Is lipoic acid a dubious anti-aging compound?
Critique of: Alpha lipoic acid dubious as anti-aging compound - September 9, 9:50 AM- Roanoke Longevity Examiner - by Cara Joyce
DAC=David A. Carlson; Director of R&D for GeroNova Research Inc. (The Lipoic Acid Company)
(DAC) Cara’s blog was forwarded to me for comment from several independent sources and since it keeps appearing on Google alerts, I think it is worth taking the time to critique it line by line. My purpose is to educate and encourage any who are interested in this fascinating molecule by utilizing the references that I am providing to supplement my commentary and for further research. Don’t believe Cara’s opinions or mine. At this end of this critique you should ask yourself whether there is sufficient evidence to make you want to add R-lipoic acid to your nutritional supplement/anti-aging program.
Cara’s blog makes allegations that lipoic acid is “dubious” as an anti-aging compound. She has also raised some legitimate questions frequently overlooked by consumers, lipoic acid vendors as well as scientists. I will first address several of her arguments which rely on misplaced and potentially misleading information. These arguments are largely based on an incomplete understanding of one of the studies from the Linus Pauling Institute (LPI) she refers to (without reference), old definitions, outdated theories of aging and how lipoic acid works in vivo and are no longer in agreement with present theories and documented studies. In addition, the latest aging research indicates new definitions of aging and what to expect from an anti-aging compound are necessary.
After a superficial read of the blog some of the points look logical and valid until they are examined more closely. Cara’s two primary arguments are based on the contentions that although widely classified as such, lipoic acid is not really an “antioxidant” (i.e. a scavenger of free radicals in the body, only in the test tube or in a single rat study). This idea was presumably derived from a couple of recent papers by a top lipoic acid research group at the Linus Pauling Institute (LPI) which I think she misconstrued.
Her second point suggests that since aging has something to do with free radicals, if lipoic acid were really an antioxidant, then it should be able to extend life spans by quenching these radicals. She claims lipoic acid use is unproven as a method to extend the maximum life span of rats or humans and is therefore unproven as a legitimate “anti-aging” compound.
The 2nd point could be made about any current “anti-aging” compound since there is to date no magic bullet that will extend our life-spans just by swallowing it. Does that prove that lipoic acid does not positively affect some aspect of the aging process? Below I will provide a modern definition of “anti-aging” and attempt to clarify the significance of the LPI studies.
(Cara): Alpha lipoic acid is a compound produced in the human body, the bodies of cows and pigs, and in plants like spinach and broccoli, and is touted as a potent energy enhancer and memory stimulant.
(DAC) There are three pharmacologically distinct forms of alpha lipoic acid (R-(+)-alpha lipoic, S- (-)-alpha lipoic and R/S (+/-)- alpha lipoic) which was not mentioned by Cara and some of her comments refer to the R form while others refer to the R/S form. Only R-(+)-alpha lipoic acid is a compound produced in the human body and can contribute to improving the “health-span” in several ways (discussed below) making it a legitimate contender as one of the most important and under-valued nutritional/”anti-aging” supplements available.
The racemic form (+/-) of alpha lipoic acid is found in many nutritional supplements. Also referred to as lipoic acid one half of this form is unnatural and not found in the body of humans, pigs, dogs, cats, rats, bats, plants, bacteria, microbes or any other living bodies (unless it is eaten in pill form, injected or added to culture medium). This should be a hint there may be something unique about the R-form of lipoic acid that differentiates it from plain old alpha lipoic acid. It also cautions against extrapolation of results of studies without consideration of the differences between the three forms.
Lipoic acid is “touted” as an energy enhancer and memory stimulant because people feel it and notice the cognitive improvements themselves, usually quite rapidly. We frequently hand out shots/droppers full of K-RALA-10 (the potassium salt of R-lipoic acid) in water after lunch at trade shows and medical conferences and then wait for people to come back with comments. Invariably the doctors and attendees come back and report they felt more focused and alert during times they would usually want a siesta. You don’t need rats, double blind placebo controlled studies and years of expert discussion to demonstrate this. My parents are in their 80’s and have become considerably more energetic and shockingly lucid after taking GeroNova Research’s R-alpha lipoic acid for the last five years.
(Cara) The supplement companies that synthesize alpha-lipoic acid (ALA) for sale in nutrition stores base their claims on a study done on aging rats that showed that the compound slowed the rate of mitochondrial decay and increased ATP output.
