α-Lipoic Acid—What’s in an Isomer?
α-Lipoic Acid May Help
Keep You Sharp
The nutrient’s antidiabetic action may also
protect against the neurodegeneration of Alzheimer’s
By Will Block
he history of medicine is full of serendipitous events. It would take a whole book to summarize the countless times when fortunate discoveries were made purely by accident by those who were looking either for something else or for nothing in particular. Some were physicians, some were medical research scientists, and some weren’t even medical types at all. But Lady Luck smiled on them, just as she had long ago on the Three Princes of Serendip, from whose ancient fairytale adventures the word serendipity is derived. (The name Serendip, by the way, came from an old Arabic word for Sri Lanka.)
© iStockphoto.com/Elena Korenbaum
A serendipitous discovery?
Fast-forward to 1997. A 74-year-old German woman goes to a medical clinic in Hannover. She shows signs of significant cognitive impairment, along with age-related diabetes and a mild form of diabetic polyneuropathy (nerve damage in the extremities, causing symptoms such as weakness, numbness, or pain). For the woman’s incipient dementia, the doctors prescribe acetylcholinesterase inhibitors—standard practice in mild to moderate cases of Alzheimer’s disease. For her diabetic polyneuropathy, they prescribe α-lipoic acid (600 mg/day).
Lady Luck Strikes a Lady
For at least three decades, α-lipoic acid had been widely used in Germany (it’s a prescription drug there) for diabetic polyneuropathy, and the elderly woman’s doctors expected it to be helpful, as usual. What they did not expect, however, was that the woman’s cognitive functions would hold fairly steady over the ensuing years—but that is what they observed.
This was in striking contrast to the typical pattern in Alzheimer’s patients treated with acetylcholinesterase inhibitors: they continue to decline, albeit at a slower rate than they would without the drugs. The German woman’s rate of decline was so unusually slow that, as of 2005, she was still living at home and functioning satisfactorily. (To make sure that she really did have Alzheimer’s, the doctors repeated the diagnostic tests several times.)
Something, it seemed, was helping this lucky woman in an unexpected way. Her doctors were inclined to doubt that it was the acetylcholinesterase inhibitors, so they surmised that it might be the α-lipoic acid (or perhaps the combination of the two). Serendipity had struck.
α-Lipoic Acid Stabilizes Cognitive Function in Pilot Study . . .
Their accidental discovery prompted the doctors to conduct a small, uncontrolled pilot study (not a gold-standard clinical trial by any means) of the effects of α-lipoic acid (600 mg/day for about 11 months) on nine patients with “probable Alzheimer’s” who were already on standard drug therapy.
The results, published in 2001, were encouraging: a stabilization of cognitive function for nearly a year, indicating that α-lipoic acid might be neuroprotective in the brain.
Two ways to represent the (R)-α-lipoic acid molecule. The carbon atom highlighted in purple is the “asymmetric carbon,” which leads to two mirror-image isomers (optical isomers).
There have thus far been no further clinical trials of α-lipoic acid for Alzheimer’s disease, but one is currently underway in the United States and is expected to be completed in February 2007. Unfortunately, despite the long-term use of α-lipoic acid in Germany for diabetic polyneuropathy, there has been no epidemiological study of the incidence of Alzheimer’s disease among those who have taken α-lipoic acid, to see whether they appear to be less susceptible to Alzheimer’s than those who have not.*
. . . Perhaps Because of This
Although α-lipoic acid cannot yet be recommended as a therapy for Alzheimer’s and related dementias, much experimental work in laboratory and animal studies suggests that it’s a promising candidate:
- It increases production of the neurotransmitter acetylcholine (ACh) by activating the enzyme responsible for ACh synthesis. (Impaired ACh function is a hallmark of Alzheimer’s disease.)
- It also increases ACh production by increasing cellular glucose uptake (acting similarly to insulin in this regard), thereby enhancing production of acetyl-coenzyme A, which is a precursor to ACh.
