Betsy Speicher

Alpha-Lipoic Acid

3 posts in this topic

Would the latest research indicate there is any value in taking alpha-lipoic acid supplements? If so, what would be the recommended dosage?

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If I can add-on: Would the r-isomer or s-isomer form be preffered in non-diabetic humans?

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Dear Betsy and Bryan,

I am aware from private conversations that there is a fair amount of interest in this topic amongst members of The Forum, and some might be sufficiently interested to start or stop taking pills based on my answer to your questions. That leads me to do two things: first, I am restating the standard disclaimer that I am not a medical doctor, and that my comments here should not be construed by readers as personal or even general medical advice; second, I am providing a particularly long and detailed elaboration of the reasoning which led to my conclusion on this topic. Readers who want only the conclusion should skip to the final paragraph of this message.

With that as preamble, let me go into details for those who are interested.

The main source of claims for a health benefit of alpha-lipoic acid (LA) appears to be Juvenon, Inc.:

www.juvenon.com

Their product, JuvenonTM, contains both LA and acetyl-L-carnitine (ALCAR), and this combination is claimed to be more beneficial than either compound alone. They recommend dosages of 400 mg LA + 1000 mg ALCAR per day for most people, while noting that some individuals prefer half or double these amounts. LA (the R isomer) is one of many molecules required for the conversion of sugar and oxygen to water and carbon dioxide, during which energy is extracted, mainly in a compartment of the cell called the mitochondrion. LA (the R or S isomer) is also an antioxidant. L-carnitine is a molecule required to transport fatty acids into mitochondria, where they are broken down to produce energy. ALCAR is a derivative that enters cells more readily than L-carnitine. JuvenonTM has various other components, mostly inactive, which it is not necessary to discuss here.

R-LA and L-carnitine occur naturally in the body. The rationale for predicting a beneficial effect of supplementation is that: (1) ALCAR should replenish an energy source (carnitine) which becomes depleted during aging, (2) such replenishment should improve the amount and efficiency of mitochondrial metabolic activity, and (3) LA should also enhance energy production, facilitating the effect of ALCAR, and should simultaneously neutralize oxidants formed as a result of the increased metabolic activity.

My questions, as I read the literature, are: (1) whether restoring LA and carnitine in older humans to the level in young humans will reverse any other age-related changes, and (2) whether there will be a price to pay in terms of side effects. A relatively minor, initial concern is that the cell naturally contains L-carnitine and R-LA, whereas the supplement contains ALCAR and equal amounts of the R and S forms of LA; however, I am not aware of any reason to be concerned by these differences of chemical formulation. On the other hand, the fact that they are "natural" products does not automatically mean that supplementation is safe, because problems can arise from changes either in types or amounts of different molecules in the body. So, the question remains: how confident can I be that long-term supplementation will be safe and beneficial? This is the question which goes beyond uncontroversial, textbook biochemistry, and on which I approach the Juvenon site and literature with a need to be taught or persuaded.

Without implying an appeal to authority, I begin by considering the source of claims for ALCAR + LA. The Juvenon Scientific Advisory Board consists of six individuals who are listed as having very extensive academic research credentials - not amateurs, but professionals in the field of aging, who are well qualified to judge the research results. For those readers who know me but are not otherwise acquainted with this field, and who might wonder how much you can trust what you read on the internet, the first thing to say is that there is no "hoax" here. The Board members do actually exist (I am professionally acquainted with three of them, and share departmental affiliation with one board member), they are established senior investigators, and they are the authors of the scientific papers listed on the Juvenon website. Of course, that is not to say that everyone who studies the biology of aging is equally optimistic about the prospects of slowing the aging process, or even about the meaning of existing data.

Turning to the evidence, the Juvenon site indicates that the product was developed based on short-term animal tests, but that in humans, it "has an overall effect of promoting a healthier, more energetic body." They state that the product was tested in approximately 50 healthy, elderly volunteers before it was brought to market, and that the "anecdotal results" obtained in this "non-clinical setting" led to a double-blind, placebo-controlled clinical trial that was conducted in 2001. It is not stated explicitly, but that probably refers to their "energy study", involving 18 men, ages 60-71, supplemented over part of a 17-week period (the 17 weeks also included "washout" and placebo feeding intervals). The results were "positive" for a majority of the 18 men for 8 out of 9 markers of oxidative stress, and the majority also scored more highly on a psychological test of "subjective perceptions related to mood and general health." I note, however, that the results were "posted at a conference", rather than published in a scientific journal, and that the site makes no claims about the magnitude or statistical significance of the effects.

Juvenon is currently recruiting 180 subjects for a study of cognitive effects of their product over a 12-week period, but results from that study will not be available for some time. I find no results in a search of the medical literature for "Juvenon", and the site advertising the planned study makes reference to peer-reviewed studies only in laboratory animals. They do also state that a study has been conducted on 43 cardiovascular patients, over an 8-week period of supplementation, but the results have yet to be analysed or presented. Consequently, we can rely only on anecdotal evidence of human effects.

