Alpha-Lipoic Acid

Alpha-lipoic acid, also known as thioctic acid, was first isolated in 1951 when it was realized that it was essential to the chemical reactions that allow every cell of the body to produce energy.

About 8 years later researchers also realized that it can also act as a powerful biological antioxidant.

R-alpha-lipoic acid is a naturally occurring, sulfur-containing, medium chain fatty acid that is either required by the diet as an essential nutrient or is produced by all living cells.

The best-known and most well characterized function of alpha-lipoic acid is as a co-factor of mitochondrial enzymes. The mitochondria are the organelle within the cells where energy is produced. Enzymes are complex proteins which are crucial catalysts for biochemical reactions and for building or synthesizing most bio-chemicals in the body. Lipoic acid has an effect on regulatory proteins and on genes involved in normal growth and metabolism.

As a supplement, lipoic acid is rapidly absorbed into the blood and the cells and readily transported through cellular membranes where it can prevent free-radical damage.

The Enantioselective Uptake

Insufficient supplies significantly increase the pathogenesis of the chronic degenerative diseases of aging. As we age, the body's proteins, DNA and lipid membranes become significantly more oxidized. This oxidation produces an overload on the antioxidant defense system of which lipoic acid is an essential part as a radical scavenger or by a pro-oxidant... mechanism.

As an antioxidant, lipoic acid scavenges free radicals, can regenerate Vitamin C and E, and increases glutathione levels. Lipoic acid might be even more effective in combination with other antioxidants.

Lipoic acid improves mitochondrial metabolic function and glycemic control, and may be useful therapeutically in such conditions as diabetes, ischemic-reperfusion injury, heavy metal poisoning, radiation damage, fungi, liver disorders, neurodegeneration and HIV infection.

(1, 2)

Alpha-Lipoic Acid Occurs In 3 Different Forms

Chirality And The Body

When molecules are produced by industrial synthesis they exist in a "racemic form", which is a 50/50 composition of the two enantiomers. Enantiomers are mirror image molecules which have identical chemical properties but may bio-chemically distinct.

In chemistry, a molecule is chiral if is not superimposable on its mirror image. Our hands are also chiral - mirror images of one another and non-superimposable - and chiral molecules are often described as being 'left handed' or 'right-handed'. "Chiral" is derived from the Greek word for hand.

Alpha-lipoic acid consists of a 50/50 mixture of the R-(natural) and S-(unnatural) enantiomers and is called a 'racemic' mixture. It is the most widely available form of lipoic acid.

R-Lipoic acid - The R (+) enantiomer) is responsible for the specific beneficial effects of alpha lipoic acid. Of primary significance, R-lipoic acid has shown to be ten times more effective than racemic alpha lipoic acid for reducing inflammation.

S-Lipoic acid - The S (-) enantiomer) is not found in nature. S-lipoic acid is a by-product from chemical synthesis of racemic alpha-lipoic acid and may inhibit the most essential properties of the R form, including interactions with proteins, enzymes and genes. (specifically FAD)

R-Lipoic acid (RLA) occurs naturally in plants and animals and is the only form that functions as a cofactor for mitochondrial enzymes. Within the mitochondria, RLA is reduced to R-Dihydrolipoic acid link (R-DHLA), the more potent antioxidant, 28 times faster than S-lipoic acid is reduced to S-dihydrolipoic acid. R-Lipoic acid was found to reach higher plasma levels than S-lipoic acid when given orally as the racemic mixture in a human study. (3)

R-Lipoic acid was more effective than S-lipoic acid in enhancing insulin-stimulated glucose transport and metabolism in insulin-resistant rat skeletal muscle, and R-Lipoic acid was more effective than racemic alpha-lipoic acid and S-lipoic acid in preventing cataracts in rats.

Much of the research over the past 30 years has been done with racemic alpha lipoic acid because the R form was not commercially available, due to its instability and the challenges of delivering the R form to the body in bio-available dosage forms compared to racemic alpha-lipoic acid.

