in performing their primary function of transmitting electrical signals. A later study showed that acetyl-L-carnitine arginate’s effect on calcium channels was responsible for the supplement’s ability to rescue nerve cells in culture from the toxic effects of amyloid beta peptide, which is thought to play a role in Alzheimer’s disease.63
In 1995, researchers published the remarkable finding that acetyl-L-carnitine arginate stimulated the outgrowth of neurites, the minute projections from nerve cell bodies that lead to new connections (synapses) between cells and allow increased signaling throughout the central nervous system (comprising the brain and spinal cord).64 Aging in the central nervous system involves a loss of neurons and a reduction in the number of synapses between the surviving cells, possibly as a result of declining levels of nerve growth factor.64
The research group’s insight was connecting acetyl-L-carnitine’s effects in stimulating nerve growth factor activity with acetyl-L-carnitine arginate’s ability to increase cell survival. Their experiment demonstrated that acetyl-L-carnitine arginate increased neurite outgrowth and did it independently of common growth factors—meaning that it might actually be capable of replacing, and not just augmenting, nerve growth factor in the aging brain.64 Acetyl-L-carnitine arginate may thus be a key component of a therapeutic strategy to avert the neurodegenerative diseases of aging.
The discovery of carnitine’s ability to maximize cellular fuel efficiency while minimizing the wear and tear on delicate cellular machinery has led to a revolution in the way scientists think about some of the most troubling age-related conditions.
The recognition that several advanced formulations of carnitine—including acetyl-L-carnitine, propionyl-L-carnitine, and acetyl-L-carnitine arginate—have very different and complementary effects opens the door to “customized” supplementation regimens, in which individuals can choose the types of carnitine that are most beneficial in addressing their unique health concerns.
1. Retter AS. Carnitine and its role in cardiovascular disease. Heart Dis. 1999 May;1(2):108-13.
2. Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA. 2002 Feb 19;99(4):1870-5.
3. Cui J, Das DK, Bertelli A, Tosaki A. Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts. Mol Cell Biochem. 2003 Dec;254(1-2):227-34.
4. Bruno G, Scaccianoce S, Bonamini M, et al. Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides. Alzheimer Dis Assoc Disord. 1995;9(3):128-31.
5. Gorini A, D’Angelo A, Villa RF. Energy metabolism of synaptosomal subpopulations from different neuronal systems of rat hippocampus: effect of L-acetylcarnitine administration in vivo. Neurochem Res. 1999 May;24(5):617-24.
6. Hagen TM, Yowe DL, Bartholomew JC, et al. Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci USA. 1997 Apr 1;94(7):3064-9.
7. Hagen TM, Wehr CM, Ames BN. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-carnitine and N-tert-butyl-alpha-phenyl-nitrone. Ann NY Acad Sci. 1998 Nov 20;854:214-23.
8. Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.
9. Han D, Handelman G, Marcocci L, et al. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors. 1997;6(3):321-38.
10. Burlina AP, Sershen H, Debler EA, Lajtha A. Uptake of acetyl-L-carnitine in the brain. Neurochem Res. 1989 May;14(5):489-93.
11. Inano A, Sai Y, Nikaido H, et al. Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2. Biopharm Drug Dispos. 2003 Nov;24(8):357-65.
12. Mecocci P, Beal MF, Cecchetti R, et al. Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain. Mol Chem Neuropathol. 1997 May;31(1):53-64.
13. Foreman PJ, Perez-Polo JR, Angelucci L, Ramacci MT, Taglialatela G. Effects of acetyl-L-carnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):117-33.
14. Manfridi A, Forloni GL, rrigoni-Martelli E, Mancia M. Culture of dorsal root ganglion neurons from aged rats: effects of acetyl-L-carnitine and NGF. Int J Dev Neurosci. 1992 Aug;10(4):321-9.
15. Abdul HM, Calabrese V, Calvani M, Butterfield DA. Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: Implications for Alzheimer’s disease. J Neurosci Res. 2006 Apr 21.
16. Dhitavat S, Ortiz D, Shea TB, Rivera ER. Acetyl-L-carnitine protects against amyloid-beta neurotoxicity: roles of oxidative buffering and ATP levels. Neurochem Res. 2002 Jun;27(6):501-5.
17. Forloni G, Angeretti N, Smiroldo S. Neuroprotective activity of acetyl-L-carnitine: studies in vitro. J Neurosci Res. 1994 Jan;37(1):92-6.
