Lipoic Acid - The Antioxidant the Others Depend On

Lipoic Acid Helps Heart Health
Antioxidant power and versatility are hallmarks of this amazing compound

f you were marooned on a desert island with just one book to read, what would it be? The classic answer, of course, is How to Build a Boat. But what if you had a choice of antioxidants? Would you pick vitamin C, vitamin E, coenzyme Q10 . . . or what? For some reason, this question seldom comes up at cocktail parties, but let's give it a whirl. Antioxidants are, after all, absolutely vital to our health - and the healthier we are, the happier we'll be and the longer we'll live.

Everyone knows that, but it's surprising how many people don't act accordingly. But you, dear reader, are not one of those people - you are an antioxidant connoisseur. You probably already know that antioxidants are one of our first lines of defense - probably the most important of all - against the ravages of aging. Indeed, if it were not for the powerful antioxidants our own bodies make in order to neutralize the harmful free radicals our bodies also make, we would be dead in an hour or two - literally.

In terms of nutrition, the effects of anything good that our bodies do - such as making antioxidants - can often be bolstered through supplementation. There's no such thing as a cell that's too proud to accept a little outside help. And one thing our cells seem to love is lipoic acid, "the antioxidant's antioxidant" (see the article by that name in Life Enhancement, July 2001). Although we get small amounts of lipoic acid (the more technical name is alpha-lipoic acid) from certain foods, such as spinach, potatoes, and red meat, it takes supplementation to provide optimal amounts of the special brand of nourishment this remarkable molecule can provide.

Lipoic acid's remarkable
ability to regenerate other
antioxidants and squeeze
the most out of them has
been demonstrated
in various ways.

What makes lipoic acid so special is its unique role as the linchpin of the body's antioxidant network (see the sidebar). This is a group of five antioxidants - vitamin C, vitamin E, coenzyme Q10, glutathione, and lipoic acid - whose beneficial actions depend in part on their ability to regenerate one another so as to maintain their antioxidant capacity.1 Ordinarily, when an antioxidant molecule neutralizes a free radical, it becomes oxidized in such a way that it can no longer be regenerated to its original antioxidant form, ready to take on another free radical in the never-ending biochemical melee. The molecular remnants of the antioxidant must then be excreted as waste products, leaving other molecules to carry on.

The Antioxidant Network

The antioxidant network, consisting of what might be called the Big Five antioxidants, is a unique biological system of mutual support and regeneration.1 Through various chemical interactions, these antioxidants salvage one another's antioxidant capacity by regenerating the antioxidant form of the molecule after it has been oxidized by a free radical. Without this network of interactions, we would have to take far more of these supplements than we do now.

Most of the research elucidating the nature of the antioxidant network has been carried out at the University of California, Berkeley, by Dr. Lester Packer and his colleagues. Dr. Packer is professor of molecular and cell biology and director of the university's Packer Laboratory.

Antioxidants keep your body from self-destructing.

Vitamin C (water-soluble) - Vitamin C (ascorbic acid) is probably the most widely known and commonly taken supplement of all. Being a vitamin, it is a substance that our body needs but cannot synthesize on its own, so we must depend entirely on outside sources - foods and supplements - for this compound. Vitamin C is critically important for a healthy immune system, helping to prevent the common cold, the flu, and other viral diseases, and it helps prevent cancer by protecting our DNA from free radical damage. It also protects against cataracts, a leading cause of vision problems as we age. One of vitamin C's most important roles, especially in terms of cardiovascular health, is to regenerate vitamin E. Lipoic acid does this too, but vitamin C does it better.

Vitamin E (fat-soluble) - Vitamin E (alpha-tocopherol and seven other closely related compounds) is transported in the bloodstream by lipoproteins - the same ones that transport cholesterol - and almost single-handedly protects their cargo of lipids from oxidation. This makes vitamin E by far the most important antioxidant for cardiovascular health, because lipid oxidation is the trigger for the formation of atherosclerotic plaque, which clogs our arteries and leads to heart attacks. Alone among the network antioxidants, vitamin E can move freely in the fatty parts of cell membranes, protecting them from free radicals. It is especially important in protecting our skin from sun damage, and it also helps against arthritis and other inflammatory diseases, and against certain forms of cancer.