Even this anecdotal evidence appears to be quite limited, both in terms of the numbers of individuals involved and the duration of supplement use. Juvenon provides brief testimonials from 12 customers who stated that their energy levels and sleep were improved by the supplements, but there is no way to know whether these subjective impressions are representative of a majority of customers, or whether they would be likely to persist. Most of the testimonials do not indicate how long the supplements were consumed, so they do not address the question whether long-term use (e.g. for several years) could have adverse effects. I did notice that one testimonial indicated a constant beneficial effect for nearly 6 months, but then a reader of the Juvenon Health Journal (07/05) wrote that the beneficial effect on sleep disappeared after just 5 weeks. Juvenon also claims to have received hundreds of e-mail messages from supplement users reporting "a wide variety of undocumented positive effects, negative side effects, alternative approaches to dosing, possible relief from various conditions, and the like." They are constructing a database to present these "anecdotal reports", but it is not yet available. Clearly, if everything presented by the proponents of these supplements is accepted, then the evidence for positive effects in humans is still very modest, and there is at least a hint at negative effects.

Moving on to the animal tests, the fundamental question is whether LA supplementation can extend the life span. The Abstract of a study of immunosuppressed mice (14/group) states that a 350 mg/kg body weight dose of the R + S mixture decreased the life span significantly, whereas the S form at 75 mg/kg and the R form at 9 mg/kg each had positive effects on only 1 out of 3 indices of longevity (H.J. Freisleben et al., Arzneimittelforschung, Vol. 42, pp. 776-80, 1997). A larger study of standard laboratory mice (60/group) showed no significant effect of LA on life span (C.-K. Lee et al., Free Radical Biology & Medicine, Vol. 36, pp. 1043-57, 2004).

The main interest in ALCAR + LA supplementation appears to be based on three studies directed by Juvenon Board members, and published in 2002 in Proceedings of the National Academy of Sciences of the USA: Vol. 99, pp. 1870-1875, pp. 1876-1881, and pp. 2356-2361. The findings of these studies are summarized in a UC Berkeley Press Release:

http://www.juvenon.com/news/press_021802.htm

In the following paragraphs, I provide brief "mini-reviews" of these articles. Note in advance, however, that none of them test for effects on longevity.

pp. 1870-1875, title: "Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress": I had five different concerns about the methodology used in this study: (i) the LA was mixed into Dyets AIN-93M chow and the unsupplemented animals were fed Purina rodent chow (I found the composition of AIN-93M but not Purina chow on the internet, so I cannot tell whether other components of the diet were different), (ii) the young and old animals were from the same strain, but apparently not from the same laboratories, so differences in handling could arise, (iii) the young rats were very young (ages listed as 2-4 months in the Abstract and 3-5 months in the Methods section; aside from the discrepancy, I wonder whether the youngest animals were immature, and in any case stronger evidence could be obtained by using more than two age groups), (iv) supplementation was for 1 month with ALCAR and 2 weeks with LA, but there is no indication here or in the Abstracts of several earlier studies that these feeding intervals were compared with other intervals, to ensure that they were long enough to obtain the maximum beneficial effect or to ensure that the effects were not transient (in other words, more evidence would be obtained from a time course than a single feeding interval), and (v) likewise, more evidence would be obtained from a dose-response curve than from supplementation at only one concentration of LA and ALCAR. The combined supplements did appear to make the animals more active and partly reversed oxidative damage caused by aging or by ALCAR alone, but I hesitate to comment about the mitochondrial function (because of the age groups employed) or the measurement of oxidant production (because it is expressed per unit of oxygen consumption, which itself declines as a function of age). I suspect those latter results do indicate a real benefit, but what I really want to know is whether ALCAR + LA would increase or decrease the life expectancy of those old rats.

pp. 1876-1881, title: "Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-alpha-lipoic acid": The key finding of this study was that supplementation with ALCAR + LA protects the enzyme which metabolizes ALCAR from age-related oxidative inactivation. In apparent agreement with the authors, I interpret the results as showing that ALCAR prevents oxidation by binding normally to the enzyme, thereby making its binding site inaccessible to oxidants. LA enhances this effect by decreasing the rate of production of the oxidant. My question here is whether these compounds would have a more general sparing effect on other enzymes, where ALCAR cannot just physically block the site of oxidation. Considering that LA decreases production of this particular oxidant, but does not increase the life span of mice, I suggest that this particular oxidant might not be the limiting factor in the aging process of mice.

pp. 2356-2361, title: "Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha-lipoic acid": The experiments presented here show modest or moderate improvements in brain function and underlying molecular and tissue structural damage in old rats fed ALCAR + LA. The report is nicely written. Alternative explanations are discussed, and ones which would render the results unimportant are excluded by additional experimentation. In general, the conclusions do not extend beyond what is justified, given the small numbers of animals and variability of the data. An important exception is the final sentence: "These results also suggest that consumption of high levels of mitochondrial metabolites may be an efficient intervention in humans for delaying brain aging and age-associated neurodegenerative diseases." I have no objection to the clinical trial on which Juvenon is now embarking, but I would like to see results from that trial or more dramatic effects in larger numbers of rats before agreeing with the suggestion about human brain aging.

To summarize, my conclusion on this subject is that there is not yet sufficient evidence to justify alpha-lipoic acid supplementation, or to disregard the idea that long-term use could have some adverse effect; however, there is enough indirect and suggestive evidence to categorize beneficial effects as at least a weak possibility. My main reservations are that testing has been conducted only on small numbers of human patients and only on a short-term basis (and likewise for the studies in rats which have been published), and that the human data is mostly unpublished and based in large part on testimonial evidence rather than documented benefits.

Sincerely,

RJM

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