Table Of Contents:
|Is All ALA The Same?|
|R-ALA & The Benefits For Diabetes|
|What Is R-ALA & What Are Some Of The Benefits Of R-ALA?|
|Information On Alpha Lipoic Acid, R-ALA, & Other Types Of ALA|
|The Many Uses For R-ALA Including As An Antioxidant & Anti-Aging|
Nobody sells S-ALA by itself as it isn't very effective, but you will get S-ALA anytime you purchase ALA. The ALA you buy from nutrition stores is in reality a 50/50 mixture of S-ALA & R-ALA. (though they won't tell you that...) Most companies don't go through the complicated and expensive process required to purify and remove the synthetic S-ALA from their products. Be aware that unless the bottle specifically states 100% R-ALA, you are only getting a 50/50 blend.
It is important for you to know that R-ALA has been shown time an time again to be up to 12 times as effective as S-ALA. There have been many studies, doctors and researchers who have stated how much more effective R-ALA is.
- R-Lipoic acid is the only form of lipoic acid that your body synthesizes and can safely metabolize. (7)
- R-Lipoic acid is the only form of lipoic acid that is proven to significantly reduce inflammation, an underlying cause of aging. (5)
- R-Lipoic acid is the only form of lipoic acid that is proven to significantly increase your cellular and mitochondrial antioxidant activity for preventing mitochondrial decay. This effectively attenuates the reported increase in oxidative stress with aging. (8)
- R-Lipoic acid is the only form of lipoic acid that is proven to improve memory, reduce brain damage, reverse cognitive dysfunction, and protect the brain from neurodegeneration associated with aging. (8,9,22)
- R-Lipoic acid is the only form of lipoic acid that is been proven to significantly increase insulin sensitivity, enhance glucose transport, increase metabolic rate and reduce the gain in body fat from aging. (10,11)
- R-Lipoic acid is the only form of lipoic acid that is proven to protect body fats against oxidative damage, chelate harmful metals and reverse stress damage in your heart. (12,13)
- R-Lipoic acid is the only form of Lipoic that is proven to significantly increase or maintain levels of other antioxidants including Coenzyme Q10, vitamin C, vitamin E and glutathione. (14,15)
- R-Lipoic acid is the only form of Lipoic acid that is proven to expand total life span. (17)
The Problems Of S-lipoic Acid:
- S-Lipoic acid produces different biological actions than R-Lipoic acid that may be undesirable. (16-18)
- S-Lipoic acid produces limited beneficial effects since it cannot bind with key enzymes. (19)
- S-Lipoic acid is less effective than R-lipoic acid as an antioxidant. (20)
- At high concentrations, S-Lipoic acid inhibits mitochondria metabolism and the antioxidant activity of R-lipoic acid (21)
- S-Lipoic acid is metabolized in the outer cell membrane. This may interfere with R-Lipoic acid's ability to penetrate the inner mitochondrial membrane and energy production. (22)
- R-Lipoic acid costs slightly more per unit than alpha-Lipoic acid. But it may be 10 times stronger than regular alpha-Lipoic acid at reducing inflammation, a primary cause of aging. And it is free of the problems from the S-form.
- Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Rad Biol Med 1995;19:227-250
- Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 1995; 50:123-126.
- Hagen et al, "(R)-alpha-Lipoic acid-supplemented Old Rats Have Improved Mitochondrial Function, Decreased Oxidative Damage, and Increased Metabolic Rate," FASEB J 1999 13:411-418
- Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. Arzneimittelforschung 1997 Jun; 47(6): 776-80
- Ulrich H, Weischer CH, et al. Pharmaceutical composition containing R-.alpha.-lipoic acid or S-.alpha.-lipoic acid as active ingredient. US Patent 5,728,735, 1998.
- Hagen et al, op. cit.
- Suh JH, et al, Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J 2001 Mar; 15(3): 700-6
- Liu J, Head E, Gharib AM, et al, 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. Proc Natl Acad Sci U S A 2002 Feb 19; 99(4): 2356-61
- Hager K, Marahrens A, Kenklies M, et al, Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontology Geriatric 2001 Jun; 32(3): 275-282
- Jacob S, Rues P, Hermann R. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Rad Biol Med 1999 Aug;27(3-4):309-14
- Moines H, Trios O, Park YC, Chow KJ, Packer L R-alpha-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes. . Arch Biochem Biophys 2002 Jan 15; 397(2): 384-91.
- Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J 2001 Mar; 15(3): 700-6
- Androne L, Gavan NA, Veresiu IA, Orasan R, In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy. In Vivo 2000 Mar-Apr; 14(2): 327-30
- Suh JH, Shigeno ET, et al, Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. FASEB J 2001 Mar; 15(3): 700-615. Lykkesfeldt J, et al, Ames BN. Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes--reversal with (R)-alpha-lipoic acid supplementation. FASEB J 1998 Sep; 12(12): 1183-9
- Streeper RS, Henriksen EJ, et al, Tritschler HJ. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 1997 Jul; 273(1 Pt 1): E185-91
- Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice Arzneimittelforschung 1997 Jun; 47(6): 776-80
- Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L. Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid Free Radic Biol Med 1997; 22(3): 535-42
- Maitra I, Serbinova E, et al. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res commun 1996; 221:422-429.
- Streeper RS, Henriksen EJ, et al, Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 1997 Jul; 273(1 Pt 1): E185-91
- M.S. Patel, et al, Stereospecific effects of lipoic acids on mammalian pyruvate dehydrogenase complex
- Packer, L; Tritschler, H; Wessel K, Neuroprotection by the metabolic Antioxidant alpha Lipoic Acid. 1997 Free Rad Biol Med 22, Nos 1/2, 359-378
Diabetes Mellitus is a group of chronic diseases associated with abnormally high levels of sugar in the blood. Glucose (sugar) builds up in the bloodstream as a result of the body's inability to produce insulin (which regulates blood/sugar levels) or the inability of insulin in the body to control sugar levels.
