Acetyl L-Carnitine and Lipoic Acid—Dual Powerhouses
Together with its ally lipoic acid,
it retards aging by enhancing mitochondrial function
Have you visited a nuclear power plant lately? If so, you probably didn’t just walk in off the street, unannounced. There’s a security perimeter, and it takes a certain amount of effort to gain entry—you have to show your bona fides and persuade the guards that you’re not a terrorist (you’re not, are you?). Similar restrictions apply to the nuclear fuel that powers the reactor: it doesn’t just flow in through a pipeline like gas or oil—it can’t flow, actually, because it’s in the form of solid rods—it must be brought in, safely, by authorized personnel. And when it’s spent, some years later, it has to be taken out, safely, for disposal somewhere (don’t ask).
Drawing of a typical human cell, which contains thousands of mitochondria and other organelles suspended in the cytoplasm.
An analogous scenario plays out in all the cells of your body, all the time. There the power plants are mitochondria, which are tiny, kidney-bean-shaped organelles found within the cytoplasm (the aqueous interior) of every cell. Each mitochondrion’s “security perimeter” is its own outer membrane (a double membrane, actually, one inside the other), virtually identical in chemical composition to the single membrane that encloses the cell itself. And the mitochondrial guards are certain molecules embedded in the outer membrane that are able to distinguish friend from foe, chemically speaking.
Fatty Acids Are Molecular Fuel Rods
Now along comes some fuel, seeking entry to a mitochondrion. The fuel is needed for chemical energy generation, a process that, with the indispensable assistance of coenzyme Q10, results in production of the body’s master energy molecule, adenosine triphosphate, or ATP.* The primary fuel for biological energy generation is glucose, but that’s not the one we’re interested in today. A secondary—but very important—type of fuel is fatty acids, the molecules that, when combined with glycerol, make fats (triglycerides).
Fatty acids are long, skinny molecules that look rodlike when depicted on paper, but they’re flexible and bendable, like a garden hose with kinks in it. They’re especially important contributors to energy production in our hearts, where the demand for energy is high all the time (if your heart decides to stop and take a rest, you’re in big trouble).
Carnitine Delivers the Fuel . . .
In any case, fatty acids can’t just waltz into a mitochondrion, any more than you could waltz into a nuclear power plant. They must be brought in safely, under the watchful gaze of the molecular sentries, by authorized “personnel.” And who are these tiny fuel facilitators? They’re molecules of carnitine, an amino acid whose main role in our bodies is to transport fatty acids into our mitochondria when they’re needed there, and to transport them and their metabolic derivatives back out in case they accumulate to excess.
Carnitine (which is technically called L-carnitine, but the meaning of the L need not concern us) is not one of the 20 amino acids commonly found in the proteins of our foods. It is made, however, in all of our body’s cells, from two that are: lysine and methionine. The principal food sources of carnitine are red meat and dairy products. This compound was once thought to be a vitamin, but since our bodies make it, we now know that it’s not.
. . . And Acetyl L-Carnitine Delivers the Deliverer
The trouble is, our carnitine levels decline with age, as is true of so many other important biological compounds. That’s where a certain nutritional supplement, acetyl L-carnitine, comes in. We take this simple chemical derivative of carnitine instead of carnitine itself because, in a nice bit of irony, carnitine is not easily transportable into our cells (especially brain cells, which are protected by the blood-brain barrier), but acetyl L-carnitine is. Once inside the cell (in the cytoplasm), the molecule’s acetyl group is removed by enzymes, and the free carnitine is ready for action. (The acetyl group does not go to waste—acetyl groups are very important in a variety of metabolic processes and are always put to good use.)
Considering the central role that cellular energy metabolism (also known as cellular respiration) plays in keeping us alive, one would expect that supplementing with acetyl L-carnitine (ALC) could enhance our mitochondrial function—which it does—and thus improve our health in various ways. Since energy is the key concept here, one might wonder whether ALC would be helpful in chronic fatigue syndrome. Indeed, it does appear to help (see “Acetyl L-Carnitine May Help with Chronic Fatigue” in the August 2004 issue). The study that demonstrated this was not well designed, however, so the results, while encouraging, are not as convincing as one would like.
A Meta-Analysis of ALC Studies
At the other end of the quality scale is a new study that evaluated the ability of ALC to help patients with mild cognitive impairment or mild Alzheimer’s disease, for which this nutrient has been used therapeutically for many years. The study was actually a meta-analysis, in which experts in a given field critically review all the recent clinical trials on a given topic, use rigorous selection criteria to identify the best ones, pool all the data from these studies, apply sophisticated mathematical techniques to the data to correct for the inevitable differences (typically many) in the study protocols, analyze the results, and draw conclusions.
