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Carnitine

Carnitine, also known as L-carnitine is an amino acid responsible for transport of fatty acids into a cell's mitochondria. It is often sold as a nutritional supplement. more...

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Like all other proteinogenic amino acids natural carnitine is the L-stereoisomer. It can be synthesised within the body from the amino acids lysine or methionine. Vitamin C (ascorbic acid) is essential to the synthesis of carnitine. It has been speculated that during growth or pregnancy the requirement of carnitine could exceed its natural production.

Role in fatty acid metabolism

Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs. This process occurs in two steps:

The formula for the above is:
RCOO- + CoA + ATP + H2O → RCO-CoA + AMP + PPi + 2H+
This reaction is reversible and its equilibrium lies near 1. However, pyrophosphate is hydrolized by a pyrophosphatase, which drives the reaction forward, and to completion.

Once activated, the acyl CoA is transported into the mitochondrial matrix. This occurs via a series of similar steps:

  1. Acyl CoA is conjugated to carnitine by carnitine acyltransferase I located on the outer mitochondrial membrane
  2. Acyl carnitine is shuttled inside by a translocase
  3. Acyl carnitine is converted to acyl CoA by carnitine acyltransferase II located on the inner mitochondrial membrane

It is important to note that carnitine acyltransferase I undergoes allosteric inhibition as a result of malonyl CoA, an intermediate in fatty acid biosynthesis.

Natural sources

The best source of natural carnitine is in red meat and dairy products. Other natural sources of Carnitine include nuts and seeds (e.g pumpkin, sunflower, sesame), legumes or pulses (beans, peas, lentils, peanuts), vegetables (artichokes, asparagus, beet greens, broccoli, brussels sprouts, collard greens, garlic, mustard greens, okra, parsley), fruits (apricots, bananas), cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other 'health' foods (bee pollen, brewer's yeast, carob, kale).

Acetyl-L-carnitine

section references:

Acetyl-L-carnitine or ALCAR, is an acetylated form of L-carnitine. ALCAR is far superior to normal L-carnitine in terms of bioavailability in that it is absorbed by the gastrointestinal tract, enters cells and crosses the blood-brain barrier more readily than unacetylated carnitine.

ALCAR has a broad range of uses including combination with alpha lipoic acid to comprise a patented formulation that has been evidenced to "rejuvenate" the mitochondria of aging mice in studies conducted by Bruce Ames and others. Accordingly, acetyl-L-carnitine has potential as a life extension supplement probably capable of improving the quality and possibily also extending the average life-span of humans. Other attributed uses for ALCAR include using it as a treatment for depression (250 mg per day for several weeks) and for clearing plaque/fatty deposits out of the veins and arteries.

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The clinical benefits of Acetyl-L-Carnitine
From Townsend Letter for Doctors and Patients, 8/1/02 by Robert Crayhon

Nutrition can play an important role in promoting brain wellness. The older we are, the more likely we are to suffer from cognitive loss. While some survive into their sixth and seventh decades with good mental function, this becomes less likely as we age further. Decline is almost universal in at least one cognitive area among those over 85. (1) Are there nutrient strategies that can slow or even prevent this decline?

Certain nutrients have also undergone examination for their role in promoting brain health in older adults. One of the most extensively researched nutrients for its role in promoting brain wellness is Acetyl-L-Carnitine (ALCAR). ALCAR has demonstrated marked positive effects on brain aging, both from a preventive and therapeutic standpoint.

ALCAR is the O-acetylated form of the fatty acyl ester L-carnitine. ALCAR benefits mitochondrial efficiency and functions as an antioxidant within the mitochondria, helping neurons maintain maximal energy levels. ALCAR increases acetylcholine levels in the brain, one of the main neurotransmitters needed for learning and memory. Acetylcholine is the main neurotransmitter deficiency that occurs with age. There is also a great deal of evidence that age-related memory loss is cholinergic in nature. Therefore, maintaining healthy acetylcholine levels must be the centerpiece of any brain antiaging strategy. ALCAR levels decline markedly as we age, even in healthy adults. (2) Restoring ALCAR levels to those seen in twenty-year olds may be desirable for older adults. Declining ALCAR levels may in fact be one of the causes of the cognitive decline seen with aging.