Diabetics suffer from many symptoms and complications. These include, but are not limited to; neurological, vascular, kidney and visual problems. Neuropathy is also a very common chronic problem for diabetics.
For well over 30 years physicians in Germany have been clinically treating Diabetics with ALA. Studies worldwide have shown ALA's ability to normalize glucose uptake and utilization. In one study, ALA was even shown to prevent diabetes in 70% of the animals tested. In another study type II diabetics were given 500mg of ALA daily and in 10 days saw a 30% increase in insulin stimulated glucose disposal.(2)
Nerve damage or neuropathy affects over 50% of diabetics and is one of its most damaging complications. A study published in "Diabetes Care" has shown that supplementing with ALA can partly restore diabetic nerve function after only four months of high-dose oral treatment.(1)
- Nagamatsu, M., et al. "Lipoic acid improves nerve blood flow, reduces oxidative stress and improves distal nerve conduction in experimental diabetic neuropathy." Diabetes Care, 18: 1160-67, 1995.
- Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996;104:284-288.
What Is R-ALA & What Are Some Of The Benefits Of R-ALA?
R-lipoic acid is the biologically active form of alpha lipoic acid. It has been called the mitochondrial antioxidant because it is a key component of mitochondrial dehydrogenase complexes. R-lipoic acid is directly involved in cell metabolism and redox states.
R-lipoic acid crosses the blood brain barrier, and helps regulate neuronal calcium homeostasis, scavenges a variety of reactive oxygen species (ROS) while recycling vitamins C, E and glutathione. R-lipoic acid has been shown to regulate pro-inflammatory cytokines, and alter the expression of "toxic genes". R-lipoic acid has been used to treat diabetes and has been recommended as a "neuroprotective agent"
Why Do I Need It?
If it is naturally occurring within our bodies, then why do we need to take lipoic acid as a supplement? There are at least four good reasons.
First, as we age, our bodies lose the ability to synthesize enough Lipoic acid, right at the time when we most need it.
Secondly, you cannot get sufficient quantities from your foods.
Third, the body produces small amounts of R-Lipoic acid for metabolism that may not be of sufficient quantity to neutralize rising free radical concentrations.
Fourth, a minimum amount is necessary for normal metabolic processes. Taking larger amounts, can have pronounced therapeutic effects.
How Is R-ALA Different From ALA?
I have to get a little technical here in order to make the terminology meaningful. In chemistry, a compound that has four different groups attached to carbon has a plane of asymmetry. That carbon is designated "chiral", meaning it has "handedness". That means that the molecule can exist in two different forms that are non super-imposable mirror images of one another. Put your right palm on the back of your left hand. What do you see? Both hands have five fingers, with the same arrangement relative to the thumb and yet the thumbs point in different directions, so the hands are said to be mirror images of one another.
Chiral molecules, like hands have this property. One of these isomeric molecules (called stereoisomers or enantiomers) rotates the plane of light in a machine called a polarimeter to the right and is designated dextro or +. The other isomer rotates the plane of light to the left and is called levo or -. There is another consideration when dealing with chiral molecules that places the four different substituents in order of priority.
The priority is determined by convention and establishes what is called the 'Absolute Configuration' of the molecule. By starting with the highest priority substituent and moving in a clockwise direction to the second highest, and on to the third and fourth designates the molecule R. If you move in the opposite direction, the absolute configuration is S. Molecules in living systems generally exist in only one form. When the same molecule is synthesized, it consists of equal amounts of both forms. Commercially available alpha Lipoic acid is a synthetic product consisting of two forms, the R+ and S- isomers in equal amounts.
As we said, naturally occurring Lipoic acid, the type your body makes and requires contains one form, the R-dextro or + form. This gives R-lipoic acid significantly more potency and efficacy. This is because the body recognizes R-lipoic acid and knows how to properly metabolize it, since all the key enzymes are structured to hold only the R-form of lipoic acid.
Does That Mean ALA Is No Good?
Remember, alpha lipoic acid is contains 50% of the natural R-form and 50% of the unnatural S-form. Most of the therapeutic value lies in the R-form. That is the reason why people get results when they take an alpha Lipoic acid supplement.
So If I Take Half The Amount Of R-ala Compared To ALA, I'll Get The Same Results?
It's not quite that simple, although until recently researchers thought this was the case. There is new evidence surfacing that the unnatural S-form may actually interfere with the beneficial properties of the R-form. In one study with mice, alpha Lipoic acid at high doses shortened the mean lifespan, but even at low doses, the R- form increased total life-span. So it is best to avoid the S-form altogether in order to achieve maximum benefits.
Information On Alpha Lipoic Acid, R-ALA, & Other Types Of ALA
Alpha Lipoic Acid:
A lipid and water soluble antioxidant, the pure R(+) enantiomer of which is produced in minute quantities by the body. WBelow we present a summary of the major research results for alpha lipoic acid (aLA) taken from published scientific studies. We give evidence that most of these highly beneficial effects are derived from the R(+) enantiomer (RLA). We show why this is particularly true for the benefits of aLA with respect to mitochondria, which benefits are almost certainly the most important for life extension purposes.
We also present studies of the properties of the S(-) enantiomer (synthesized only by man) and of the racemate (50/50 mixture of R & S - RSLA). Finally, we present evidence of the relative merits of the different forms of aLA which are available (ie pure R(+) and racemate) in the retail marketplace.
- 10 patients with diabetic neuropathy were given 70 days of treatment with a single dose of 600 mg of alpha lipoic acid [RSLA] per dayR.