The "Redox Couple" of lipoic acid and dihydrolipoic acid

Oxidation and reduction (redox reactions) involves the transfer of an electron from a donor to an acceptor. When the donor loses an electron, it is transformed from its reduced form to its oxidized form; when an acceptor gains an electron, it changes from its oxidized form to its reduced form. Together, the oxidized and reduced forms of a redox component are called a "redox couple."

There are always at least two compounds involved, one which loses an electron and one which gains an electron.

Alpha-lipoic acid occurs in two forms in the body: R-lipoic acid (RLA) and R-dihydrolipoic acid (R-DHLA). The two make up a "redox couple." Alpha-lipoic acid has a low redox potential, which means that its reduced form, dihydrolipoic acid, very readily donates electrons to other compounds.

R-lipoic acid donates an electron to R-DHLA, and the R-DHLA is then oxidized back into R-lipoic acid, and the R-lipoic acid is then reduced back into R-DHLA thus continuing the redox cycle. As the two forms swap electrons, they rapidly convert. Many of the properties of lipoic acid depend on this ability to rapidly swap electrons.

Alpha lipoic acid is the foundation of an antioxidant network involved in the conversion of the oxidized forms of four different cellular antioxidants back to their active protective forms.

Lipoic acid can reduce oxidized glutathione to reduced glutathione. It seems to directly reduce the vitamin E radical, formed when vitamin E quenches lipid peroxidation, back to vitamin E. Lipoic acid will reduce the semidehydroascorbyl (reduced ascorbate) back to ascorbate (vitamin C), which in turn, links it to vitamin E, because vitamin C can also reduce the vitamin E radical. These antioxidants are tightly interlinked, with alpha-lipoic acid playing a role in recycling many of the key antioxidants in the cell.

Antioxidant/Pro-Oxidant

Antioxidant

Antioxidants defuse free radicals and other biologically damaging molecular fragments in the body via its scavenging mechanism.

Alpha-lipoic acid is a key component in the antioxidant network. It acts as an antioxidant, however, only when there is an excess of it, and it is in the "free" state in the cells, because when it's bound in mitochondrial enzyme complexes where it performs its metabolic role, it has no access to areas where oxidative stress may be occurring or is it able to interact with and alter the redox status of critical in a variety of enzymes.

The body only makes very trace amounts of lipoic acid necessary for normal metabolic processes and there is very little free lipoic acid circulating in the body, unless taken as a supplement. Taking supplemental lipoic acid may have pronounced therapeutic effects by altering the cellular redox status which regulates the expression of genes and plasma by altering the redox and ?? of plasma amino thiols. (4, 5)

What makes lipoic acid special as an antioxidant is its versatility - it helps deactivate an unusually wide array of cell-damaging free radicals in many bodily systems. It has potent antioxidant actions in every cell of the body, protects membranes by boosting and recycling levels of other antioxidants (vitamin C, vitamin E, Coenzyme Q10 and glutathione) when it is in its reduced form, dihydrolipoic acid.

Alpha-lipoic acid and dihydrolipoic acid neutralize free radicals in both the fatty and watery regions of cells, in contrast to vitamin C, which is water soluble and vitamin E, which is fat soluble. (4) In addition, lipoic acid may be able to do the work of other antioxidants when the body is deficient in them. (1, 5)

Evidence suggests that the "redox-couple" of lipoic acid and dihydrolipoic acid is more powerful together than either compound alone. In general, dihydrolipoic acid has superior anti-oxidant activity to lipoic acid.

Between them, they have been shown to scavenge (inactivate) hydroxyl and peroxyl radicals, as well as hypochlorous acid, singlet oxygen and nitric oxide. They also are able to chelate transition metals, which are involved in oxidative reactions.

Pro-oxidant

Pro-oxidants are molecules that promote oxidation of another molecule by accepting electrons. Examples of pro-oxidants include free radicals, reactive oxygen species (ROS)* and reactive nitrogen species (RNS).