Optimizing Neuronal Energy

For brain longevity, it is essential that neurons maintain a constant supply of energy to protect against cell loss. ALCAR maximizes neuronal energy production, (3,4) and regenerates mitochondrial function, especially cellular respiration, mitochondrial membrane potential, and cardiolipin levels. (5)

Brain Protector

ALCAR significantly reduces the amounts of damaged fats such as lipofuscin as the brain ages, a sign that ALCAR is slowing brain aging. (6) Double-blinded studies in humans show that ALCAR also protects against such ischemia-induced free radical damage to neurons. (7,8) Brain levels of ALCAR often determine how many cells survive an ischemic event. (9) ALCAR also acts as an antioxidant through its ability to naturally raise production as well as release of the free radical scavenger melatonin. (10,11)

Antioxidant levels in the substantia nigra decline with age, (12) increasing risk of damage to the dopanergic neurons in this region of the brain. ALCAR increases levels of glutathione in the neurons of the substantia nigra, which suggests that ALCAR may help protect and be useful in the prevention and perhaps the treatment of Parkinson's disease. (13) ALCAR has been found to protect against MPTP induced Parkinsonism in primates (14) and may protect against Parkinson's in humans. (15)

Increasing Molecules Needed for Memory

ALCAR increases levels of nerve growth factor (NGF)--an important brain healing compound. In the central nervous system, nerve growth factor (NGF) protects cholinergic neurons. NGF helps increase levels of choline acetyltransferase (ChAT), which makes the valuable neurotransmitter acetylcholine. The aging process reduces both nerve growth factor levels and the ability of neurons to bind to this valuable cellular messenger. ALCAR ameliorates these age-related deficits, therefore demonstrating another way it naturally helps create more acetylcholine needed for neuronal transmission, learning, and recall. (16) ALCAR has been found to optimize the response of the NMDA receptors and lessen their decline in number. (17,18)

Treating Depression

Research has shown that ALCAR is one of the most valuable compounds for relieving depression, (19,20) especially in older adults. (21) The usual dose used is 3 g/day. (22)

Reversing Senility

There are over 30 studies which show that ALCAR slows or prevents age related decline in mental function. (23) 1.5 g/day of ALCAR given to 236 older adults for 45 days significantly increased the effectiveness of performance on all the measures of cognitive functioning, memory performance, and constructional thinking. (24) Twenty adults given 1.5 g of ALCAR per day showed that it reversed many of the signs of aging. Cognitive ability, depression, behavioral and self-sufficiency performances and quality of life all improved. (21) Studies of 40 senile patients given 1.5 g/day of ALCAR for 40 days (25) and of 481 subjects given 2 g for 150 days showed similar results. (26) Two g/day of ALCAR enhances learning in older adults. (27,28) ALCAR also improves directional and word memory after only a few weeks of treatment. (29)

Speeding Stroke Recovery

One-hundred sixty patients who had had a stroke a year or more ago were given 1.5 g ALCAR each day orally for eight weeks. This caused a marked degree of functional recovery, as well as improved mood and attention conditions. (30) Twenty patients with chronic cerebrovascular disease who suffered an ischemic stroke at least 6 months before were given a single 1.5 g dose of ALCAR intravenously, leading to acutely enhanced cerebral blood flow. (31)

Slowing Alzheimer's

Thirty AD patients given 2.5-3 g/day ALCAR for 6 months achieved less mental deterioration according to a wide range of mental function tests. (32) One year treatment with ALCAR in 130 patients with AD led to a slower rate of deterioration in 13 of the 14 outcome measures. (33) Two g of ALCAR given to 20 AD patients for 24-weeks enhanced short term memory. (34)

Research shows that AD subjects under 65 may benefit the most from ALCAR. A study of 334 subjects diagnosed with AD showed that ALCAR slows the progression of AD, particularly in younger subjects. (35) Another 1-year, double-blinded study using 3 g/day of ALCAR or placebo for 12 months in 358 patients showed ALCAR slows the decline of early-onset AD patients aged 65 or younger. (38)

ALCAR has also been found useful in enhancing visual memory and attention in Down's syndrome patients. (37) This is a group at increased risk to AD, and lifelong supplementation of ALCAR may be of particular benefit to them.