(DAC) First, GeroNova is the only supplement company to my knowledge involved in the synthetic process chemistry associated with lipoic acid production. Most supplement companies encapsulate a product made by foreign chemical manufacturers and do not synthesize lipoic acid or anything else.
Cara is referring to a study that used R-lipoic acid not racemic lipoic acid (ALA). Even though I believe in the superiority of R-lipoic acid over racemic alpha lipoic acid, I have cited a multitude of studies showing a positive effect of both forms of alpha lipoic acid on multiple of biomarkers of aging, not “a” study as she states.
One recent study by Rick Weindruch & Tom Prolla’s group at the University of Wisconsin showing lipoic acid altered gene transcription profiles in aging mouse cerebellums as effectively as caloric restriction (the most widely established method of life extension in animal models). I’ve been trying to get these guys to compare R-lipoic, S-lipoic and racemic lipoic acid but so far they have only used the racemic form (R/S-lipoic acid).
(Cara) Are aging rats biochemically similar to aging humans? In some ways they are similar, but in many ways rats, of course, are radically different biochemically than humans.
(DAC) It is clear that wild-type rats have biochemical similarities and differences with humans and animal models should be validated before extrapolating positive or negative results to humans. In many aging studies specific strains or genetically modified (transgenic) rats with human genes inserted are used specifically because they are accepted and well characterized models for aging and various human diseases.
(Cara) Should people slow mitochondrial degradation and pump out greater quantities of ATP?
(DAC) Yes. The age-related changes in mitochondrial function affect both rats, mice and humans similarly, which is one of the reasons why rats and mice are used in these studies. Additionally they are short lived and easier to study than long lived species.
(Cara) Perhaps so if ALA is working on healthy cells; however, if ALA works equally well to lengthen the lifespan of the multitude of cancer cells which arise in the body and which the body actively tries to destroy then probably no.
(DAC) This is a valid and frequently overlooked point concerning the possibility of inadvertently lengthening the lifespan or causing proliferation of cancer cells. Is there any evidence lipoic acid consumers should be concerned about this?
A recent study showed lipoic acid was good at destroying human lung cancer cells.
Choi SY, Yu JH, Kim H. Mechanism of alpha-lipoic acid-induced apoptosis of lung cancer cells. Ann N Y Acad Sci (2009)1171:149-55.
Another recent study showed lipoic acid killed liver cancer cells.
Shi DY, Liu HL, Stern JS, Yu PZ, Liu SL. Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway. FEBS Lett (2008) 582(12)1667-71.
There is some evidence that high concentrations (100 uM) of lipoic acid in cell culture destroyed cancer cells while sparing normal cells but low concentrations (1uM) acted as a growth factor and increased cellular proliferation.
Dovinova I, Novotny L, Rauko P, Kvasnicka P: Combined effect of lipoic acid and doxorubicyn in murine leukemia. Neoplasma (1999) 46:237–241.
Bilska A, Wodek L. Lipoic acid - the drug of the future? Pharmacol Rep (2005) 57(5):570-7. (free download here)
Animal studies indicate the activation of a cytoprotective transcription factor named Nrf2 (which I believe is a large a part of the primary “anti-aging” mechanism of action of R-lipoic acid) also requires ~100 uM and can be achieved using 600-800 mg of our “BioenhancedTM R-lipoic acid products. So the same concentration that killed cancer cells also induces the protective mechanisms that lead to an “anti-aging” effect. This also argues for the superiority and possibly the safety of high doses of R-lipoic acid versus low, “supplemental” doses of alpha lipoic acid which yields blood and tissue levels 75% lower.
Another study, by Karen van de Mark et al, showed lipoic acid caused apoptosis of cancer cells (lipoic acid blows up cancer cells by activating a self destruct program) but the relevance of these studies to the doses used and concentrations achieved by humans is not known. It may be possible to achieve these high concentrations by direct injection of lipoic acid into a tumor and should be studied more carefully in the future.
Van de Mark K, Chen JS, Steliou K, Perrine SP, Faller DV. Alpha-lipoic acid induces p27Kip-dependent cell cycle arrest in non-transformed cell lines and apoptosis in tumor cell lines. J Cell Physiol (2003) 194(3)325-40.
Lipoic acid itself is not carcinogenic or mutagenic and there is no evidence that people consuming it are feeding pre-existing cancers.
Cremer DR, Rabeler R, Roberts A, Lynch B. Safety evaluation of alpha-lipoic acid (ALA). Regul Toxicol Pharmacol (2006) 46(1)29-41. Epub 2006 Aug 14.