Redox active molecules such as classical "anti-oxidants" have the potential of acting as both pro- and antioxidants depending on the redox state of their biological environment leading to the formation and propagation of new radical species.

In addition to their antioxidant activities, both lipoic acid and dihydrolipoic acid may exert pro-oxidant actions through reduction of iron (by reducing fe3+ to fe2+) or by their own conversion to ROS or reactive sulfur species (RSS) by single electron oxidations or reductions that can damage certain proteins. (6,7)

It is now clear that many of the positive benefits and potentially deleterious side effects of alpha lipoic acid are paradoxically the result of pro-oxidant effects. Since lipoic acid can interchange between a reduced form and an oxidized form, it displays reducing (antioxidant) and pro-oxidant properties related to dosage, half-life and metabolism.

Research indicates that free radicals produced by alpha-lipoic acid (acting as pro-oxidants) are involved in activation of insulin signal pathway receptors and in elevated glucose uptake in muscle and fat cells. On the other hand, alpha-lipoic acid appears to protect the insulin-signaling cascade from oxidative stress-induced insulin resistance through its reducing capacities.

Lipoic acid and dihydrolipoic acid can effectively induce apoptosis in human colon cancer cells by a prooxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria. (8-11)

The ability of lipoic acid and/or lipoic acid to function as either anti- or pro-oxidants, at least in part, is determined by the type of oxidative stress and the physiological circumstances.

* Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides. They are very small molecules and are highly reactive due to the presence of unpaired valence shell electrons. ROSs form as a natural byproduct of the normal metabolism of oxygen but can damage cell membranes by causing oxidative stress.

Lipoic Acid Increases Intracellular Glutathione

Glutathione is an intracellularly and necessary water-soluble antioxidant compound (a tri-peptide, made from glutamic acid, cysteine and glycine) made needed for cellular energy production and proper immune function, overall health and longevity. Glutathione is synthesized from the sulfur-containing amino acid cysteine. The availability of cysteine inside a cell determines its rate of glutathione synthesis.

The level of glutathione is among the highest concentration of water soluble substances in cells.

Lipoic acid is the most effective antioxidant that can boost cellular levels of glutathione. (12) In addition to quenching free radicals, glutathione protects against cataract formation, prevents liver damage, slows the initiation of cancers and aids in the elimination of heavy metals. Glutathione levels can quickly be depleted when the body is exposed to high levels of oxidative stress during times of illness, infection, trauma or surgery. Glutathione deficiency is also seen in cases of low protein intake, diabetes, liver disease, cataracts, HIV infection, respiratory distress syndrome, cancer and idiopathic pulmonary fibrosis, among other conditions that produce oxidative stress.

Dihydrolipoic acid has been found to increase the uptake of cysteine by cells in culture, leading to increased glutathione synthesis Dihydrolipoic acid may also improve intracellular antioxidant capacity by inducing glutathione synthesis and altering the GSH:GSSG. Glutathione is only an anti-oxidant in its reduced form. (13)

Lipoic Acid: Aging and Disease Prevention

Lipoic acid plays a crucial role in protecting the mitochondria. Mitochondria are cellular organelles that oxidize proteins, fats and carbohydrates to a usable form of energy. Free radicals or reactive oxygen species (ROS) are also produced by mitochondria as a byproduct of energy production.

If not neutralized by antioxidants, ROS may damage mitochondria over time, causing them function less efficiently and to generate more damaging ROS in a self-perpetuating cycle. As we age, mitochondrial function is impaired, which is an important factor in many of the adverse effects of aging and age-related diseases. (14)

Short-term dietary supplementation with alpha-lipoic acid has been found to decrease mitochondrial ROS production and improve mitochondrial function. (15,16) A series of studies in aged rats found that combined dietary supplementation of R-lipoic acid and acetyl-L-carnitine link improved mitochondrial energy metabolism, decreased oxidative stress, increased physical activity and improved measures of short-term memory. (17,18)

Prevents Inflammation

Another exciting area of research resulted from the recent discovery that chronic systemic inflammation is a prerequisite for ALL the chronic degenerative disease of aging.