18. Brooks JO, III, Yesavage JA, Carta A, Bravi D. Acetyl L-carnitine slows decline in younger patients with Alzheimer’s disease: a reanalysis of a double-blind, placebo-controlled study using the trilinear approach. Int Psychogeriatr. 1998 Jun;10(2):193-203.
19. Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer’s disease. Neurobiol Aging. 1995 Jan;16(1):1-4.
20. Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-carnitine in Alzheimer’s disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin. 2003;19(4):350-3.
21. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003 Mar;18(2):61-71.
22. Pettegrew JW, Levine J, Gershon S, et al. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord. 2002 Feb;4(1):61-6.
23. Cruciani RA, Dvorkin E, Homel P, et al. L-carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: a preliminary analysis. Ann NY Acad Sci. 2004 Nov;1033:168-76.
24. Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-L-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol. 2006 May;16(4):281-7.
25. Tomassini V, Pozzilli C, Onesti E,et al. Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci. 2004 Mar 15;218(1-2):103-8.
26. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar;66(2):276-82.
27. Bianchi G, Vitali G, Caraceni A, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer. 2005 Aug;41(12):1746-50.
28. Moyle GJ, Sadler M. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf. 1998 Dec;19(6):481-94.
29. Pisano C, Pratesi G, Laccabue D, et al. Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clin Cancer Res. 2003 Nov 15;9(15):5756-67.
30. Maestri A, De Pasquale CA, Cundari S, et al. A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy. Tumori. 2005 Mar;91(2):135-8.
31. Ghirardi O, Lo GP, Pisano C, et al. Acetyl-L-Carnitine prevents and reverts experimental chronic neurotoxicity induced by oxaliplatin, without altering its antitumor properties. Anticancer Res. 2005 Jul;25(4):2681-7.
32. Hart AM, Wilson AD, Montovani C, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 2004 Jul 23;18(11):1549-60.
33. Osio M, Muscia F, Zampini L, et al. Acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in human immunodeficiency virus patients: an open label study. J Peripher Nerv Syst. 2006 Mar;11(1):72-6.
34. Raccah D. Physiopathology of diabetic neuropathies. Functional exploration of peripheral involvement. Diabetes Metab. 1998 Nov;24 Suppl 3:73-8.
35. De GD, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3(4):223-31.
36. Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94.
37. Hart AM, Wiberg M, Youle M, Terenghi G. Systemic acetyl-L-carnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma. Exp Brain Res. 2002 Jul;145(2):182-9.
38. Feher J, Papale A, Mannino G, Gualdi L, Balacco GC. Mitotropic compounds for the treatment of age-related macular degeneration. The metabolic approach and a pilot study. Ophthalmologica. 2003 Sep;217(5):351-7.
39. Hotta N, Koh N, Sakakibara F, et al. Effect of propionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocin-induced diabetes: comparison with an aldose reductase inhibitor. J Pharmacol Exp Ther. 1996 Jan;276(1):49-55.
40. Hotta N, Koh N, Sakakibara F, et al. Effects of propionyl-L-carnitine and insulin on the electroretinogram, nerve conduction and nerve blood flow in rats with streptozotocin-induced diabetes. Pflugers Arch. 1996 Feb;431(4):564-70.
41. Micheletti R, Giacalone G, Bianchi G. Effect of propionyl-L-carnitine on the mechanics of right and left papillary muscles from volume-overloaded rat hearts. J Cardiovasc Pharmacol. 1996 Jan;27(1):52-7.
42. Shug A, Paulson D, Subramanian R, Regitz V. Protective effects of propionyl-L-carnitine during ischemia and reperfusion. Cardiovasc Drugs Ther. 1991 Feb;5 Suppl 1:77-83.
43. Lango R, Smolenski RT, Narkiewicz M, Suchorzewska J, Lysiak-Szydlowska W. Influence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass. Cardiovasc Res. 2001 Jul;51(1):21-9.
44. Broderick TL, Driedzic W, Paulson DJ. Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat. Mol Cell Biochem. 2000 Mar;206(1-2):151-7.
45. Sethi R, Wang X, Ferrari R, Dhalla NS. Improvement of cardiac function and beta-adrenergic signal transduction by propionyl L-carnitine in congestive heart failure due to myocardial infarction. Coron Artery Dis. 2004 Feb;15(1):65-71.
