Acetyl-L-carnitine

Carnitine is approved as a drug in the United States to protect against muscle wasting diseases, including heart muscle weakness and low energy levels. Despite FDA-approval, few conventional doctors prescribe carnitine to support those with cardiomyopathy, congestive heart failure, chronic fatigue, etc. The failure of doctors to prescribe this natural amino acid correlates directly with the lack of drug company advertising for the product. There is little economic motivation for drug companies to promote the benefits of carnitine to doctors when their patients can choose from hundreds of lower cost carnitine supplements available over the counter. In addition to its "FDA-approved" indications, acetyl-L-carnitine has been shown to maintain immune competence1 and reduce the formation of a cell-clogging pigment called lipofuscin2.

The most important anti-aging effect of acetyl-L-carnitine, however, is to work with coenzyme Q10 and alpha lipoic acid to maintain the function of the mitochondria3. When the mitochondria function dwindles, degenerative disease becomes an inevitable consequence. Foundation members use acetyl-L-carnitine as a multi-purpose anti-aging supplement. Newly published research shows this amino acid may be even more effective than previously shown.

The effects of aging were dramatically demonstrated when scientists measured cell energy activity and respiration rates in the heart mitochondria of rats. Both cellular energy and respiration was depressed around 40% in the older rats. When acetyl-L-carnitine was administered, their heart rates became almost completely restored to the metabolic function level of young control rats4. This study showed that the heart mitochondrial content of cardiolipin, a key agent necessary for mitochondrial substrate transport, was markedly reduced in aged rats. Treatment of aged rats with acetyl-L-carnitine reversed the age-associated decline in cardiolipin content. This newly identified mechanism helps explain why acetyl-L-carnitine is so beneficial in treating congestive heart failure in humans

Aging causes alterations in brain cell metabolism. Acetyl-L-carnitine has been shown to counteract several mechanisms of brain cell damage. A new study shows that acetyl-l-carnitine protects against temporary cerebral ischemia (no blood flow) by maintaining the cell's energy cycle5. Other recent studies show that acetyl-L-carnitine protects brain cells against glutamate-induced and ammonia-induced toxicity6. As people grow older, circulation to the brain diminishes, which sets off a cascade of pathological events that results in neurological impairment. Acetyl-L-carnitine appears to protect against some of the known negative effects that aging induces in the brain.

In animal stroke models, an 11-point neurologic deficit scoring system evaluated the treatment progression of acetyl-L-carnitine against a control vehicle. Acetyl-L-carnitine was shown to protect brain cells against ischemic injury and to improve neurological outcome with the treated animals being significantly improved over the controls. This study suggests that acetyl-L-carnitine might someday be used in hospital emergency rooms and stroke recovery centers to improve the prognosis of patients (with thrombotic or embolic stroke) who are often given little hope of full recovery.

Acetyl-L-carnitine may facilitate nerve regeneration after nerve injury9. Scientists surgically severed nerves and observed the typical motor-neuron degeneration that occurred at the site of the injury. Acetyl-L-carnitine was shown to have significant neuro-protective effect against the degeneration of traumatized motor-neurons. These observations prompted the scientists to postulate a better hypotheses concerning motor-neuron regeneration and even the possibility of inducing neuronal proliferation. These findings have practical applications in those who have suffered from loss of nerve function.

Another study showed that acetyl-L-carnitine prevented ethanol-induced brain cell alterations indicative of human fetal alcohol syndrome.10 The scientists who conducted this rat study stated that acetyl-L-carnitine might have an indirect anti-depressant benefit by protecting brain cells against the known neuro-toxicity effects of alcohol.

It is well known that many anti-viral HIV-drugs contribute to peripheral neuropathy. Doctors in London noted that treatment with acetyl-L-carnitine may assist in the treatment of drug-induced peripheral neuropathy.11

In two related studies of diabetic nerve degeneration and neuropathy, acetyl-L-carnitine was shown to accelerate nerve regeneration after experimental injury.12 In the first study, doctors at the Hines VA Hospital in Illinois showed that diabetic rats treated with acetyl-L-carnitine maintained near normal nerve conduction velocity without any adverse effects on glucose, insulin or free fatty acid levels. These observations led the scientists to summarize that acetyl-L-carnitine can accelerate nerve regeneration after experimental injury. In another study, doctors at the Nagoya University School of Medicine in Japan showed that carnitine deficiency was closely related to the pathogenesis of diabetic neuropathy. The doctors concluded acetyl-L-carnitine has great potential for the treatment of this type of neuropathy.13