Lipoic acid reverses the cellular redox status (from a more oxidized to a more reduced state) which prevents inflammation, associated with all of the chronic degenerative diseases of aging. (19,20)

New tests can measure levels of a variety of chemicals in the blood that are markers for the degree of inflammation within the tissues of the body. In general, as we age these levels increase and predispose us toward the developing cancer, heart disease, Alzheimer's, etc. All these disease processes have a common underlying basis that may be positively affected by lipoic acid.

Functions in Disease

Lipoic acid has been shown to be beneficial in humans and animals as a preventive and/or treatment for many age-related diseases such as heart disease, ischemia-reperfusion injury, diabetes, cataract formation, macular degeneration, HIV activation, multiple sclerosis, ALS, neurodegeneration, hypertension, hyperglycemia, Burning mouth syndrome, radiation injury, liver ailments, including chronic hepatitis C, Parkinson's and Alzheimer's disease, immunosuppression, autoimmune disease, rheumatoid arthritis, elevated cholesterol, systemic psoriasis, lupus, eczema, burns, skin cancer, elevated levels of toxic metals as well as declines in energy, muscle strength and brain function. (21-27)

Alpha-lipoic acid has been used in Germany since the 1960's to treat diabetic and alcoholic neuropathies and alcoholic liver disease, thought to result in part from free-radical damage. (28)

Lipoic acid and insulin resistance

The development of insulin resistance has been shown to be an early step in the development of cardiovascular diseases in diabetic patients.

Lipoic acid can help decrease insulin resistance; it speeds the removal of glucose from the bloodstream by enhancing insulin function, and thus helps control blood sugar, underlying many cases of coronary heart disease and obesity. Lipoic acid is a key factor in the cellular process that metabolizes glucose for energy production and enhances glucose utilization. (29, 30)

Improvement of insulin sensitivity and enhancement of cardiac antioxidant status suggest that lipoic acid may be useful as a cardio protective agent in insulin-resistant states. (31)

Data from animal studies suggests that the R-isomer may be more effective in improving insulin sensitivity than the S-isomer. (32, 33) plus new

Diabetes

Studies have shown that alpha lipoic acid can be used to prevent and treat both type I and type II diabetes and the complications of diabetes. Among the most serious complications of diabetes is nerve damage, especially in the eye (retinopathy) and heart attacks resulting from atherosclerosis.

In animal models, long-term administration of lipoic acid inhibited the development of diabetic retinopathy. (34)

Glycation

Alpha lipoic acid has shown to prevent glycation* and the accumulation of advanced glycation end products (AGEs).

Advanced glycation end-products are considered to play an important role in the development of retinopathy in diabetes and are responsible for the development of many of the diseases of aging.

In both animals and humans, lipoic acid can help to prevent and treat the pathologies of diabetes through its antioxidant and antiglycation effects. Lipoic acid protects proteins, such as albumin, in the blood by connecting with it and preventing the glucose from destroying it. (35)

*Glycation is the process by which sugars link with proteins and causes them to bind together, These abnormal compounds are called advanced glycation end products (AGEs). They prevent the proteins from functioning properly, stiffening tissues and collagen in the blood vessel walls, leading to the complications of diabetes and in many age-related chronic diseases such as cardiovascular diseases, high blood pressure, Alzheimer's disease, cancer, peripheral neuropathy and other sensory losses such as deafness and blindness. This range of diseases is the result of the very basic level at which glycations interfere with molecular and cellular functioning throughout the body and the release of highly oxidizing side products such as hydrogen peroxide. Glycations also cause weakening of the collagen in the blood vessel walls, which may lead to aneurisms that may cause strokes if in the brain.