By the nature of the process (if it’s done well, with complete objectivity), these conclusions will have a much higher level of statistical validity than was possible in any one study—which is the whole point. This is especially helpful when different studies that appear to be of high quality have nonetheless given conflicting results—a not uncommon occurrence with clinical trials, which can be very difficult to design and conduct well. A major bugaboo, always, is the potential for inadvertent bias owing to some aspect of the protocol. The meta-analysts must make strenuous efforts to ferret out any methodological biases and correct for them.
ALC Protects Brain Function … By Powering Brain Cells?
The authors of the new meta-analysis evaluated 90 studies, of which 21 made the grade. All were randomized, double-blind, placebo-controlled studies that had been published between 1983 and 2000, having been conducted in Italy, Great Britain, Germany, and the United States. They ranged in duration from 3 to 12 months, and the ALC dosages ranged from 1500 mg (1.5 g) to 3000 mg (3.0 g) per day; the supplement was well tolerated in all the studies. The total number of patients included in the studies was 1479, of whom 1204 had end-study assessments and were available for analysis; their average age was 72, and 59% were women.
A total of 54 kinds of evaluation scales were employed in the studies. They included 12 clinical test batteries to assess the severity of the disease (limited to mild cognitive impairment or mild Alzheimer’s); 40 psychometric tests to assess memory, attention/performance, higher intellectual functions, learning, and drawing; and two clinician ratings on disease change during the study.
With regard to the two dosages used, there were no significant differences in outcomes, which were convincingly positive. In the authors’ own words,
Our meta-analysis of placebo-controlled studies found a significant advantage for Alcar [acetyl L-carnitine] compared to placebo, and this was seen both in a composite measure of effect size on clinical and psychometric assessment scales and on the clinicians’ assessment of improvement. … The secondary analysis of the psychometric tests shows highest efficacy for Alcar on memory and intellectual functions. This is important because memory deficits and disturbed intellectual function are the most pronounced deficits in mild cognitive impairment. … In summary, the positive effect in this meta-analysis of Alcar compared with placebo in improving mild cognitive impairment or preventing deterioration suggests that Alcar should be considered for treatment of these important conditions.
It’s not unreasonable to think that these positive results could be due, at least in part, to the role of carnitine in enhancing mitochondrial energy production in brain cells. It stands to reason, after all, that the better the individual cells of the brain are functioning, the better the brain as a whole can function.
Mitochondrial Damage May Cause Aging
An important question regarding brain function is the degree to which the mitochondria might be suffering damage caused by the nemesis of biological molecules: free radicals,or reactive oxygen species. These destructive entities are believed to be a major factor in the aging process throughout the body, but especially in the brain, where cellular energy metabolism runs at the highest level found in any tissue. In a cruel irony, the primary source of free radicals is … cellular energy metabolism, the very process that makes life possible. And it occurs in the mitochondria.
Thus, mitochondrial damage is strongly implicated in aging, which reinforces the idea that supplemental acetyl L-carnitine may be beneficial in retarding this process—and indeed there is much evidence that it is beneficial. There is a problem, however: whereas carnitine can improve mitochondrial function, it can’t prevent free radical damage, because it’s not an antioxidant. In fact, carnitine (at very high dosages in old rats) has been observed to increase, not decrease, oxidant activity in mitochondria.
ALC Needs Lipoic Acid for Optimal Efficacy
It’s therefore important—in the opinion of the renowned scientist Bruce Ames, a professor of biochemistry and molecular biology at the University of California, Berkeley, and the leading authority on the mitochondrial theory of aging—that supplemental acetyl L-carnitine be accompanied by an antioxidant to offset this effect and help prevent free radical damage to the mitochondria.
The antioxidant that Professor Ames recommends is lipoic acid (also called alpha-lipoic acid), an unusual kind of fatty acid that was also once thought, incorrectly, to be a vitamin. It has been described by Ames’s equally renowned UC Berkeley colleague Lester Packer—the leading authority on antioxidants—as the linchpin of the body’s antioxidant network and the “antioxidant’s antioxidant.” Lipoic acid is that important. (See “Can Acetyl L-Carnitine and Lipoic Acid Slow the Aging Process?” in the October 2004 issue.)