- "Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment for 4 weeks in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid [RSLA]."R
- "The chronic administration of lipoic acid reduces the activities of biotin-dependent pyruvate carboxylase and beta-methylcrotonyl-CoA carboxylase; enzyme activities remain normal if biotin at pharmacological doses is administered together with lipoic acid. Even without supplemental biotin, the decreases in enzyme activities are not dramatic and would presumably not cause pathology in patients."R However, this last conclusion is likely made for moderate doses of aLA and biotin is so importantR that it should probably be supplemented for dosages of aLA above 50 mg daily.
- In a study of iv and oral dosage of RSLA in 12 healthy volunteers, the area under the curve of serum concentration for 200 mg iv and 600 mg oral was 3.4 times that for 200 mg oral. The half-life (in the range of 25.3-32.7 min) was not significantly different between dosage amounts and types. Note that this serum half-life does not necessarily imply that RSLA is of no value to the body after a few half lives since is may have simply left the blood to enter the cells to provide benefits there.R
- In a trial of 39 NIDDM patients with cardiac autonomic neuropathy (CAN), treatment with RSLA using a well-tolerated oral dose of 800 mg/day for 4 months slightly improved CAN.R
- Alphap-lipoic acid reaches peak levels in cortex, retina, optic nerve, sciatic nerve, femoral nerve and spinal cord of rats within one-helf hour of administration of an oral dose of 10 mg/kg; by 24 h levels declined to 5% of those at one-half hour. Over 21 d of oral administration (10 mg/kg/d) levels rose progresively and remained relatively stable in the same regions of CNS and peripheral nerves. This study conclusively demonstrates that alpha-lipoic acid is taken up by all areas of the CNS and peripheral nerves.R
Proven Benefits Of aLA, RSLA & RLA:
- "Lipoic acid, a potent thiol antioxidant and mitochondrial metabolite, appears to increase low molecular weight antioxidant status and thereby decreases age-associated oxidative insult."R.
- "Feeding old rats ALCAR and/or [RLA] improved performance on memory tasks, reduced brain mitochondrial structure decay, and reduced oxidative damage in the brain. The combination of ALCAR and [RLA] showed a greater effect than ALCAR or [RLA] alone. These results suggest that feeding a combination of mitochondrial metabolites to old animals may prevent mitochondrial decay in neurons and restore cognitive dysfunction.
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"R.
- "Feeding old rats high levels of key mitochondrial metabolites [RLA and ALCAR] can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction"R.
- "ALCAR+[RLA] partially reversed the age-related decline in average mitochondrial membrane potential and significantly increased hepatocellular O2 consumption, indicating that mitochondrial-supported cellular metabolism was markedly improved by this feeding regimen. ALCAR+[RLA] also increased ambulatory activity in both young and old rats; moreover, the improvement was significantly greater in old versus young animals and also greater when compared with old rats fed ALCAR or [RLA] alone"R.
- In an investigation of "the role of the thiol antioxidant dihydrolipoic acid (DHLA) and intracellular glutathione (GSH) in RLA-stimulated glucose transport" and an exploration of "the hypothesis that RLA could increase glucose uptake into 3T3-L1 adipocytes in an oxidant-mimetic manner"R, the following was found:
- "3T3-L1 adipocytes have a low capacity to reduce R-LA and the oxidized form of lipoic acid is responsible for stimulating glucose uptake,
- R-LA modulates glucose uptake by changing the intracellular redox status, and
- the insulin receptor is a potential cellular target for R-LA action."
- "Endothelial activation and monocyte adhesion are initiating steps in atherogenesis thought to be caused in part by oxidative stress. The metabolic thiol antioxidant alpha-lipoic acid has been suggested to be of therapeutic value in pathologies associated with redox imbalances. We investigated the role of (R)-alpha-lipoic acid (RLA) vs. glutathione and ascorbic acid in tumor necrosis factor alpha (TNF-alpha) -induced adhesion molecule expression and nuclear factor kappaB (NF-kappaB) signaling in human aortic endothelial cells (HAEC). ... Our data show that clinically relevant concentrations of LA, but neither vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte adhesion by inhibiting the IkappaB/NF-kappaB signaling pathway at the level, or upstream, of IkappaB kinase."R
- In obese Zucker rats, RLA (30 mg/kg body weight by ip injection once daily) and exercise training "interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle"R. However, in insulin-sensitive lean Zucker rats, "the beneficial interactive effects of exercise training and RLA on skeletal muscle insulin action --- are not apparent"R.
An important observation of the study of lean rats was that chronic supplementation with RLA was associated with a significantly reduced rate of body weight gain of fat mass. In both studies, RLA supplementation reduced the levels of protein carbonyls (an indicator of long-term oxidative damage). Another important finding was that use of RLA without exercise caused a significant increase in serum free fatty acid levels.
- "600 mg [RLA] was given daily to nine patients with AD and related dementias (receiving a standard treatment with acetylcholinesterase inhibitors) in an open study over an observation period of, on average, 337+/-80 days. The treatment led to a stabilization of cognitive functions in the study group... Despite the fact that this study was small and not randomized, this is the first indication that treatment with [RLA] might be a successful 'neuroprotective' therapy option for AD and related dementias."R
- "When cultured rat L6 muscle cells were exposed to glucose oxidase and glucose to generate H2O2 and cause oxidative stress, there was a marked decrease in insulin-stimulated glucose transport. Pretreatment with LA over the concentration range of 10-1,000 pmol/l protected the insulin effect from inhibition by H2O2. Both the R and S isomers of LA were equally effective. In addition, oxidative stress caused a significant decrease (approximately 50%) in reduced glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated protein kinase.
Pretreatment with LA prevented both of these events, coincident with protecting insulin action. These studies indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance."R
- In a study in which "some rats were ... supplemented with 0.2% (w/w) [RLA] for 2 wk prior to death"R, the following statements were made and results found:
- RLA "increases or maintains levels of other low molecular weight antioxidants such as ubiquinone, glutathione (GSH), and ascorbic acid."