Diabetic peripheral neuropathy

Over one third of diabetics develop peripheral neuropathy, a type of nerve damage that may result in decreased sensitivity, numbness, and pain, particularly in the lower extremities. In addition to the pain and disability caused by diabetic neuropathy, it is a leading cause of lower limb amputation in 85,000 diabetics per year. Evidence suggests that oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defense is implicated in the pathogenesis of diabetic neuropathy.

Clinical studies to evaluate the effect of lipoic acid on diabetic neuropathy have been undertaken mainly in Germany where a beneficial effect was first reported over 40 years ago. (36)

Markers of oxidative stress are increased in diabetic patients in relation to the severity of polyneuropathy. Treatment with lipoic acid can result in prevention or improvement of the diabetes-induced neurovascular and metabolic abnormalities. Studies have shown that lipoic acid reduces the chief symptoms of diabetic polyneuropathy to a clinically meaningful degree. Oral treatment of lipoic acid for 4-7 months tends to reduce neuropathic deficits and improve cardiac autonomic neuropathy. Lipoic acid has shown to favorably influence impaired microcirculation oxidative stress and increased levels of markers for vascular dysfunction. (37)

Another study has shown that alpha lipoic acid appears to be effective in the treatment for not only peripheral and autonomic diabetic neuropathy, but also diabetic mononeuropathy of the cranial nerves leading to full recovery of the patients. (38, 39)

It is important to note that lipoic acid treatment of sensory deficiency was most effective in patients with a short history of diabetic neuropathy and mild initial neurological disorders. (40)

Vascular complications

Several studies in humans have examined the effect of lipoic acid administration on endothelial function. The inner lining of blood vessels plays an important role in preventing vascular disease. Endothelial function in individuals with diabetes (type I and type II) is often impaired, and diabetics are at increased risk for vascular disease. Alpha-lipoic acid improves endothelium-dependent vasodilation (blood vessel relaxation) in diabetic patients and improved a measure of capillary perfusion in the fingers of diabetic patients with peripheral neuropathy. (41, 42)

Ischemia-reperfusion injury

Ischemia-reperfusion injury occurs when a burst of free radicals is produced during reoxygenation of tissue that has become deficient in oxygen. It is important in cardiac tissue (especially with the introduction of clot-dissolving drugs for the treatment of heart attack) and in the brain.

During reperfusion, glutathione levels drop in the brain, indicating oxidative stress, but when alpha-lipoic acid is administered, the glutathione levels in the brain are raised.

In a remarkable animal study on cerebral ischemia reperfusion injury, blood flow was restricted through the carotid arteries for 30 minutes and then released. Eighty percent of these animals died in 24 hours. Only 20 percent of the animals died when they were treated with lipoic acid.

Dihydrolipoic acid was been shown to prevent ischemia-reperfusion injury by regenerating vitamin E in the heart. Dihydrolipoic acid also increased ATP production in the heart and was shown to reduce the amount of tissue which dies due to a lack of oxygen resulting from a blood clot or blocking of an artery and was shown to be effective in ameliorating or preventing damage. (43-46)

HIV/AIDS

Acquired immunodeficiency syndrome (AIDS) results from infection with the human immunodeficiency virus (HIV). Research has shown that a person infected with the HIV virus but not yet manifesting the full blown syndrome characterized as AIDS prevents the virus from activating within the body by consuming large doses of R-Lipoic acid every day. A person that has AIDS may prevent the virus from further replication by consuming 4-5 grams/day of R-Lipoic acid. R-lipoic acid inhibits the replication of HIV and other viruses by eliminating reactive oxygen species (ROS) and subsequently halts HIV transcription.

Dr. Lester Packer has found that lipoic acid protects Nuclear Factor kappa-B (NF kappa-B) from activating HIV to replicate. (47,48)

Lipoic Acid and Alzheimer's Disease

Alzheimer's disease is a progressive neurodegenerative disorder that usually manifests in people aged 50 or older, although it is a progressive neurodegenerative disease that may actively impair brain function throughout life after significant damage has accumulated. Oxidative stress and inflammation plays an important role in neuron degeneration in both Alzheimer's disease. Accumulation of insoluble protein deposits and their cross-linking by AGEs (advanced glycation end products) in the brain is a feature of aging and neurodegeneration, especially in Alzheimer's disease.