Coenzyme Q10 (fat-soluble) - This antioxidant is structurally similar to vitamin E (which it helps to regenerate), but it is not a vitamin, because it is synthesized by the body. It can be taken as a supplement - and it should be, especially for its proven benefits in maintaining cardiovascular health, in particular. This is all the more important because our bodies produce less and less of this vital molecule as we age. Coenzyme Q10 is found in all cell membranes, but it is particularly prevalent in the cells' mitochondria, where it acts as a kind of chemical "spark plug" for the Krebs cycle, which generates the energy that all life processes require. Energy metabolism also produces torrents of free radicals - far more than we get from outside sources - and coenzyme Q10, in a nice bit of mitochondrial double duty, helps mop them up. But the champion in that regard is glutathione.

Glutathione (water-soluble) - This is the body's master antioxidant, the most important of all. It is synthesized in our cells, where it leads the charge against the relentless tide of free radicals produced when glucose is burned to produce energy via the Krebs cycle. Glutathione plays a vital role in liver function, where it is instrumental in detoxifying drugs and pollutants, and it is also important for a strong immune system. It is an effective regenerator of vitamin C. Supplementing with glutathione is pointless, because it is a tripeptide - three amino acids linked in a chain - which is easily decomposed by digestive juices in the stomach. Fortunately, our bodies make glutathione in abundance (its cellular concentration is several million times greater than that of vitamin E, for example), and lipoic acid helps to maintain those levels through regeneration. The best way to boost glutathione levels, in fact, is to take lipoic acid.

Lipoic acid (water- and fat-soluble) - Last but not least is lipoic acid, which is "the most versatile and powerful antioxidant in the entire antioxidant defense network," according to Dr. Packer. Originally thought to be a vitamin of the B class, we now know that it is not a vitamin, because our bodies synthesize tiny amounts of it. As described in the accompanying article, lipoic acid plays the central role in the antioxidant network.

  1. Packer L, Colman C. The Antioxidant Miracle. John Wiley & Sons, New York, 1999.

With the Big Five of the antioxidant network, however, chemical interactions among these molecules tend to regenerate them from their oxidized state back to "fighting form" so they can stay in the fray. The molecule that is most effective in stimulating these regenerative processes - and the only one that can regenerate all the others - is lipoic acid. It is this capability, more than lipoic acid's action as a formidable antioxidant in its own right, that may represent its principal contribution to human health and longevity - especially with regard to glutathione, the most important antioxidant of all.

The regenerative processes are not perfect, however, and there is inevitably a steady loss of precious antioxidant molecules. Actually, it's not all that steady, because the rate of loss of antioxidants depends on the rate of production of the free radicals they seek and destroy - and free radicals tend to come in waves, especially after a meal or after vigorous physical exercise, when metabolic processes are at their peak. In any case, the antioxidant losses must be made up by chemical synthesis within the body or by supplementation from without. With the vitamin antioxidants, supplementation is not an option, but a necessity, because, by definition, vitamins cannot be synthesized by the body.

Although our bodies do make a little lipoic acid, and our food contains a little, supplementation is the only way to obtain optimal amounts. Lipoic acid is readily absorbed from the digestive tract and transported to all of the body's five trillion cells. Unlike most other antioxidants, it is soluble in both aqueous (watery) environments, such as blood and cellular fluid, and lipidic (fatty) environments, such as cell membranes and brain tissue.* This dual nature makes lipoic acid exceptionally versatile, allowing it to go wherever it wants and exert its antioxidant action in a variety of ways.

*The brain consists entirely of nerve cells (neurons), which are high in fat content. So if someone calls you a fathead, don’t be offended - maybe they're just making a scientific observation.

This versatility explains, in part, lipoic acid's role as the linchpin in the antioxidant network. Take, for example, vitamin C. Lipoic acid is able to regenerate this water-soluble molecule in the blood and other aqueous environments, such as the "aqueous humor" (the gel-like liquid in the eye, where the concentration of vitamin C is about 25 times greater than in the blood). Or take vitamin E, which is found mainly in lipidic environments, such as cell membranes - the chemical opposite of an aqueous environment. No problem for lipoic acid - it feels right at home there too, and regenerates vitamin E - but only, apparently, when vitamin C is also present.

If you're an alert reader, that last sentence should have you saying, "Whoa! How can that be? Didn't we just establish that the operating environments of vitamins C and E are mutually exclusive?" Well, not exactly. Bear in mind that our innards are full of complex substances with elements of both aqueous and lipidic properties - sort of like ice cream, for example, in which both watery and fatty components coexist in intimate, delicious union.