ALC Helps Nerve Pain in Diabetes
The most common complication of late-stage type 1 or type 2 diabetes is peripheral neuropathy (nerve damage), a generalized disorder of nerves in the extremities, usually beginning in the feet and working its way upward. It can lead to numbness of the extremities (which is dangerous because injuries may go unnoticed), but it can also cause pain that can be severe. Other symptoms include weakness and a loss of sensation of temperature (also dangerous!) or vibration.
Diabetic patients are known to be deficient in carnitine. Because preclinical studies with acetyl L-carnitine have shown this compound to be helpful in correcting a number of metabolic disturbances that play a role in the early pathogenesis of diabetic neuropathy, a large international research team undertook a study to assess ALC’s ability to help patients who have this disorder.
The study was actually carried out as two parallel, randomized, double-blind, placebo-controlled studies, each of 52 weeks’ duration, with different dosages of ALC: 500 mg and 1000 mg, each taken 3 times daily, for totals of 1500 and 3000 mg/day, respectively. The 1257 patients, aged 18–70, had type 1 or type 2 diabetes with established peripheral neuropathy. (Type 2 diabetes, as terrible a disease as it is, is less severe than type 1 diabetes, and it progresses at a slower pace.)
The researchers found that ALC supplementation at 3000 mg/day significantly improved pain symptoms in the 27% of patients who had reported pain as their most bothersome symptom at the outset of the studies. The patients who benefited the most were those whose diabetes was of the shortest duration, which underscores the importance of early intervention rather than waiting for the condition to worsen and become less responsive to treatment.
Biopsies of the sural nerve (a major nerve in the calf) showed that ALC at both dosages improved the number of nerve fibers and the regeneration of nerve-fiber clusters. Thus, some of the nerve damage caused by diabetic neuropathy was reversed. Finally, there was an increase in vibration perception, another indication of improved nerve function.
- Sima AAF, Calvani M, Mehra M, Amato A, for the Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy. Diabetes Care2005;28:89-94.
Carnitine and Lipoic Acid Improve Heart Function
Scientists in India have just published a study providing further evidence for the efficacy of carnitine and lipoic acid in combating the mitochondrial damage associated with aging. After administering very large doses of carnitine and lipoic acid to both young and old laboratory rats for 1 month, they examined the rats’ heart cells for evidence of certain enzyme activities related to cellular energy metabolism. The dual-purpose supplement substantially reversed the age-related decay in mitochondrial enzyme activities in the old rats’ hearts, bringing these activities to near-normal levels (the supplementation had no effect in the young rats). The positive effects were greater with the combined supplements than with either one alone.
The authors cited other research showing that this same supplement combination can stimulate the reversal of age-related decline in the functional integrity of mitochondrial membranes, which play an important role in overall mitochondrial function, and that it can help prevent oxidative damage to mitochondrial DNA. The latter finding is particularly important because the age-related degradation of mitochondrial DNA is believed to be a major cause of the symptoms of aging in general—this is a key feature of the mitochondrial theory of aging alluded to above.
A Surprise Ending
Carnitine plays a vital role in our bodies, and the evidence that its derivative acetyl L-carnitine can help protect us from the insidious decay of the aging process—especially when partnered with its ally lipoic acid—is very strong. It’s surprising, therefore, that ALC (and, for that matter, lipoic acid) is not more widely known and appreciated by the general public. It’s one of those supplements that have somehow managed to remain largely under the radar despite offering substantial benefits for our health and longevity. But at least you now know about it. So power up with ALC and lipoic acid!
And for a variety of other health benefits that ALC can offer—including one that’s kind of hard to believe, but true—see “Acetyl L-Carnitine Can Help Straighten Your Penis”in the October 2001 issue. (Now aren’t you glad you read this article all the way to the end?)
- Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double-blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol 2003;18:61-71.
- Ames BN, Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Ann NY Acad Sci 2004;1033:108-16.
- Hagen TM, Ingersoll RT, Wehr CM, Lykkesfeldt J, Vinarsky V, Bartholomew JC, Song MH, Ames BN. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci USA1998;95:9562-6.
- Packer L, Colman C. The Antioxidant Miracle. John Wiley & Sons, New York, 1999.
- Savitha S, Sivarajan K, Haripriya D, Kokilavani V, Panneerselvam C. Efficacy of levo-carnitine and alpha-lipoic acid in ameliorating the decline in mitochondrial enzymes during aging. Clin Nutr 2005;online preprint: PMID 15919137.