Two placebo controlled trials showed ALCAR improves mental parameters in patients with organic brain syndrome after only eight weeks. (38) Alcoholics with cognitive impairment also benefit from ALCAR. (39)

Healing Physically Damaged Neurons

Animal models of sciatic nerve injury show that ALCAR dramatically increases the speed of nerve healing and prevents loss of nerve function. (40) ALCAR should be considered in all cases where physical injury to neurons occurs, including brain injuries. (41)

In summary, ALCAR has proven itself safe and effective in ameliorating the symptoms of cognitive loss in older adults, relieving depression, speeding stroke recovery, and slowing the progression of Alzheimer's disease. What are now needed are prospective, randomized trials of ALCAR in subjects who take it from middle age onward to see if ALCAR can prevent the cognitive loss in healthy adults.

Benefits of Acetyl-L-Carnitine

* Protects and Enhances Mitochondrial Function (16)

* Enhances Immune Function and IGF-1 levels (17)

* Protects against the loss and reduction in axonal transport of substance P (18)

* Reduces HPA axis hyperactivity (19)

* Increases hippocampal synaptic contact zones (20)

* Protects against stress-induced neuroendocrine changes (21)

* Enhances long-term memory (22)

* Increases learning capacity (23)

* Prevents age-related memory deterioration (24)

* Helps maintain a normal number of both axosomatic synapses and giant bouton vesicles (25)

* Increases membrane fluidity and counters the increase in membrane viscosity seen both in aging and in neuronal lipid peroxidation (26)

* Protects cell membranes from physical stress (27)

* Reduces lipofuscin accumulation in neurons (28)

* Helps neurons remain energetic by using alternate energy sources such as lipids and ketones (29)

* Increases the efficiency of neuronal transmission (30)

* Protects against ischemia/reperfusion induced cellular damage (31) and lowers lactic acid levels and speeds recovery from ischemic events (32)

* Protects neuronal RNA from damage (33)

* Helps maintain cholinergic transmission between neurons (34)

* Protects against DNA breakage (36)

References

(1.) Korten AE, Henderson AS, Christensen H, Jorm AF, Rodgers B, Jacomb P, Mackinnon AJ. A prospective study of cognitive function in the elderly. Psychol Med 27 (4): 919-30, 1997.

(2.) Costell M, O'Connor JE, Grisolia S. Age-dependent decrease at carnitine content in muscle at mice and humans. Biochem Biophys Res Commun 161 (3): 1135-43, 1989.

(3.) Gadaleta MN, Corrnio A. Pesce V, Lezza AM, Cantatore P. Aging and mitochondria. Biochimie 80 (10): 803-70, 1998.

(4.) Carla A, Calvani M, Bravi D, Bhuachalla SN. Acetyl-L-camitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere. Ann N Y Acad Sci 695:324-6, 1993.

(5.) Hagen TM, Wehr CM, Ames BN. Mitochondrial decay in aging. Reversal through supplementation of acetyl-L-camitine and N-tert-butyl-alpha-phenyl-nitrone.Ann N Y Acad Sci 854:214-23, 1998.

(6.) Ramacci MT, De Rossi M, Lucreziotti MR, Mione MC, Amenta F. Effect of long-term treatment with acetyl-L-carnitine on structural changes of ageing rat brain. Drugs Exp Clin Rex 14 (9): 593-601. 1988.

(7.) Calvani M, Anigoni-Martelli E. Attenuation by acetyl-L-camiline of neurological damage and biochemical derangement following brain schemia and reperfusion. Int J clin React 21(1): 1-6. 1999.

(8.) Gaspamtto A, Corbucci GG, De Blasi RA, Antonelli M, Bagiella E, D'Iddio S, Trevisani C. Influence of acetyl-carnitine infusion on haemodynamic parameters and survival of circulatory-shock patients. Int J Clin Pharmacol flea 11(2):83-92, 1991.