Cremer DR, Rabeler R, Roberts A, Lynch B. Long-term safety of alpha-lipoic acid (ALA) consumption: A 2-year study. Regul Toxicol Pharmacol (2006) 46(3)193-201.
There are several studies by Dr Mantovani et al (a cancer specialist) showing lipoic acid in combo with other nutrients was beneficial to cancer patients. More importantly the studies indicate the possibility of Nrf2 activation in humans. I consider this to be at the top of the list for how R-alpha lipoic acid performs its magic. It’s known to help protect normal cells from becoming abnormal tumor cells.
Please type lipoic acid, Mantovani, into the PubMed search engine for the www.pubmed.org references.
(Cara) One of the proposed mechanisms of aging involves cell damage by highly reactive compounds called free radicals. Free radicals oxidize compounds essential to healthy cell functioning and so disturb that functioning. Anti-oxidants can prevent destruction of essential compounds or restore the correct chemical state of those compounds, depending on the mechanism of action of the anti-oxidant.
(DAC) The current thinking in the aging/gerontology research community is that free radicals are implicated in aging but not necessarily causative. Many other factors contribute to age-related decline. It is more likely that the cellular defense systems break down and accumulated damage to macromolecules is the result leading to many of the changes associated with old age. Since free radicals also have many critical roles in maintaining normal cell function it is not surprising that you can’t stop aging simply by eating antioxidants.
Cara’s argument is misplaced because it is now clear that aging is not “caused” by free radicals and that lipoic acid is NOT (primarily) an antioxidant and antioxidants can’t cure or reverse aging. This does not mean that lipoic acid has no beneficial effects in reversing some critical age-related biomarkers.
On the other hand, R-lipoic acid has been shown to increase our natural defenses against many metabolic and environmental insults and likely (and paradoxically) works by a pro-oxidative/stressor mechanism to help the cell become more resilient to oxidants and stress.
Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep (2005) 10(1)52-60.
Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress.
Curr Med Chem (2004) 11(9) 1135-46. Review.
Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A (2004) 101(10) 3381-6. Epub 2004 Feb 25.
Suh JH, Wang H, Liu RM, Liu J, Hagen TM.(R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys (2004) 423(1) 126-35.
Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Ann N Y Acad Sci (2002) 959:491-507. Review.
A few years ago I attended the SENS conference in Cambridge, UK where the point was made that life extension (increasing the life span) alone is not the “gold standard” or even the primary goal since long lived people would almost all be susceptible to and to ultimately die from Alzheimer’s disease or cancer. Therefore, if lipoic acid can help protect geriatrics from either disease then it could qualify as an “anti-aging” compound. Our study below was based on a human clinical trial of AD patients in Germany and showed that lipoic acid slowed the progression of AD.
Maczurek A, Hager K, Kenlies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Advanced Drug Delivery Reviews (2008).
See the above references for potential anti-cancer effects of lipoic acid.
(Cara) “… depending on the mechanism of action of the anti-oxidant”.
(DAC) This last part of the previous statement is misplaced and floating here without any clear purpose.
(Cara) Alpha lipoic acid is advertised also as an anti-oxidant that dissolves in both fat and water and so scavenges free radicals more effectively than even vitamins C and E, since vitamin C is only water soluble and vitamin E is only fat soluble. The evidence for such activity in the human body is absolutely absent from the literature.
(DAC) After recently viewing the U-tube blogs about lipoic acid, I can see why Cara would want to make this point. Unfortunately her argument is not technically correct since the evidence for such activity is present in the literature.
The chemical structure and properties of lipoic acid prove indisputably that it is soluble in both fat and water layers of the cell but as Cara indicated this does not mean this is how it “functions” (meaning its mechanism of action) in the cell, since this argument is usually connected to its antioxidant activities. The aqueous and fat solubility of lipoic acid clearly has an effect on how lipoic acid gets absorbed, travels in blood, enters the cell, indicates where it is likely to concentrate within and even what it might react with. I guarantee lipoic acid can be found in both aqueous and fatty parts of the cell since we have solid experimental evidence.
Please see my previous blogs about the limitations of labeling or branding lipoic acid as an antioxidant/radical scavenger.
I agree with Cara and Tory Hagen’s group from LPI that lipoic acid is likely NOT primarily an in vivo antioxidant (meaning a scavenger of free radicals). Despite this, it is NOT accurate to claim there is no evidence of antioxidant activity in humans.
A study by Karen Marangon et al showed 600 mg/day of lipoic acid reduced urinary isoprostanes and reduced low density lipoprotein (LDL) and plasma oxidation in 16 human subjects, thus proving an antioxidant effect.