46. El Alaoui-Talibi Z, Guendouz A, Moravec M, Moravec J. Control of oxidative metabolism in volume-overloaded rat hearts: effect of propionyl-L-carnitine. Am J Physiol. 1997 Apr;272(4 Pt 2):H1615-24.
47. Gomez-Amores L, Mate A, Revilla E, Santa-Maria C, Vazquez CM. Antioxidant activity of propionyl-L-carnitine in liver and heart of spontaneously hypertensive rats. Life Sci. 2006 Mar 20;78(17):1945-52.
48. Ferrari R, De GF. The propionyl-L-carnitine hypothesis: an alternative approach to treating heart failure. J Card Fail. 1997 Sep;3(3):217-24.
49. Chiddo A, Gaglione A, Musci S, et al. Hemodynamic study of intravenous propionyl-L-carnitine in patients with ischemic heart disease and normal left ventricular function. Cardiovasc Drugs Ther. 1991 Feb;5 Suppl 1:107-11.
50. Lagioia R, Scrutinio D, Mangini SG, et al. Propionyl-L-carnitine: a new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol. 1992 Feb;34(2):167-72.
51. Lango R, Smolenski RT, Rogowski J, et al. Propionyl-L-carnitine improves hemodynamics and metabolic markers of cardiac perfusion during coronary surgery in diabetic patients. Cardiovasc Drugs Ther. 2005 Aug;19(4):267-75.
52. Corbucci GG, Montanari G, Mancinelli G, D’Iddio S. Metabolic effects induced by L-carnitine and propionyl-L-carnitine in human hypoxic muscle tissue during exercise. Int J Clin Pharmacol Res. 1990;10(3):197-202.
53. Brevetti G, Fanin M, De A, V, et al. Changes in skeletal muscle histology and metabolism in patients undergoing exercise deconditioning: effect of propionyl-L-carnitine. Muscle Nerve. 1997 Sep;20(9):1115-20.
54. Hiatt WR. Carnitine and peripheral arterial disease. Ann NY Acad Sci. 2004 Nov;1033:92-8.
55. Gentile V, Vicini P, Prigiotti G, Koverech A, Di SF. Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes. Curr Med Res Opin. 2004 Sep;20(9):1377-84.
56. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004 Apr;63(4):641-6.
57. Cavallini G, Modenini F, Vitali G, Koverech A. Acetyl-L-carnitine plus propionyl-L-carnitine improve efficacy of sildenafil in treatment of erectile dysfunction after bilateral nerve-sparing radical retropubic prostatectomy. Urology. 2005 Nov;66(5):1080-5.
58. Rampello L, Giammona G, Aleppo G, Favit A, Fiore L. Trophic action of acetyl-L-carnitine in neuronal cultures. Acta Neurol (Napoli). 1992 Feb;14(1):15-21.
59. Tewari K, Simard JM, Peng YB, Werrbach-Perez K, Perez-Polo JR. Acetyl-L-carnitine arginyl amide (ST857) increases calcium channel density in rat pheochromocytoma (PC12) cells. J Neurosci Res. 1995 Feb 15;40(3):371-8.
60. Taglialatela G, Angelucci L, Ramacci MT, et al. Acetyl-L-carnitine enhances the response of PC12 cells to nerve growth factor. Brain Res Dev Brain Res. 1991 Apr 24;59(2):221-30.
61. Taglialatela G, Angelucci L, Ramacci MT, et al. Stimulation of nerve growth factor receptors in PC12 by acetyl-L-carnitine. Biochem Pharmacol. 1992 Aug 4;44(3):577-85.
62. Westlund KN, Lu Y, Werrbach-Perez K, et al. Effects of nerve growth factor and acetyl-L-carnitine arginyl amide on the human neuronal line HCN-1A. Int J Dev Neurosci. 1992 Oct;10(5):361-73.
63. Scorziello A, Meucci O, Calvani M, Schettini G. Acetyl-L-carnitine arginine amide prevents beta 25-35-induced neurotoxicity in cerebellar granule cells. Neurochem Res. 1997 Mar;22(3):257-
64. Taglialatela G, Navarra D, Olivi A, et al. Neurite outgrowth in PC12 cells stimulated by acetyl-L-carnitine arginine amide. Neurochem Res. 1995 Jan;20(1):1-9.