(9.) Corbucci GG, Melis A. Piga M, Marchionni A, Calvani M. Influence of acetyl-camitine on some mitochondrial enzymic activities in the human cerebral tissue in conditions of acute hypoxia. Int J Issue React 14(4): 183-94, 1992.

(10.) Fraschini F, Esposti D, Demartini G, Scaglione F, Lucini V. Mariani M, Stankow B, Mends M. In vivo and in vitro studies on modulation of the pineal endocrine function by L-acetyl-camitine in the rat. Psychoneuroendocrinology 16(5):417-22,1991.

(11.) Esposti D, Mariani M, Demartini G, Lucini V. Frsschini F, Mancia M. Modulation of melatonin secretion by acetyl-L-camitine in adult & old rats. J Pineal Res 17(3):132-6, 1004.

(12.) Fariello RG. Peroxidative stress and cerebral aging. Int J Clin Pharmacol Res 10(1-2):49-51. 1990.

(13.) Fariello RG, Ferraro TN, Golden GT, DeMattel M. Systemic acetyl-L-camitine elevates nigral levels of glutathione and GABA. Life Sci 43(3):289-92. 1988.

(14.) Bodis-Wollner I, Chung E, Ghilardi MF, Glover A, Onofrj M, Pasik P. Samson V. Acetyl-levo-carnitine protects against MPTP-induced parkinsonism in primates. J Neural Transm Park Dis Dement Sect3(1):63-72, 1891.

(15.) Puca FM. Genco S, Specchio LM, Brancasi B, D'Ursi R, Prudenzano A, Miccoli A, Scarcia R, Martino R, Savarese M. Clinical pharmscodynamics of acetyl-L-carnitine in patients with Parkinson's disease. Intl Clin Pharmacol Res 10 (1-2): 129-43. 1990.

(16.) Angetucci L, Ramacci MT. Tagilalatela G, Hulsebosch C, Morgan B, Werrbach-Perez K, Ferns-Polo R. Nerve growth factor binding in aged rat central nervous system: effect of acetyl-L-camiline. J Nesrusci Res 20(4):491-6, 1988.

(17.) Castorina M, Ambrosini AM, Giuliani A, Pacifici L, Ramacci MT. Angelucci L A cluster analysis study of acetyl-L-carmitine effect on NMDA receptors in aging. Exp Gerontol 28(6):537-48, 1993.

(18.) Castornia M, Ambrosini AM, Pacific L. Ramacci MT, Angetucci L Age-dependent loan of NMDA receptors in hippocampus, striatum, and frontal cones of the rat: prevention by acetyl-L-camitine. Neurochem Res 19(7):795-8 1994.

(19.) Tempesta E, Casella L. Pirrongelli C, Janiri L, Calvani M, Ancona L. L-acetyl-carnitine in depressed elderly subjects. A cross-over study vs placebo. Drugs. Exp Clin Res 13(7):417-3,1987.

(20.) Garzya G, Corallo D, Flare A, Lecciso G. Petrelli G, Zotti C. Evaluation of the effects of L-acetylcamitine on senile patients suffering from depression. Drugs Exp Clin Res 16(2):101-6, 1990.

(21.) Guarsanchelli C, Fugazza G, Pistarini C. Pathological brain ageing: evaluation of the efficacy of a pharmacological aid. Drugs Exp Clin Res 14(11):715-9, 1988.

(22.) Bella R, Biondi R, Raffaele R, Pennisi G. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res 10(6): 355-60, 1990.

(23.) Dowson JH, Wilton-Cox H, Calrns MR. Ramacci MT. The morphology of lipopigment in rat Purkinje neurons after chronic acetyl-L-camitine administration: a reduction in aging-related changes. Biol Psychiatry 32(2):179-87, 1992.

(24.) Cipolli C, Chiari G. [Effects of L-acetylcamitine on mental deterioration in the aged: initial results]. Clin Ter 132(6 Suppl): 479-510, 1990.

(25.) Bonavita E. Study of the efficacy and tolerability of L-acetylcamitine therapy in the senile brain. Int J Clin Pharmacol Ther Toxicol 24(9):511-6. 1986.