- It chelates certain metal ions, notably iron and copper, that are implicated in the production of harmful reactive oxygen species (ROS), such as hydrogen peroxide and the hydroxyl radical.
- As an antioxidant, it scavenges ROS, thereby tending to inhibit inflammatory processes. It also helps regenerate other antioxidants—most notably glutathione, the body’s most important antioxidant—to their active states. And it induces the synthesis of glutathione and other antioxidants by activating the enzymes responsible for those processes. Because of its central role in the body’s self-regenerating antioxidant network, it’s called “the antioxidant’s antioxidant.”
α-Lipoic Acid—Nonidentical Twins
In addition to the above, it’s important to know that α-lipoic acid acts as a critical cofactor for a number of biochemical processes involved in cellular energy metabolism—it is, in fact, essential for aerobic life as we know it. And it’s useful to know that α-lipoic acid exists in the form of two isomers with different chemical properties. (Isomerism, in case you’ve forgotten, is the existence of molecules with the same molecular formula but different molecular structures; there are several different kinds of isomerism. See the sidebar “Mirror, Mirror in the Cell” for why the isomerism of α-lipoic acid is important.)
Mirror, Mirror in the Cell
If you look at your nose in a mirror, it will look just like your real nose: the one could be superimposed on the other with no discernible difference. If you look at your right hand in a mirror, however, you’ll see that it looks just like your left hand. A hand and its mirror image are not superimposable (which is why you can’t fit your right hand into a left-handed glove).
This same kind of mirror-image asymmetry exists in innumerable molecules, including most biologically active ones. The phenomenon is called optical isomerism, and the two molecules (isomers) of the pair are said to be optically active, because they interact with light waves differently. And because their molecular structures are different, they have different chemical properties under certain conditions, including most biological conditions. Thus they have different—usually dramatically different—biological activities.
The importance of optical isomerism in almost all life processes cannot be overstated, because nature, as it turns out, shows very strong preferences when it comes to optical isomers. In most cases, one member of the pair will be biologically active while the other will be a dud, having little or no biological activity.
α-Lipoic acid, however, is an exception to this rule: both of its isomers are biologically active, but to very different degrees in different cellular functions.
For purposes of nomenclature, optical isomerism can be handled in different ways, according to different systems of rules. One system involves the prefixes
R (from the Latin rectus, right) and S (from the Latin sinister, left). Since this system is appropriate for use with α-lipoic acid, we have the two isomers called
(R)-α-lipoic acid and (S)-α-lipoic acid (the parentheses are standard practice in this system of nomenclature).*
The two isomers of α-lipoic acid are (R)-α-lipoic acid and (S)-α-lipoic acid.* Only the R-isomer occurs in nature, in both plants and animals, but the S-isomer can be made synthetically, and it too is biologically active (as we saw in the sidebar). Synthesizing individual isomers of optically active compounds, however, is usually more difficult and expensive than synthesizing them together in equal amounts. The latter is standard practice, and the resulting 50:50 combination of isomers is called a racemic mixture.
(R)-α-Lipoic Acid Is Usually the More Biologically Active Isomer
Almost all supplemental α-lipoic acid is racemic: 50% R and 50% S. Thus, to obtain 100 mg, say, of (R)-α-lipoic acid, one could take either 100 mg of that isomer or 200 mg of ordinary, racemic α-lipoic acid (called simply α-lipoic acid), which contains 100 mg of (R)-α-lipoic acid and 100 mg of (S)-α-lipoic acid.
Almost all studies with α-lipoic acid have used the racemic mixture, but a few have used the individual isomers. Not surprisingly, it was found that the naturally occurring (R)-α-lipoic acid is, in most cases, more biologically active (often much more so) than the synthetic
(S)-α-lipoic acid. In cellular energy metabolism and in the biochemical pathway for the synthesis of acetylcholine in brain cells, e.g., the R-isomer is much more biologically active.