Then too, vitamin C has some degree of solubility in fats (in fact,some active forms of vitamin C, such as ascorbyl palmitate, are highly fat-soluble), and vitamin E has some solubility in water, so the two can get together more easily than one might at first think. Most biochemical compounds, in fact, have some degree of dual solubility, which adds greatly to the complexity of life processes - and it also makes life possible in the first place.

Lipoic acid's extraordinary regenerative capabilities do not end with the vitamins. Inside our cells, it also regenerates water-soluble glutathione, mainly in the cytoplasm (the cellular fluid), and it regenerates fat-soluble coenzyme Q10 in the mitochondria, the tiny cellular power plants where glucose is metabolized. This metabolism releases energy and abundant waste products, including torrents of free radicals. (For information on the great biological importance of glutathione and coenzyme Q10, see the sidebar.)

Lipoic acid is an effective inhibitor
of both lipid oxidation and plasma
oxidation, making it a valuable
ally in our never-ending fight
against heart disease.

Wherever it goes, lipoic acid also acts as a primary antioxidant to neutralize reactive oxygen and nitrogen species, including such damaging ones as hydroxyl and peroxyl radicals, superoxides, hypochlorous acid, and peroxynitrites.

Lipoic acid's remarkable ability to regenerate other antioxidants and squeeze the most out of them has been demonstrated in various ways. It has been shown, e.g., that lipoic acid supplementation can prevent the symptoms of scurvy in vitamin C-deficient guinea pigs, and the symptoms of vitamin E deficiency in rats that were fed a diet lacking in vitamin E.2

Although most studies on lipoic acid's antioxidant properties and its central role in the antioxidant network have been carried out on laboratory animals, clinical trials on human beings are also being pursued. A study published recently in the journal Free Radical Biology and Medicine was designed to investigate the effect of lipoic acid supplementation, both alone and in combination with alpha-tocopherol (the principal constituent of vitamin E), on various measures of oxidative stress in healthy people.3

One measure of oxidative stress is lipid oxidation, specifically, the oxidation of LDL, or low-density lipoprotein, the "bad" cholesterol. This process is strongly implicated as a primary cause of atherosclerosis, which often leads to cardiovascular disease, including heart attacks. Another measure of oxidative stress is plasma oxidation, specifically, the oxidation of proteins in the blood plasma. Both processes result in products that are deleterious to health.

In the 16-week study, 31 healthy adult volunteers (15 men and 16 women) were randomly assigned to two groups. One group was given 600 mg per day of lipoic acid for 8 weeks, while the other group was given 400 IU (international units) per day of alpha-tocopherol for 8 weeks. After the first 8 weeks, each group received the other supplement as well as the one they were already taking, so for the final 8 weeks of the study, each group was taking identical amounts of both lipoic acid and alpha-tocopherol.

The results of the study showed convincingly that lipoic acid is an effective inhibitor of both lipid oxidation and plasma oxidation, making it a valuable ally in our never-ending fight against heart disease. Lipoic acid supplementation did not, however, have any effect on the concentrations of alpha-tocopherol in either LDL or plasma. This is consistent with the finding from another study that lipoic acid is capable of regenerating vitamin E only in the presence of vitamin C (which the patients in the study were not taking).4 Thus, it appears that lipoic acid's antioxidant action in this case is not tied to the regeneration of alpha-tocopherol.

The study also showed that alpha-tocopherol inhibits lipid oxidation but not plasma oxidation. This finding is consistent with vitamin E's poor solubility in water, and it underscores the versatility of lipoic acid, which has no such limitation.

Regardless of how you get your lipoic acid, you will receive five trillion "thank you's" in return, from your body's grateful cells.


  1. Packer L, Colman C. The Antioxidant Miracle. John Wiley & Sons, New York, 1999.
  2. Podda M, Tritschler HJ, Ulrich H, Packer L. Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem Biophys Res Commun 1994;204:98-104.
  3. Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I. Comparison of the effect of alpha-lipoic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 1999;27(9/10):1114-21.
  4. Kagan VE, Serbinova EA, Forte T, Scita G, Packer L. Recycling of vitamin E in human low-density lipoproteins. J Lipid Res 1992;33:385-97.

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