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.
A brand new, ahead of press study showed that lipoic acid prevented the age related decline to human skeletal muscle associated with oxidative stress.
Wray DW, Nishiyama SK, Monnet A, Wary C, Duteil SS, Carlier PG, Richardson RS. Antioxidants and Aging: NMR-based Evidence of Improved Skeletal Muscle Perfusion and Energetics. Am J Physiol Heart Circ Physiol (2009).
As I discussed in my book chapter and OCC presentation, it would be more technically correct to label lipoic acid as a” redox stressor” that induces cellular protective mechanisms and therefore makes the cell more resistant to the ravages of time.
Carlson DA, Young KL, Fischer SJ, Ulrich H. An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Human Subjects. Chapter 10 in: Packer L, Patel M, eds. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. London, England: Taylor & Francis Publishers (2008):235-270.
Further characterization of the lipoic acid enantiomers provide new research opportunities. Stereochemistry, Pharmacokinetics & Metabolism: Toward a Comprehensive Mechanism of Action. Oxygen Club of California PowerPoint presentation by David A. Carlson ( March 15, 2008).
(DAC) If aging can not be “cured” by antioxidants because aging is NOT caused by free radicals then what is the relevance of claiming lipoic acid is not an antioxidant? I fail to see how lipoic acid is disqualified as an “anti-aging” compound. What if lipoic acid worked by a different mechanism that has nothing to do with its antioxidant effects? Does Cara mean there is no evidence lipoic acid can make you live longer?
Aging studies are difficult to do in long lived species which is why transgenic rats or mice are used. Cara’s statement is misleading because as mentioned both above and below several human and animal studies have demonstrated lipoic acid can improve a number of markers of oxidative stress and aging. Again the question remains as to how? Lipoic acid clearly will react with many radical species that it encounters but the problem is that it is present in such low concentrations within the cell relative to other antioxidants such as vitamin C and glutathione (by factors of 100-1000) and so briefly that it is not likely to be its primary mechanism of action in the body.
This short time lipoic acid is in the body is also the rationale proposed for using a controlled release form of lipoic acid (CRLA). Please see my arguments against CRLA. View pdf
(Cara) The only evidence available about the anti-oxidant quality of alpha-lipoic acid is that it works as an anti-oxidant in a lab dish, not in a living mammal. Hydrochloric acid is a powerful anti-oxidant in a dish but does that mean it will work effectively in the human body? Absolutely not. Hydrochloric acid is, as everyone knows, a potent caustic poison.
(DAC) I have no idea what she is talking about regarding HCl. I just spoke to Dr. Anthony Sanchez, a GeroNova chemist and he had no idea what she is talking about either as we could find no reference of hydrochloric acid being an in vitro antioxidant. It would be surprising if it were an antioxidant since it is not redox active (giving and/or receiving electrons). Calling HCl a caustic poison without pointing out that it occurs naturally in the stomach and is necessary for digestion seems misdirected at best.
I have said and published repeatedly that lipoic acid is likely NOT (primarily) a scavenger of free radicals in vivo but that doesn’t mean that it has no antioxidant effects. For example as I discussed in a previous blog, R lipoic acid activates the Antioxidant Response Element (ARE) which causes cells to increase production of protective genes and enzymes which reduce oxidative stress without necessarily directly scavenging radicals. View here:
(Cara) According to the Linus Pauling Institute in Oregon, alpha-lipoic acid introduced to cells is rapidly converted to dihydrolipoic acid and transported out of the cell--perhaps in such short order that it has no time to repair or prevent damage to any compounds.
(DAC) I think she means researchers at LPI. She doesn’t mention them by name but she is presumably talking about a couple of Tory Hagen’s latest papers. See my previous blog for references.
That is not exactly what they said; they said that lipoic acid has unique properties although it is not likely functioning as a radical scavenger.
Please see their final quote here:
They do not say that it “has no time to repair or prevent damage to any compounds”. In fact because of the unique and low redox potential of lipoic acid it can affect the redox status of many compounds despite its low concentrations and short intracellular residence time. This is one of the things differentiating lipoic acid from the other so called antioxidants.
(Cara) In addition, alpha lipoic acid has been shown to worsen Type 1 diabetes in rats that were altered to have the disease.