Research has shown that supplementation with lipoic acid led to stabilization of cognitive functions and could indirectly strengthen the anti-glycation defense system and might be a successful neuroprotective therapy for Alzheimer's disease and related dementias. (49, 50)

Radiation Injury

Lipoic acid, alone or together with Vitamin E, is an effective treatment for radiation exposure, lessening oxidative damage and normalizing organ function and protects the eye from the damaging effect of ultraviolet exposure. (51-54)

Lipoic acid and DNA

Alpha-lipoic acid has the ability to protect the genetic material, DNA, in the cell nucleus from a protein complex called Nuclear Factor kappa-B (NF-kappa-B). Genes are "blocks" of DNA that operate as a unit within a chromosome to control a specific cell function by regulating the production of a specific protein. Genes are capable of managing the formation of body proteins through processes called gene expression and regulation.

Any factor interfering with normal gene regulation can profoundly influence health and lifespan. Free radicals and other reactive oxygen species can influence gene expression and regulation.

When NF kappa-B is activated, it in turn can activate or damage genes, which in turn determines our health.

Old animals, including man, have more NK-kappa-B bound to their genes than do young animals. The most studied effect of NK-kappa-B has been its effect on the immune system, but it is also known to lead to defective skin cells and aged skin, and to defective cells in all body organs which results in decreased function of all body systems.

An advantage of alpha-lipoic acid is that it is relatively very small molecule and is readily transported through cellular membranes including the nuclear membrane. Thus, it not only can terminate free radicals in the blood stream and on the cellular membrane, alpha-lipoic acid can protect NF kappa-B in the cytosol and even protect the DNA in the nucleus. (55-57)

Lipoic and Bone Loss

Alpha-lipoic acid may have therapeutic applications in halting or attenuating bone loss associated with increased oxidative stress and inflammation. (58,59)

Food sources

Most food-derived alpha-lipoic acid lipoamide-containing enzymes is bound to the amino acid, lysine (lipoyllysine). Most dietary alpha-lipoic acid is absorbed as lipoyllysine. Animal tissues that are rich in lipoyllysine include kidney, heart and liver, though these animal organs are generally not part of our regular diet. Lipoyllysine is also found in muscle tissue, with higher concentrations in dark meats, such as duck and venison. Plant sources that are rich in lipoyllysine include spinach, broccoli and tomatoes. Somewhat lower amounts of lipoyllysine have been measured in peas, brussel sprouts and rice bran. Digestive enzymes do not break the bond between alpha-lipoic acid and lysine very effectively. (60-61)

Safety

There are no reports of toxicity from alpha-lipoic acid overdose in humans. In individuals with diabetes and/or impaired glucose tolerance, lipoic acid supplementation may lower blood glucose levels. Individuals on diabetic medications should monitor blood glucose levels. Diabetic medication doses may need to be adjusted to avoid hypoglycemia. Because controlled safety studies in pregnant and lactating women are not available, the use of lipoic acid supplements by pregnant or breastfeeding women is not recommended.

Drug Interactions

Alpha-lipoic acid supplements may affect the optimal dose of medications used to control blood glucose in diabetics. Individuals on such hypoglycemic agents should monitor their blood glucose levels and consult their health care provider for dosage adjustments if necessary to prevent hypoglycemia.

Side Effects

Side effects are rare, but may include allergic skin reactions in the form of a rash or hives. Some people report gastrointestinal effects, such as nausea. For this reason, taking the product with food is recommended.

Some people have found that when they take the product with dinner, they feel energized at night and have difficulty falling asleep. Persons who experience this effect may switch to taking R-lipoic acid at lunch instead of dinner, or reduce the daily dose.

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