- "Overall, our results show that the aging rat myocardium exhibits increased oxidant production, significantly lower ascorbic acid levels, and a marked increase in steady-state levels of oxidative DNA damage. [RLA] supplementation significantly reverses the age-related decline in myocardial ascorbic acid content, and lowers the rate of oxidant production and the steady-state levels of oxidative DNA damage. Our results thus indicate that dietary supplementation with lipoic acid may be an effective means to lower increased myocardial oxidative stress with age."
- "Thus, in addition to its antioxidant effect, dihydrolipoic acid [reduced RLA] may protect against lipid peroxidation by chelating free metal ions in vivo."
- "Our present findings suggest that [RLA] supplementation may be a safe and effective means of improving systemic decline in over all metabolic function and also increase protection against both endogenous and external production of ROS."
"However, long-term feeding studies with [RLA] are needed to determine whether benefits of [RLA] seen in old animals can be sustained over time."
- RLA "increases or maintains levels of other low molecular weight antioxidants such as ubiquinone, glutathione (GSH), and ascorbic acid."
- "Dietary supplementation of rats with (R)-lipoic acid [0.5% (wt/wt)] for 2 weeks completely reversed the age-related decline in hepatocellular GSH levels and the decreased (with age) lethal dosage of tert-butylhydroperoxide (t-BuOOH)to hepatocytes. An identical supplemental diet fed to young rats did not enhance the resistance of hepatocytes to t-BuOOH, indicating that antioxidant protection was already optimal in young rats. Thus, this study shows that cells from old animals are more susceptible to oxidant insult and (R)-lipoic acid, after reduction to an antioxidant in the mitochondria, effectively reverses this age-related increase in oxidant vulnerability."R
- In an in vivo study of ischaemia-reperfusion (I-R) of rats, a 14 week supplementation of 10,000 IU vitamin E/kg and 1.65 g alpha-LA/kg of diet did not influence cardiac performance or the incidence of dysrhythmias, even though it did decrease lipid peroxidation during I-R in young (4 months) adult ratsR. However, in a concurrent experiment with old (18 months) adult rats, the same supplemental regimen was found to protect the aged rat heart from I-R-induced lipid peroxidation by scavenging numerous reactive oxygen species, and this protection was associated with improved cardiac performance during reperfusionR.
- "In this study we investigated the cellular mechanism of action of alpha-lipoic acid in 3T3-L1 adipocytes. Short-term treatment of 3T3-L1 adipocytes with R (+) alpha-lipoic acid rapidly stimulated glucose uptake in a wortmannin-sensitive manner, induced a redistribution of GLUT1 and GLUT4 to the plasma membrane, caused tyrosine phosphorylation of insulin receptor substrate-1 and of the insulin receptor, increased the antiphosphotyrosine-associated and insulin receptor substrate-1 associated phosphatidylinositol 3-kinase activity and stimulated Akt activity.
These results indicate that R (+) alpha-lipoic acid directly activates lipid, tyrosine and serine/threonine kinases in target cells, which could lead to the stimulation of glucose uptake induced by this natural cofactor. These properties are unique among all agents currently used to lower glycaemia in animals and humans with diabetes."R.
- "In the present report, we have set out to investigate the potential capacity of both the oxidised and reduced forms of RS-alpha-lipoic acid, and its separate R-(+) and S-(-)enantiomers, to prevent cell death induced with L-homocysteic acid (L-HCA) and buthionine sulphoximine (BSO) in rat primary cortical and hippocampal neurons... RS-alpha-lipoic acid, RS-alpha-dihydrolipoic acid, and S-alpha-lipoic acid failed to protect cells against the degeneration induced by prolonged exposure to BSO, whereas the natural form, R-alpha-lipoic, was partially active under the same conditions.
The present results indicate a unique sensitivity of hippocampal neurons to the effect of L-HCA-mediated toxicity, and suggest that RS-alpha-lipoic acid, and in particular the R-alpha-enantiomeric form is capable of preventing oxidative stress-mediated neuronal cell death in primary cell culture."R.
- In a randomized clinical trial, "a total of 31 healthy adults were supplemented for 2 months either with alpha lipoic acid (LA) (600 mg/d, n = 16), or with alpha tocopherol (AT) (400 IU/d, n = 15) alone, and then with the combination of both for 2 additional months. LA significantly increased the lag time of LDL lipid peroxide formation for both copper-catalyzed and AAPH-induced LDL oxidation, decreased urinary F2-isoprostanes levels, and plasma carbonyl levels after AAPH oxidation.
AT prolonged LDL lag time of lipid peroxide formation and conjugated dienes after copper-catalyzed LDL oxidation, decreased urinary F2-isoprostanes, but had no effect on plasma carbonyls. The addition of LA to AT did not produce an additional significant improvement in the measures of oxidative stress. In conclusion, LA supplementation functions as an antioxidant, because it decreases plasma- and LDL-oxidation and urinary isoprostanes"R.
- "This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes"R.
- "We also observed that the insulin-mimetic nutrient alpha-lipoic acid (LA; R-enantiomer) is able to stimulate glucose uptake in cytokine-treated cells that are insulin resistant. This study shows that cytokine-induced glucose uptake in skeletal muscle cells is redox sensitive and that, under conditions of acute infection that is accompanied with insulin resistance, LA may have therapeutic implications in restoring glucose availability in tissues such as the skeletal muscle."R
- "When a diet supplemented with RLA (0.5% w/w), a mitochondrial coenzyme, was fed to old rats to determine its efficacy in reversing the decline in metabolism seen with age for 2 wk, hepatocytes from untreated old rats vs. young controls had significantly lower oxygen consumption and mitochondrial membrane potential, whereas supplementation reversed the age-related decline in O2 consumption and increased mitochondrial membrane potential in old rats.