(DAC) What does T1D have to do with aging? T1D is considered to be an autoimmune disorder with genetic components and most experts that have used lipoic acid clinically do so for T2D and subsequent neuropathies which is associated with aging. Is Cara now relying on a single rat study to imply that maybe a similar thing could happen in humans? She can’t have it both ways. Previously she rejected lipoic acid as an anti-aging compound because she claimed there was only a single rat study (which I countered by providing multiple references). Most studies showing a benefit of lipoic acid in diabetics have been in T2D and in the ensuing neuropathy not T1D. Significantly, a recent Bosnian study showed that lipoic acid was beneficial in treating neuropathy in both T1D and T2D in humans. I guess we don’t have to rely on animal models in this case.
Burekovi A, Terzi M, Alajbegovi S, Vukojevi Z, Hadzi N. The role of alpha-lipoic acid in diabetic polyneuropathy treatment. Bosn J Basic Med Sci (2008) 8(4) 341-5.
(Cara) On the other hand, a recent study showed that it reduced triglycerides in mice.
(DAC) This is another apparent difference between animals and humans. We have seen no evidence alpha lipoic acid or R-lipoic acid reduces triglycerides (TG’s) in humans but maybe this is because the R-lipoic acid itself is incorporated into TG’s and the usual tests are not sensitive enough to determine the composition of the TG’s. The effect of R-lipoic acid (as sodium R-lipoate) on atherosclerosis & TG’s is being investigated now in a placebo-controlled clinical trial at LPI that we provided the capsules for.
(Cara) One pharmacological study indicated that a dose of 600 mg/day for about three weeks decreased peripheral neuropathy (nerve damage outside the central nervous system) associated with diabetes.
( DAC) There are many studies. See references:
(Cara) Another study showed a marked reversal of liver damage in alpha-lipoic acid dosed humans.
(DAC) I’m not sure what study she is referring to here but there were several European and Japanese studies done in the 50’s and 60’s demonstrating this in humans as well as Dr Berkson’s studies showing liver regeneration in humans after Amanita poisoning. The benefit to lipoic acid to liver function and repair was one of the earliest recognized benefits of LA but has been under appreciated. Certainly liver damage and loss of function is associated with aging so this suggests a benefit to aging humans. Remember, liver physiology affects many systems outside the liver.
(Cara) At the present the data on alpha lipoic acid is conflicting and full of more gaps than facts, so its benefit to human longevity is not established.
(DAC) I’m not sure what data is “conflicting”. Does she mean conflicting results from various animal studies or has she found studies that show lipoic acid shortens the lifespan? Again this is the problem with trying to extrapolate the results of animal studies to humans without qualification. One interesting study showed that R-lipoic acid increased the life-spans of immunosuppressed mice (frequently used in aging studies) but S-lipoic acid shortened their lives, once again indicating differences between the forms of lipoic acid, specifically related to aging.
Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. Arzneimittelforschung (1997) 47(6) 776-80.
Most experts on aging no longer consider increased longevity (increasing the maximum lifespan of 90% of the population of a test species) as the desired endpoint for aging studies. It is far more relevant to find compounds and methods to increase the “health-span” (improving life quality for longer periods of time rather than the dramatic decline and loss of function occurring in most humans between the 5th and 8th decades of life).
Aging studies and the effects of nutrients and drugs on longevity is extremely challenging to do in long lived species. It is easier to correlate changes to specific markers known to change with age. In this case R-lipoic acid has passed the preliminary tests but we still have a long way to go to determine the optimal dosing strategies and synergism with other compounds. I am currently writing an article for peer review providing a comprehensive list of age-related markers improved by lipoic acid.
When I asked Dr. Aubrey de Grey what he thought about the benefits of R-lipoic acid in aging and cellular redox control, he said that it would not add a 1000 years to our life spans but probably at least 10 years. That is a significant gain for a vital 90 year old. Even if lipoic acid will not make us live 20 years longer it has been shown to reduce or improve many of symptoms of aging that ultimately break us down & kill us. Therefore, R-lipoic acid is in my opinion one of the best “anti-aging” compounds currently available.
(Cara) Synthetic ALA is sold at Nature's Outlet in several locations in Roanoke. The primary food sources for ALA are beef and pork, and these are sold at all grocery stores in Roanoke, including Sav-A-Lot, Food Lion and Kroger.
(DAC) The best natural source of RLA is spinach but you would have to eat 700 lbs/day in order to obtain a 100 mg dose. This is obviously not very practical and no one has shown that the EXTREMELY low amounts found in beef, pork or spinach have ANY effect whatsoever. As mentioned above, the anti-aging benefits are achieved by higher and not lower doses.
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