(26.) Salvioli G, Neri M. L-acetylcamitine treatment of mental decline in the elderly. Drugs Exp Clin Res 20 (4): 169-76, 1994.

(27.) Herrmann WM, Stephan K. Efficacy and clinical relevance of cognition enhancers. Alzheimer Dis Assoc Disord 5(Suppl 1): S7-12, 1991.

(28.) Passerl M, Cucinotta D, Bonati PA, lannuccelli M, Parnetti L, Senin U. Acetyl-L-camitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res 10(1-2): 75-9, 1990.

(29.) Arrigo A, Casale R, Buonocore M, Clano C. Effects of acetyl-L-camitine on reaction times in patients with cerebrovascular insufficiency. Int J Clin Pharmacol Res 10(1-2): 133-7. 1990.

(30.) Patti F, Marano P. Cappello S. Effects of L-Acetylcarnitine on functional recovery of hemiplegic patients. Clin Trials J 25 (Supp 1): 87-101, 1988.

(31.) Postiglione A, Soricelli A, Cicerano U, Mansi L, De Chiara S. Gallotta G, Schettini G, Salvatore M. Effect of acute administration of L-acetyl carnitine on cerebral blood flow in patients with chronic cerebral infarct. Pharmacol Res 23(3): 241-6, 1991.

(32.) Sano M, Bell K, Cole L, Dooneief G, Lawton A, Legler L, Marder K, Naini A, Stern Y, Mayenux R. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol 49 (11): 1137-41,1992.

(33.) Spagnoli A, Lucca U, Menasce G, Bandera L. Cizza G, Forloni G, Tettamanti M, Frattura L, Tiraboschi P, Comelli M, et al. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology 41(11): 1726-32, 1991.

(34.) Rai G, Wright G, Scott L, Beston B, Rest J, Exton-Smith AN. Double-blind, placebo controlled study of acetyl-l-camitine in patients with Alzheimer's dementia. Cur Med Res Opin 11(10): 638-47. 1990.

(35.) Brooks JO, 3rd, Yesavage JA, Cans A, Bract C. Acetyl L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double-blind, placebo-controlled study using the bilinear approach. Int Psychogeriatr 10(2):193-293, 1998.

(36.) ThaI LJ, Carla A, Clarke WR, Ferris SH, Friedland RP, Petersen RC, Pettegrew JW, Pleiffer E, Raskind MA, Sano M. Tuszynski MH, Woolson RF. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology 47(3):705-11, 1996.

(37.) De Falco PA, D'Angelo E, Grimaldi G, Scafuro F, Sachez F, Caruso G. [Effect of the chronic treatment with L-acetyl-carnitine In Down's syndrome]. Clin Ter 144 (2): 123-7, 1994.

(38.) Herrmann WM, Dietrich B, Hiersemenzel R. Phermaco-electroencephalographic and clinical effects of the cholinergic substance acetyl-L-carnitine -- in patients with organic brain syndrome. Int J Clin Pharmacol Res 10(1-2): 81-4. 1990.

(39.) Tempesta E, Troncon R, Janiri L, Colusso L, Riscica P. Saraceni G, Gesmundo E, Calvani M, Benedetti N, Pole P. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharmacol Res 10(1-2): 101-7, 1990.

(40.) De Angelis C, Scarfo C, FalcineIII M, Ferns E, Reda E, Ramacci MT. Angelucci L. Acetyl-L-carnitine prevents age dependent structural alterations in ref peripheral nerves end promotes regeneration following sciatic nerve injury in young end senescent rats. Exp Neurol 128 (1): 103-14, 1994.

(41.) De Angelis C, Scarfo C, Falcinelli M, Reda E, Ramacci MT. Angelucci L. Levocamitine acetyl stimulates peripheral nerve regeneration and neuromuscular junction remodelling following sciatic nerve injury. Int J Clin Pharmacol Res 12(56):269-79, 1992.

Correspondence:

Robert Crayhon, MS

Designs for Health Institute, Inc.

5345 Arapahoe Ave #3 Boulder, Colorado 80303 USA

Email: Robert@dfhi.com

COPYRIGHT 2002 The Townsend Letter Group
COPYRIGHT 2002 Gale Group

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