Ambulatory activity, a measure of general metabolic activity, was almost threefold lower in untreated old rats vs. controls, but this decline was reversed in old treated rats. Malondialdehyde (MDA) levels, an indicator of lipid peroxidation, were increased fivefold with age in cells from unsupplemented rats, whereas supplementation reduced MDA levels markedly. Both glutathione and ascorbic acid levels declined in hepatocytes with age, but their loss was completely reversed with RLA acid supplementation. Thus, RLA supplementation improves indices of metabolic activity as well as lowers oxidative stress and damage evident in aging"R.
- "A two-week dietary supplementation of old animals with 0.5% RLA acid prior to cell isolation almost completely reversed the age-associated effects on ascorbic acid concentration, recycling and biosynthesis after oxidative stress"R.
- The chelating power of LA against copper is due solely to its reduced form, DHLA. "in our LDL experiments at physiological pH, DHLA [but not LA] is able to either reductively inactivate Cu2+ when Cu2+ is in excess, or effectively chelate Cu2+ when DHLA is in excess. The Cu2+:DHLA complex [which is stable at low pH or in the absence of oxygen] eventually undergoes copper-catalyzed oxidation, copper is released and LDL peroxidation proceeds. DHLA, thus, has both pro- and antioxidant properties depending upon the ratio of Cu2+:DHLA and the pH. These results provide an additional mechanism of thiol-mediated formation of radicals and metal chelation."R
- "In diabetic rats, after 6 weeks of diabetes, 2 weeks of racLPA treatment corrected 20% sciatic motor and 14% saphenous sensory NCV deficits. The ED50 for motor nerve conduction velocity (NCV) restoration was approximately 38 mg kg(-1) day(-1). aLA also corrected a 49% diabetic deficit in sciatic endoneurial blood flow. R and S-LA enantiomers were equipotent in correcting NCV and blood flow deficits. Treatment of diabetic rats with low doses (20 mg kg(-1) day(-1)) of aLA and gamma linolenic acid (GLA), while having modest effects on their own, showed evidence of marked synergistic action in joint treatment, completely correcting motor NCV and blood flow deficits."R
- "In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days. The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days.
In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo.
A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM"R.
- In a group of 14 immunosuppressed NMRI-mice (nu/nu) raised and kept under germ-reduced conditions, RLA "(9 mg/kg body weight) expanded the total life span of its group."R
- "In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was higher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin... Thioctic acid provoked an upward shift of the glucose-uptake insulin dose-response curve. The molar content of GLUT1 and GLUT4 transporters was measured in both cell lines. 3T3-L1 adipocytes were shown to have >10 times more glucose transporters but similar ratios of GLUT4:GLUT1 than L6 myotubes.
The effect of (R)-thioctic acid on glucose transporters was studied in the L6 myotubes. Its stimulatory effect on glucose uptake was associated with an intracellular redistribution of GLUT1 and GLUT4 glucose transporters, similar to that caused by insulin, with minimal effects on GLUT3 transporters. In conclusion, thioctic acid stimulates basal glucose transport and has a positive effect on insulin-stimulated glucose uptake. The stimulatory effect is dependent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a physiologically relevant compound can stimulate glucose transport via the insulin signaling pathway."R
- "Using an in vitro lipid peroxidation model with an ascorbate-iron-EDTA system and an incubation medium containing 20 mM glucose which increased lipid peroxidation up to fourfold, a dose-dependent and statistically significant reduction in lipid peroxidation was seen in rat brain and sciatic nerve with similar potencies for both enantiomers and the racemate of alpha-lipoic acid. This effect was unassociated with any reduction in the loss of alpha-tocopherol."R
- RLA "improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days."R
- "(R)-alpha-lipoic acid, may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging"R.
- RLA "supplementation may increase cellular and mitochondrial antioxidant status, thereby effectively attenuating any putative increase in oxidative stress with age"R.
Negative Results & Limitations:
- "For 6 wk, lean Zucker rats either remained sedentary, received R-ALA (30 mg. kg body wt(-1). day(-1)), performed exercise training (ET - treadmill running), or underwent both R-ALA treatment and ET. ET alone or in combination with R-ALA significantly increased (P < 0.05) peak oxygen consumption (28-31%) and maximum run time (52-63%).
During an oral glucose tolerance test, ET alone or in combination with R-ALA resulted in a significant lowering of the glucose response (17-36%) at 15 min relative to R-ALA alone and of the insulin response (19-36%) at 15 min compared with sedentary controls.
Insulin-mediated glucose transport activity was increased by ET alone in isolated epitrochlearis (30%) and soleus (50%) muscles, and this was associated with increased GLUT-4 protein levels. Insulin action was not improved by R-ALA alone, and ET-associated improvements in these variables were not further enhanced with combined ET and R-ALA. Although ET and R-ALA caused reductions in soleus protein carbonyls (an index of oxidative stress), these alterations were not significantly correlated with insulin-mediated soleus glucose transport. These results indicate that the beneficial interactive effects of ET and R-ALA on skeletal muscle insulin action observed previously in insulin-resistant obese Zucker rats are not apparent in insulin-sensitive lean Zucker rats."R
- "We only observed a beneficial effect of [RLA] only in old and not in young animals."R
- "The decline observed in the plasma concentration was steep (t1/2, 0.5 h)"R. ie RLA or RSLA have short plasma half-lives.
- RLA did not improve "longer-term memory ... in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days ... for young mice"R.
- This study revealed a marked stereospecificity in the prevention of induced cataract, and in the protection of lens antioxidants, in newborn rats by alpha-lipoate, R- and racemic alpha-lipoate Cataract formation was decreased from 100% to 55% by R-alpha-lipoic acid and 40% by rac-alpha-lipoic acid. S-alpha-lipoic acid had no effect on induced cataract formation. The lens antioxidants glutathione, ascorbate, and vitamin E were depleted to 45, 62, and 23% of control levels, respectively, by the cataract inducing treatment, but were maintained at 84-97% of control levels when R-alpha-lipoic acid or rac-alpha-lipoic acid were administered; S-alpha-lipoic acid administration had no protective effect on lens antioxidants.
When enantiomers of alpha-lipoic acid were administered to animals, R-alpha-lipoic acid was taken up by lens and reached concentrations 2- to 7-fold greater than those of S-alpha-lipoic acid, with rac-alpha-lipoic acid reaching levels midway between the R-isomer and racemic form. Reduced lipoic acid, dihydrolipoic acid, reached the highest levels in lens of the rac-alpha-lipoic acid-treated animals and the lowest levels in S-alpha-lipoic acid-treated animals. These results indicate that the protective effects of alpha-lipoic acid against induced cataract are probably due to its protective effects on lens antioxidants, and that the stereospecificity exhibited is due to selective uptake and reduction of R-alpha-lipoic acid by lens cellsR.
- "Whereas mitochondrial ATP synthesis was increased when the R-enantiomer was previously added to the working rat heart at 0.05-0.1 mumol concentration, with the S-enantiomer ATP synthesis remained within the control range. Mitochondrial membrane fluidity ... revealed a trend towards increase with the R- and decrease with the S-enantiomer."R
- "In feeding experiments, however, R lipoate significantly inhibited glucose oxidase-mediated skin inflammation, while S lipoate was only marginally protective."R
- RLA "is the naturally occurring cofactor in alpha-ketoacid dehydrogenases. We show both photometrically by NADH+H+ oxidation and by HPLC product analysis that this enantiomer is rapidly reduced by NADH+H+ catalyzed by porcine heart lipoamide dehydrogenase/diaphorase. The racemate exhibits approximately 40% activity as compared to the form while the S(-) enantiomer photometrically shows little activity and yields no detectable reduced lipoic acid."R
- The reduction of exogenous alpha-lipoic acid to dihydrolipoate by mammalian cells and tissues confers additional antioxidant protection to the cell. Both (R+) and (S-) isomers of alpha-lipoic acid were analyzed as substrates with glutathione reductase from several sources and with mammalian lipoamide dehydrogenase. Mammalian glutathione reductase catalyzed faster reduction of (S)-lipoic acid (1.4-2.4-fold greater activity) than of (R)-lipoic acid, whereas lipoamide dehydrogenase had a very marked preference for (R)-lipoic acid (18-fold greater activity) over (S)-lipoic acid"R.
- "The hyperglycemic effects of D-glucose [on erythrocyte membrane fluidity] were corroborated with isolated, reconstituted membrane proteins and erythrocyte glucose carrier, indicating that, in general, the observed divergent biochemical/biophysical changes of the red cell membrane are influenced by the glucose transport protein GluT1. The natural R-form and the S-form of alpha-lipoic acid were compared with racemic R-/S-forms for their efficiencies in alterations of red cell membrane fluidity. Decreased fluidities in presence of 10 mM glucose were found to be influenced in differentiated ways: the S-form was highly active in increasing fluidity at 4 nmol/mg and increasingly less active up to 20 nmol/mg protein. By contrast the R-form of lipoic acid was moderately efficient in increasing fluidity through a larger concentration range between 4 and 80 nmol/mg protein"R.
The studies listed above have shown that:
- SLA has effects in the body which are different than RLA.
- Although SLA is an excellent antioxidant (but RLA is better) none of the other effects of SLA have been shown to be beneficial.
- Since SLA does not naturally occur in the body and consequently the body has not developed mechanisms to deal with it, the effects of non-physiological doses of SLE are more likely to be harmful than are non-physiological doses of RLA which does occur naturally in the body and for which it does have mechanisms to deal with it.
- Therefore, SLA should not be considered as mere filler in the racemic mixture of enantiomers which is widely available on the supplement market, but should be considered potentially harmful until proven otherwise. This not to say that non-physiological doses of RLA may not also be harmful, only that they are less likely to be so. In particular, RLA is likely to be less harmful and more beneficial than the racemate generally used.
The concluding remarks from the chapter on RLA in The Handbook of Antioxidants, aptly summarize these conclusions:
"Since, the popularity and the interest in LA as an antioxidant are rising, there is, therefore, a need for better understanding of the pharmacology of this compound. Frequently, the two enantiomers of LA the R- and the S- forms do not have the same potency and biological efficacy. Occasionally, the biological effects exerted by one enantiomer were contradicted by the other form.
However, so far R-LA, which is the natural ofrm of LA, was superior and with more potent phamacological activity than S-LA in all of in vitro models and clinical experiments. The two enantiomers of LA should be looked on as two different pharmacological agents, antioxidants, or drugs."R
Alpha Lipoic acid is a natural substance found in certain foods and also produced in the human body. Alpha Lipoic acid is a disulfide compound found naturally in mitochondria as the coenzyme for pyruvate dehydrogenase and a-ketoglutarate dehydrogenase. Alpha lipoic acid (ALA) is a unique, vitamin-like antioxidant which exists in two forms, R-alpha-lipoic acid and S-alpha-lipoic acid. These two forms contain the same number and composition of atoms but have different arrangements of the atoms in their respective molecules. Natural lipoic acid is R Alpha lipoic acid. Synthetic lipoic acid contains a 50/50 mixture of the two forms.
Studies with the mixture demonstrated beneficial effects in treating a number of diseases and conditions. More recent research has shown that the R Alpha Lipoic acid alone is far more effective than S Alpha Lipoic acid or the mixture. Recently, pure R Alpha Lipoic acid has become available as a nutritional supplement. R Alpha Lipoic Acid as an Antioxidant
R Alpha Lipoic acid is regarded by many as the supreme antioxidant. R-Lipoic acid is unique in that it functions as both a fat and water-soluble antioxidant that can easily cross cell membranes. Thus, it can confer free radical protection to both interior and exterior cellular structures. Vitamin E is a potent biological antioxidant that acts to stabilize highly reactive free radicals in lipid (fatty) tissues and cell membranes. In the process of quenching fatty free radicals, vitamin E becomes a free radical itself. The vitamin E radical is then regenerated by vitamin C (ascorbic acid).
This process recycles vitamin E from a radical back into an antioxidant again, but results in the formation of a new free radical in the form of unstable vitamin C. Vitamin C is next recycled by glutathione. Up to this point vitamins E, C and glutathione work in concert to control free radicals and prevent cellular damage. But this is also an important stage where the antioxidant regeneration cycle runs into a limiting factor determined by the availability of glutathione. The concentration of these key antioxidants, vitamins E, C and glutathione diminishes with age and the individual becomes more susceptible to oxidative damage and inflammation.
Cell membrane integrity, the immune system, organs and DNA integrity all go down hill as antioxidants diminish. Glutathione is an important free-radical deactivator. Cellular glutathione levels are considered by many life extension experts to be the single best predictor of how long an individual will live. Glutathione also plays a vital role in protecting against cataract formation, enhancing immune function, preventing liver damage, slowing the initiation of cancers and eliminating heavy metals.
Glutathione is quickly depleted when the body experiences high levels of oxidative stress from causes such as illness, infection, trauma, medication, environmental toxins and surgery. Glutathione deficiency is also associated with low protein intake, diabetes, liver disease, cataracts, HIV infection, respiratory distress syndrome, cancer, and idiopathic pulmonary fibrosis. R-Lipoic acid boosts glutathione levels. Alpha lipoic acid enhances glutathione (GSH) levels.
Glutathione is the most important water-soluble antioxidant and is linked to detoxification of xenobiotics, modulation of signal transduction, prostaglandin metabolism, regulation of immune response, control of enzyme activity and peptide hormones, etc.
The availability of the amino acid Cysteine is known as the rate-limiting factor in glutathione synthesis. Lipoic acid is taken up rapidly by the cell and reduced to DHLA, which in turn reduces cystine to cysteine and accelerates the biosynthesis of GSH. In summary, R Lipoic Acid acts as a potent anti-oxidant on its own, serves to regenerate other anti-oxidants like vitamin E, Vitamin C and glutathione, and increases the production of glutathione.
R Alpha Lipoic Acid For Improving Mitocondrial Function:
The mitochondria are structures inside each individual cell that produce the energy that the cell needs to function. The mitochondria are analagous to an engine, boiler room or furnace. As the cells age, the activity of the mitochondria decreases, resulting in lower energy production, slower metabolism and and increased oxidative stress and damage. Clinical studies with rats have demonstrated that supplementation with R Alpha Lipoic acid improved mitocondrial function, increases metabolic rate and decreases oxidative damage.
Ambulatory activity, a measure of general metabolic activity was almost threefold lower in untreated rats compared to treated rats. The decline was reversed in old rats fed R Alpha Lipoic Acid.
R Alpha Lipoic Acid As A Chelating Agent:
Studies with rats and mice have shown that R Alpha Lipoic Acid provided protection against the toxic effects of arsenic, cadmium and mercury. It may also bind to other metals including iron, copper and zinc. The chelating action of R Alpha Lipoic Acid is considered to be relatively weak compared to other chelating agents. Some of the harmful effects of heavy metal poisoning are associated with oxidative damage. In addition, lipoic acid's antioxidant properties reduce the harmful effects of heavy metals.
Reduction Of Aging From Glycation By R Alpha Lipoic Acid:
Glycation is the formation of chemical bonds between protein molecules and glucose. This process impairs the physiological function of those proteins and contributes to the effects of aging and many disease processes, especially those associated with diabetes. These sugar-damaged proteins are referred to as advanced glycosylation end products (AGEs). AGEs increase with the length of hyperglycemia and are thought to be responsible for the kidney damage and advanced atherosclerosis seen in diabetes.
Researchers have found that noncovalent binding of alpha-lipoic acid to albumin protected proteins against glycation. Thus R Alpha Lipoic Acid acts as an anti-aging nutrient by both its anti-oxidant properties and its anti glycation properties.
Clinical Uses For R Alpha Lipoic Acid:
Large amounts of free radicals are created in tissue that has been injured by trauma or ischemia. Ischemia is caused by low oxygen levels from blood clots, stroke, etc. Treatment of this type of injury with anti-oxidants could be expected to reduce the effects of the damage. These types of injuries include heart attack, stroke, burns, sprains, strains, contusions, etc.
The treatment of some of these entities with alpha lipoic acid have been documented in the literature and some have not. Because alpha lipoic acid helps to conserve and increase production of glutathione, it may be beneficial in treating certain diseases that affect the liver. These include exposure to various toxins, alcoholic liver disease, aminita mushroom poisoning, hepatitis, etc. Alpha lipoic acid is beneficial to individuals with type II diabetes.
First, it improved the overall control of blood sugar and reduced blood sugar and insulin levels. Second, its anti-oxidant and anti-glycation effects reduce the damage caused by high blood sugar levels. Perhaps the best use of r alpha lipoic acid is as a life extension nutrient. It acts as an anti-oxidant, anti-glycation agent, blood sugar normalizer, mitochondria activator and glutathione enhancer. All of these effects counter the effects of aging, increase energy and enhance the quality of life.