In some other cellular functions, however (e.g., in red blood cells), the S-isomer shows equivalent or even somewhat greater biological activity than the R-isomer. Thus it too appears to have therapeutic value, in a tissue-specific manner. These conclusions are drawn from animal studies; there have not yet been any human studies to confirm them.
α-Lipoic Acid Is Highly Bioavailable and Extremely Safe
(R)-α-Lipoic acid is found in a wide variety of foods of plant and animal origin, and deficiencies of this nutrient have never been reported, which suggests that humans are able to synthesize enough of it to meet their routine needs. Nonetheless, supplemental α-lipoic acid is considered highly beneficial, particularly because of its potent antioxidant and insulin-mimetic effects and its role in cellular energy metabolism. It’s absorbed rapidly and efficiently (i.e., it’s highly bioavailable), especially if taken on an empty stomach; some studies have indicated that the R-isomer is absorbed better than the S-isomer; both isomers, however, are rapidly metabolized and eliminated.
Not surprisingly, it was found that the
naturally occurring (R)-α-lipoic acid
is, in most cases, more biologically
active (often much more so) than the
synthetic (S)-α-lipoic acid.
The amounts of α-lipoic acid (racemic) available in typical dietary supplements (200–600 mg/day) are likely about 1000 times greater than the amounts that could be obtained from food, but adverse side effects from such amounts are virtually unknown. A possible consequence of taking large amounts of α-lipoic acid, however, is a modest reduction in the body’s ability to use the B-vitamin biotin. This has not been observed in humans, and whether or not α-lipoic acid supplementation increases our requirement for biotin is unknown—it’s a theoretical possibility.
Rats Seem to Like Biotin with Their α-Lipoic Acid
In a study published in 1997, researchers in Arkansas injected rats daily for 28 days with therapeutic doses of α-lipoic acid (racemic). This moderately reduced the activities of certain biotin-dependent enzymes, possibly because the structural similarities between the α-lipoic acid and biotin molecules allowed the former to displace (to a degree) the latter at the enzymes’ active sites—without, however, activating the enzymes.
Another possibility was that α-lipoic acid inhibited the transport of biotin from the bloodstream into the rats’ cells. In any case, when the researchers administered biotin along with the α-lipoic acid, the suppressed enzyme activities were restored. (The biotin molecule, by the way, can exist in the form of not just two optical isomers, but eight; only one of them occurs in nature.)
One of the less important (though still essential) members of the B-complex, biotin plays a special role in glucose utilization, and it functions in the metabolism of fats and the synthesis of fatty acids and amino acids; it also helps to maintain healthy skin, nails, and hair. Biotin is well absorbed, and deficiencies are very rare. There is no indication that older adults have an increased requirement for this vitamin.
Hit the Bottle!
Wouldn’t it be great if the German doctors’ accidental discovery turned out to be valid, as seems likely from the available evidence gleaned from laboratory and animal studies? Serendipity is a wonderful thing—too bad it can’t be bottled and sold. Among the many things that can be bottled and sold, however, are nutritional supplements. Can you take a hint?
- Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G. Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Therapeut 2006 [online preprint, doi 10.1016/j.pharmthera.2006.07.001]
- Hager K, Marahrens A, Kenklies M, Riederer P, Münch G. Alpha-lipoic acid as a new treatment option for Alzheimer type dementia. Arch Gerontol Geriatr 2001;32:275-82.
- Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames BN. (R)-α-Lipoic acid-supplemented old rats
have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J 1999;13:411-8.
- Higdon J. Lipoic acid. Linus Pauling Institute, Corvallis, OR, 2006.
- Zempleni J, Trusty TA, Mock DM. Lipoic acid reduces the activities of
biotin-dependent carboxylases in rat liver. J Nutr 1997;127:1776-81.
Will Block is the publisher and editorial director of Life Enhancement magazine.