Traditionally, some diabetics have suffered with peripheral neuropathy at various times throughout the course of their illness. Scientists now know that several mechanisms may produce this neuropathy in diabetics. In 1997, French doctors published a study stating that some of the most promising treatments for diabetic neuropathy may be gamma linolenic acid (GLA), antioxidants, aminoguanidine and, once again, acetyl-L-carnitine.14 It seems a particular enzyme in diabetics, which limits the availability of gamma linoleic acid, also decreases the endothelial synthesis of nitric oxide and of L-carnitine. The authors felt, though experimental, these treatments were a promising solution for diabetics.

Reports on acetyl-L-carnitine for the treatment of Alzheimer's disease have been contradictory. Some studies show encouraging degrees of efficacy, while other studies show no benefit. A placebo-controlled study at Stanford University School of Medicine in California showed that Alzheimer's disease patients under age 62 benefitted more from acetyl-L-carnitine than older patients.15 The doctors concluded that acetyl-L-carnitine slows the progression of Alzheimer's disease in younger subjects. Though this is an important study, Alzheimer's patients over 61 may want to still consider ALC for its other known neurological benefits, which were not evaluated in this study.

Acetyl-L-carnitine enhances energy production in every cell of the body. Two recent studies illustrate the unique ability of acetyl-L-carnitine to increase cellular respiration in aging models. A study from Berkeley examined liver parenchymal cells in old mice after feeding them a 1.5% solution of acetyl-L-carnitine for one month. The results show that acetyl-L-carnitine supplementation significantly reverses the age-associated decline of mitochondrial membrane function.16 A similar second study, also from Berkelely, again concluded the ability of acetyl-L-carnitine to reverse age-related mitochondrial decay.

Glycosylation and glycation are terms used to describe the binding of sugars to proteins that form non-functioning structures (crosslinks) in the body. Glycation-induced protein cross linking is most notable in the lense of the eye (cataract), the brain (senility) and the collagen of the skin. Protein glycation has been implicated in the development of cataracts. Scientists recently evaluated the effects of L-carnitine and acetyl-L-carnitine on the glycation of lens proteins. The results show that acetyl-L-carnitine suppresses glycation by 42%, but that l-carnitine has no effect.7 Additional evaluation shows that acetyl-L-carnitine produces a 70% reduction in one measurement of Advanced Glycation End products (AGEs). It is the formation of AGEs that makes cataract irreversible. This in-vitro study shows, for the first time, that acetyl-L-carnitine (but not L-carnitine) may prevent cataract by preventing glycation-mediated protein damage in the eye lense.

The optimal dose range of acetyl-L-carnitine for healthy people is 1000 mg to 2000 mg day. Those with neurological deficit should consider 3000 mg a day. Synergistic nutrients that could be taken with acetyl-L-carnitine include coenzyme Q10 (100-300 mg/day) and alpha lipoic acid (250-500 mg/day).

(1) Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2.

Calabrese V, Ravagna A, Colombrita C, Scapagnini G, Guagliano E, Calvani M, Butterfield DA, Giuffrida Stella AM. Department of Chemistry, Biochemistry and Molecular Biology Section, Faculty of Medicine, University of Catania, Catania, Italy. calabres@mbox.unict.it  J Neurosci Res. 2005 Feb 15;79(4):509-21.

Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-gamma-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases.

(2)  Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes.

Calabrese V, Giuffrida Stella AM, Calvani M, Butterfield DA. Department of Chemistry, Biochemistry and Molecular Biology Section, Faculty of Medicine, University of Catania, 95100 Catania, Italy. calabres@mbox.unict.it   J Nutr Biochem. 2006 Feb;17(2):73-88. Epub 2005 Oct 18.

Aging is associated with a reduced ability to cope with physiological challenges. Although the mechanisms underlying age-related alterations in stress tolerance are not well defined, many studies support the validity of the oxidative stress hypothesis, which suggests that lowered functional capacity in aged organisms is the result of an increased generation of reactive oxygen and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular macromolecules, which can translate into oxidative injury, impaired function and cell death in vulnerable tissues such as the brain. To survive different types of injuries, brain cells have evolved networks of responses, which detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. The heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response, there is now a strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity.