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Or, how good IS the ALA that we are all gulping down? As most of you know by now, the commercially available ALA is a racemic mixture of the R and S enatiiomers of alpha lipoic Acid. We should also be aware of the fact that most of the studies quoted used the RLA (naturally occuring) not the S. There remains some question as to the ultimate effectiveness of the racemic mixture vs the RLA. This rather long article quoted from http://morelife.org/lifespan/reaching/researchems/RLA.html
I apologize for the length but think this issue needs to be addressed:
==============================================
R-alpha Lipoic Acid
The pure enantiomer produced in minute quantities by the body which is the source of the proven benefits.
Below we present a summary of the major research results for alpha lipoic acid (aLA) taken from published studies in the peer-reviewed literature. We give evidence that these highly beneficial effects are mostly caused by 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 extensionists. We also present studies of the properties of the S enantiomer (synthesized only by man) and its differences with RLA and the racemate (50/50 mixture of R & S - RSLA).
Safety and Interactions
10 patients with diabetic neuropathy were given 70 days of treatment with a single dose of 600 mg of alpha lipoic acid [RSLA] per day9.
"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]"10.
"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"15.
However, this last conclusion is likely made for moderate doses of aLA and biotin is so important4 that it should probably be supplemented for dosages of aLA above 50 mg daily.
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.18
Proven Benefits
" 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"1.
"feeding old rats high levels of key mitochondrial metabolites [RLA and ALCAR] can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction"2.
"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"3.
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"5, 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."
RLA and exercise training "interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle"6.
"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 avarage, 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"7.
In a study in which "some rats were ... supplemented with 0.2% (w/w) [RLA] for 2 wk prior to death"8, 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."
"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"10.
"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, wheras 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"12.
"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"13.
"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"14.
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"17.
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"22.
Potential Benefits
RLA "supplementation may increase cellular and mitochondrial antioxidant status, thereby effectively attenuating any putative increase in oxidative stress with age"7.
Negative Results and Limitations
"we only observed a beneficial effect of [RLA] only in old and not in young animals"7.
"The decline observed in the plasma concentration was steep (t1/2, 0.5 h)"11. 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"22.
Nill Value, Different, or Negative Results for the S enantiomer
"Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means)"11.
The individual effects of the pure R-(+) and S-(-) enantiomers of alpha-lipoic acid to enhance insulin-stimulated glucose metabolism in skeletal muscle was studied in obese Zucker rats: an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia. Generally, RLA had major positive effects on all studied parameters. SLA had either no effect on all parameters except: 1) a negative chronic effect on insulin (15% increase versus 17% decrease for RLA), 2) a lesser positive chronic effect on 2-deoxyglucose uptake (65% increase by RLA versus 29% by SLA), 3) glucose transporter (GLUT-4) protein was unchanged after chronic RLA treatment but was reduced to 81 +/- 6% of obese control with SLA treatment. The study conclusion was: "the R-(+) enantiomer being much more effective than the S-(-) enantiomer"16.
In a group of 14 immunosuppressed NMRI-mice (nu/nu) raised and kept under germ-reduced conditions, SLA, even at 75 mg/kg body weight per day, increased the 50% survival rate, but did not expand "the total life span of its group"17.
"An intact organ, the isolated perfused rat heart, reduced R-lipoate six to eight times more rapidly than S-lipoate ... On the other hand, erythrocytes, which lack mitochondria, somewhat more actively reduced S- than R-lipoate ... Thus, mechanisms of reduction of alpha-lipoate are highly tissue-specific and effects of exogenously supplied alpha-lipoate are determined by tissue glutathione reductase and dihydrolipoamide dehydrogenase activity"19.
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 cells20.
"Racemic lipoic acid is therapeutically applied in pathologies in which free radicals are involved. The in vivo reduction of lipoic acid may play an essential role in its antioxidant effect. It was found that mitochondrial lipoamide dehydrogenase reduces the R-enantiomer 28 times faster than the S-enantiomer of lipoic acid. S-lipoic acid inhibits the reduction of the R enantiomer only at relatively high concentrations"21.
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"23.
Conclusions:
SLA clearly has effects in the body which are different than RLA.
Besides its antioxidant role (which the R-form does better) none of these effects have been shown to be beneficial.
Since SLA does not naturally occur in the body, these effects are potentially harmful.
SLA should not be considered as mere filler, but should be considered overall potentially harmful until proven otherwise.
References
Proc Natl Acad Sci U S A 2002 Feb 19;99(4):2356-2361.
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.
Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN.
Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720; Children's Hospital Oakland Research Institute, 5700 Martin Luther King, Jr., Way, Oakland, CA 94609; Institute for Brain Aging and Dementia, University of California, Irvine, CA 92697-4540; and Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331.
PMID: 11854529
Abstract
Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1876-1881.
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.
Liu J, Killilea DW, Ames BN.
Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720; and Children's Hospital Oakland Research Institute, Oakland, CA 94609.
PMID: 11854488
Abstract
Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1870-1875.
Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress.
Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN.
Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720; Children's Hospital Oakland Research Institute, Oakland, CA 94609; Department of Pharmacology and Pathobiology, Royal Veterinary and Agricultural University, Copenhagen DK-1870, Denmark; and Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
PMID: 11854487
Abstract
Metabolism 2002 Feb;51(2):163-8.
Effects of biotin on glucotoxicity or lipotoxicity in rat pancreatic islets.
Yoshikawa H, Tajiri Y, Sako Y, Hashimoto T, Umeda F, Nawata H.
Department of Medicine and Bioregulatory Science, Graduated School of Medical Sciences, Kyushu University, Fukuoka, Japan.
PMID: 11833042
Abstract
Arch Biochem Biophys 2002 Jan 15;397(2):384-91.
R-alpha-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes.
Moini H, Tirosh O, Park YC, Cho KJ, Packer L.
Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, California, 90033
PMID: 11795898
Abstract
J Appl Physiol 2001 Jul;91(1):145-53.
Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats.
Saengsirisuwan V, Kinnick TR, Schmit MB, Henriksen EJ.
Muscle Metabolism Laboratory, Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721-0093, USA.
PMID: 11408425
Abstract
Arch Gerontol Geriatr 2001 Jun;32(3):275-282.
Alpha-lipoic acid as a new treatment option for Alzheimer type dementia.
Hager K, Marahrens A, Kenklies M, Riederer P, Munch G.
Department of Medical Rehabilitation and Geriatrics, Henriettenstiftung, SchwemannstraBe 19, D-30559, Hannover, Germany
PMID: 11395173
Abstract
FASEB J 2001 Mar;15(3):700-6.
Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid.
Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM.
Linus Pauling Institute, Department of Biochemistry, Oregon State University, Corvallis, Oregon 97331, USA.
PMID: 11259388
Abstract OR Full text (.pdf)
In Vivo 2000 Mar-Apr;14(2):327-30.
In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy.
Androne L, Gavan NA, Veresiu IA, Orasan R.
Diabetes Center & Clinic, Cluj Napoca.
Publication Types: Clinical Trial
PMID: 10836205
Abstract
Free Radic Biol Med 1999 Aug;27(3-4):309-14.
Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.
Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K.
Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl and City Hospital, Baden-Baden, Germany. [email protected]
Publication Types: Clinical Trial, Multicenter Study, Randomized Controlled Trial
PMID: 10468203
Abstract
Eur J Pharm Sci 1999 Apr;8(1):57-65.
Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data.
Breithaupt-Grogler K, Niebch G, Schneider E, Erb K, Hermann R, Blume HH, Schug BS, Belz GG.
Center for Cardiovascular Pharmacology, Mathildenstrasse 8, 55116, Mainz, Germany.
Publication Types: Clinical Trial
PMID: 10072479
Abstract
FASEB J 1999 Feb;13(2):411-8.
(R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate.
Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
PMID: 9973329
Abstract OR Full Text
FASEB J 1998 Sep;12(12):1183-9.
Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes--reversal with (R)-alpha-lipoic acid supplementation.
Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN.
Department of Molecular and Cell Biology, University of California at Berkeley, 94720, USA. [email protected]
PMID: 9737721
Abstract OR Full Text
Diabetes 1997 Sep;46 Suppl 2:S62-6.
Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy.
Ziegler D, Gries FA.
Diabetes Research Institute at the Heinrich Heine University, Dusseldorf, Germany.
Publication Types: Clinical Trial, Multicenter Study, Randomized Controlled Trial, Review
PMID: 9285502
Abstract
J Nutr 1997 Sep;127(9):1776-81.
Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver.
Zempleni J, Trusty TA, Mock DM.
Department of Pediatrics, University of Arkansas for Medical Sciences and the Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
PMID: 9278559
Abstract OR Full Text
Am J Physiol 1997 Jul;273(1 Pt 1):E185-91.
Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ.
Department of Physiology, University of Arizona, Tucson 85721-0093, USA.
PMID: 9252495
Abstract
Arzneimittelforschung 1997 Jun;47(6):776-80.
Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice.
Freisleben HJ, Neeb A, Lehr F, Ackermann H.
Gustav-Embden-Zentrum der Biologischen Chemie, Laboratorium fur Mikrobiologische Chemie, Frankfurt/Main Germany.
PMID: 9239459
Abstract
Diabetes Care 1997 Mar;20(3):369-73.
Comment in: Diabetes Care. 1997 Dec;20(12):1918-20.
Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie.
Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G.
Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany.
Publication Types: Clinical Trial, Multicenter Study, Randomized Controlled Trial
PMID: 9051389
Abstract
Free Radic Biol Med 1997;22(3):535-42.
Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid.
Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L.
Department of Molecular and Cell Biology, University of California at Berkeley 94720-3200, USA.
PMID: 8981046
Abstract
Biochem Biophys Res Commun 1996 Apr 16;221(2):422-9.
Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats.
Maitra I, Serbinova E, Tritschler HJ, Packer L.
Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3200, USA.
PMID: 8619871
Abstract
Biochem Pharmacol 1996 Feb 9;51(3):233-8.
Reduction of lipoic acid by lipoamide dehydrogenase.
Biewenga GP, Dorstijn MA, Verhagen JV, Haenen GR, Bast A.
Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, Amsterdam, The Netherlands.
PMID: 8573188
Abstract
Pharmacol Biochem Behav 1993 Dec;46(4):799-805.
The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits.
Stoll S, Hartmann H, Cohen SA, Muller WE.
Central Institute for Mental Health, Department of Psychopharmacology, Mannheim, Germany.
PMID: 8309958
Abstract
Biochem Biophys Res Commun 1995 Jan 17;206(2):724-30.
Glutathione reductase and lipoamide dehydrogenase have opposite stereospecificities for alpha-lipoic acid enantiomers.
Pick U, Haramaki N, Constantinescu A, Handelman GJ, Tritschler HJ, Packer L.
Department of Biochemistry, Weizman Institute, Rehovot, Israel.
PMID: 7826393
Abstract
I apologize for the length but think this issue needs to be addressed:
==============================================
R-alpha Lipoic Acid
The pure enantiomer produced in minute quantities by the body which is the source of the proven benefits.
Below we present a summary of the major research results for alpha lipoic acid (aLA) taken from published studies in the peer-reviewed literature. We give evidence that these highly beneficial effects are mostly caused by 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 extensionists. We also present studies of the properties of the S enantiomer (synthesized only by man) and its differences with RLA and the racemate (50/50 mixture of R & S - RSLA).
Safety and Interactions
10 patients with diabetic neuropathy were given 70 days of treatment with a single dose of 600 mg of alpha lipoic acid [RSLA] per day9.
"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]"10.
"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"15.
However, this last conclusion is likely made for moderate doses of aLA and biotin is so important4 that it should probably be supplemented for dosages of aLA above 50 mg daily.
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.18
Proven Benefits
" 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"1.
"feeding old rats high levels of key mitochondrial metabolites [RLA and ALCAR] can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction"2.
"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"3.
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"5, 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."
RLA and exercise training "interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscle"6.
"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 avarage, 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"7.
In a study in which "some rats were ... supplemented with 0.2% (w/w) [RLA] for 2 wk prior to death"8, 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."
"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"10.
"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, wheras 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"12.
"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"13.
"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"14.
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"17.
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"22.
Potential Benefits
RLA "supplementation may increase cellular and mitochondrial antioxidant status, thereby effectively attenuating any putative increase in oxidative stress with age"7.
Negative Results and Limitations
"we only observed a beneficial effect of [RLA] only in old and not in young animals"7.
"The decline observed in the plasma concentration was steep (t1/2, 0.5 h)"11. 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"22.
Nill Value, Different, or Negative Results for the S enantiomer
"Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means)"11.
The individual effects of the pure R-(+) and S-(-) enantiomers of alpha-lipoic acid to enhance insulin-stimulated glucose metabolism in skeletal muscle was studied in obese Zucker rats: an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia. Generally, RLA had major positive effects on all studied parameters. SLA had either no effect on all parameters except: 1) a negative chronic effect on insulin (15% increase versus 17% decrease for RLA), 2) a lesser positive chronic effect on 2-deoxyglucose uptake (65% increase by RLA versus 29% by SLA), 3) glucose transporter (GLUT-4) protein was unchanged after chronic RLA treatment but was reduced to 81 +/- 6% of obese control with SLA treatment. The study conclusion was: "the R-(+) enantiomer being much more effective than the S-(-) enantiomer"16.
In a group of 14 immunosuppressed NMRI-mice (nu/nu) raised and kept under germ-reduced conditions, SLA, even at 75 mg/kg body weight per day, increased the 50% survival rate, but did not expand "the total life span of its group"17.
"An intact organ, the isolated perfused rat heart, reduced R-lipoate six to eight times more rapidly than S-lipoate ... On the other hand, erythrocytes, which lack mitochondria, somewhat more actively reduced S- than R-lipoate ... Thus, mechanisms of reduction of alpha-lipoate are highly tissue-specific and effects of exogenously supplied alpha-lipoate are determined by tissue glutathione reductase and dihydrolipoamide dehydrogenase activity"19.
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 cells20.
"Racemic lipoic acid is therapeutically applied in pathologies in which free radicals are involved. The in vivo reduction of lipoic acid may play an essential role in its antioxidant effect. It was found that mitochondrial lipoamide dehydrogenase reduces the R-enantiomer 28 times faster than the S-enantiomer of lipoic acid. S-lipoic acid inhibits the reduction of the R enantiomer only at relatively high concentrations"21.
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"23.
Conclusions:
SLA clearly has effects in the body which are different than RLA.
Besides its antioxidant role (which the R-form does better) none of these effects have been shown to be beneficial.
Since SLA does not naturally occur in the body, these effects are potentially harmful.
SLA should not be considered as mere filler, but should be considered overall potentially harmful until proven otherwise.
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