Dosage Of R Alpha Lipoic Acid:
As a nutritional supplement, doses of 50 to 100 mg. per day are generally recommended. As a Therapeutic agent, higher doses may be used. In Germay, dosages of 600 mg. per day are prescribed for preventing the damaging effects of hyperglycemia in diabetes. Larger doses, 1200 mg. given intravenously, have been used to treat aminita mushroom poisoning.
R Alpha Lipoic Acid Side Effects & Precautions:
Clinical research has shown no evidence of carcinogenic effects with administration of alpha lipoic acid. Serious side effects have not been observed, even at high doses. Minor side effects include skin reactions and gastrointestinal effects, such as nausea and vomiting. However, these effects have only been observed in a small percentage of subjects who received intravenous infusions of 1,200 mg or more of alpha lipoic acid per day.
Alpha Lipoic Acid supplementation may reduce glucose and insulin levels in diabetics. Diabetics taking insulin or glucose lowering drugs will have to monitor their sugar levels and adjust medication as needed. Diabetics taking alpha lipoic acid supplements should work with their physician to monitor and and adjust any medication that they may be using. There is a lack of available data regarding use of alpha lipoic acid during pregnancy.
During more than three decades of scientific research and clinical usage no serious adverse effects have been reported as a consequence of alpha lipoic acid supplementation. The LD50 is approximately 400-500 mg/kg after oral dosing in dogs. High doses of alpha lipoic acid should be accompanied ty thiamine administration. An experiment done with rats showed that administration of alpha lipoic acid in extremely high doses (20 mg./kg) in the presence of a thiamine deficiency proved fatal. It would probably be beneficial to include a B-complex supplement in a regimen containing alpha lipoic acid.
R-Form Of ALA Has Great Benefits:
R-Alpha-Lipoic Acid is a naturally occurring substance that acts as a coenzyme in energy production in cellular metabolism and functions as an ideal antioxidant. Evidence shows that R-Alpha-Lipoic Acid delays the aging process, improves brain function and memory, stimulates immune function and supports liver health.
R-Alpha-Lipoic Acid is also indicated for several pathologies that include arteriosclerosis, atherosclerosis, arthritis, cancer, ischemia-reperfusion injury, apoptosis, and HIV infection, all involving inflammation. It also offers protection against the sequelae of diabetes, such as neuropathy, cataract, and cardiovascular disease. R-Alpha-Lipoic Acid ameliorates insulin sensitivity in type II diabetes.
R-Alpha-Lipoic Acid can directly and indirectly recycle ascorbate, glutathione, coenzyme Q10 and vitamin E. Hence, the idea of an "antioxidant network". In addition, lipoic acid has both water-soluble and membrane-soluble characteristics, enabling it to reduce oxidized antioxidants at the lipid/water interface.
R-Alpha-Lipoic Acid may also exhibit antioxidant activity by metal chelating which explains the usefulness of lipoic acid for the detoxification in heavy metal poisoning.
Conventional chemical synthesis of lipoic acid yields a mixture of R- and S-enantiomers. Lipoic acid from Alpha Science is processed in such a way as to yield the active R- isomer only with a purity guaranteed to be higher than 99%. Bioavailability of R- and S- alpha-lipoic acid has extensively been studied in humans using single dose administration.
Generally, there was no difference between R- and S- alpha-lipoic acid concentrations in plasma after intravenous administration. However, after oral intake of the combined mixture, at least a 60% higher response was found for R-lipoic acid than for the S-form.
Studies To Reference
- Nichols, T.W. Alpha lipoic Acid: Biological Effects and Clinical Implications,
- Moini, H., Tirosh, O., R-Alpha Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes; Archives of Biochem & BioPhys 397, No2 384-391 (2002)
- Liu, J. Killilea, D.W. et.al., 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. Proc Nat Acad Sci 99, 1876-1881 (2002)
- Liu, J., Atamna, H., et.al. Delaying Brain Mitochondrial Decay and Aging with Mitochondrial Antioxidants and metabolites. Ann NY Acad Sci 959:133-166 (2002)
- Liu, J., Head, E., et.al., 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. Proc Natl Acad Sci USA 99, 2356-2361 (2002)
- Hagen, T.M., Liu, J., et. al.; Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress, Proc Nat Acad Sci USA vol99, issue 4, 1870-1875 (2002)
- Hager, K., Marahrens, A.,et.al. Alpha lipoic acid as a new treatment option for Alzheimer type dementia, Arch Geron Geriatr 32 (3): 275-282 (2001)
- Hagen, T.M., Shigeno,E.T. et.al. Oxidative Stress in the Aging Rat Heart is Reversed by Dietary Supplementation with (R)-Lipoic Acid. FASEB J. 15, 700-706. (2001)
- Hagen, T.M. Increased mitochondrial decay and oxidative stress in the aging rat heart: improvement by dietary supplementation with (R)-lipoic acid. In, Free Radicals in Chemistry, Biology and Medicine 27, 262-271. (2000)
- Hagen, T.M., Vinarsky, V., et.al. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antiox. Redox Signaling 2, 473-483. (2000)
- Hagen, T.M., Ingersoll, R.T. et.al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 13, 411-418. (1999)
- Lykkesfeldt, J. Hagen, T.M., Age-associated decline in ascorbic acid concentration, recycling and biosynthesis in rat hepatocytes-reversal with (R)-alpha-lipoic acid supplementation. FASEB J. 12, 1183-1189. (1998)
- Packer, L; Tritschler, H.J.; Neuroprotection by the Metabolic Antioxidant Alpha Lipoic Acid; Free Rad Biol Med 22, Nos 1 / 2, 359-378 (1997)
- Hermann, R.; Niebch, G.; Enantioselective pharmacokinetics and bioavailability of different racemic alpha lipoic acid formulations in healthy volunteers. Eur J Pharm Sci 4: 167-174 (1996)