R Lipoic Acid
Introducing... R-Lipoic Acid
Does your lipoic acid supplement contain only the form found in nature? Or does it also include a synthetic by-product that may interfere with the natural form's beneficial effects?
R-Lipoic Acid and R-Dihydrolipoic Acid
The only naturally occurring forms of alpha lipoic acid:

Alpha-Lipoic Acid Occurs In 3 Different Forms
When molecules are produced by industrial synthesis they exist in a "racemic form", which is a 50/50 composition of the two enantiomers. Enantiomers are mirror image molecules which are chemically unique.
Alpha-lipoic acid consists of a 50/50 mixture of the R-(natural) and S- (unnatural) enantiomers and is called a 'racemic' mixture. It is the most widely available commercial form of lipoic acid.

There is evidence that the two enantiomers of alpha-lipoic acid have different biological activities.

R-Lipoic Acid (the R (+) enantiomer) is the form of lipoic acid that occurs naturally in plants, animals and the body and is responsible for the specific beneficial effects of alpha lipoic acid. R-lipoic acid (RLA) is the only form that functions as a cofactor for mitochondrial enzymes. Of primary significance, R-lipoic acid has shown to be ten times more effective than racemic alpha lipoic acid for reducing inflammation.
Alpha-lipoic acid
Alpha-lipoic acid
enantiomers in the patent literature.
S-Lipoic acid (The S (-) enantiomer) is not found in nature. S-Lipoic acid (SLA) is a by-product from chemical synthesis of racemic alpha-lipoic acid and may inhibit the most essential properties of the R form, including interactions with proteins, enzymes and genes.
Alpha-lipoic acid consists of 50/50 racemic mixture of the R and S enantiomers. Much of the research over the past 30 years has been done with racemic alpha lipoic acid because the R form was not commercially available. This was due to its instability and tendency to form polymerization products once isolated from the S form, and due to the challenges of delivering the R form to the body in bio-available dosage forms compared to racemic alpha-lipoic acid.
There is a clear indication of what the specific uses are claimed for the different

Functions in Health and Disease
-Lipoic Acid (RLA) and its reduced form, R-Dihydrolipoic Acid (R-DHLA) may prove to be the most important nutraceutical compounds on the market today
The redox couple has powerful antioxidant functions, serves as a critical co-factor in ATP production, regulates lipid and carbohydrate metabolism, signal transduction, gene transcription and cellular proliferation.

RLA/R-DHLA is neuroprotective, chelates heavy metals, can reverse enzyme and DNA oxidative damage and crosses the blood brain barrier. R-Lipoic Acid has been shown to be more effective by a factor of 8-10 over the commercially available alpha lipoic acid for reducing inflammation, and with R-DHLA, regulates the pro-inflammatory COX-2 and LOX pathways. This indicates the unnatural SLA is interfering with the body's utilization of the R form.
Alpha-lipoic acid
R-Lipoic Acid (RLA) and R-Dihydrolipoic acid have superior activity in vivo
Some recent studies have suggested that the S-enantiomer has an inhibiting effect on the R-enantiomer, substantially reducing its biological activity and actually adding to oxidative stress rather than reducing it. Furthermore, the S-enantiomer has been found to reduce the expression of GLUT-4s in cells, responsible for glucose uptake, and hence reduce insulin sensitivity.
The superior activity of R-Lipoic Acid is due to stereospecific binding, whereas SLA competitively inhibits interactions at the redox-active sites of signaling proteins, transcription factorsa, histonesb and flavoenzymesc.

arw Regulatory proteins that initiate the transcription of certain genes upon binding with DNA.

arw Small proteins that are rich in basic amino acids and that bind to DNA, forming chromatin.

arw Proteins that use a specific redox cycle to catalyze a variety of biological redox transformations.
The Benefits Of R-Lipoic Acid
arw R-Lipoic Acid significantly reduces inflammation, an underlying cause of the degenerative diseases of aging and is more potent by a factor of 10 over commercial ALA.1

arw R-Lipoic acid was found to reach higher plasma levels than S-lipoic acid when given orally as the racemic mixture in a human study.2

arw R-Lipoic Acid protects body fats against oxidative damage and reverses stress damage in the heart.3

arw R-Lipoic Acid was more effective than the S form in a battery of metal chelation tests. One hypothesis of the cause of diabetic complications involves overloading by transition metals which could explain the stereospecific effect of the R-form.4

arw R-Lipoic Acid is the form of lipoic acid found in nature and therefore the form preferred by critical mitochondrial enzymes.5, 6 A significant factor in aging is the decay of the mitochondria - and as we age, the efficiency of the mitochondria diminishes, as well as their quantity per cell.

arw R-Lipoic acid is the only form of lipoic acid that was shown to expand total life span in immuno-suppressed mice.7

arw R-Lipoic acid was much more effective than S-lipoic acid in enhancing insulin-stimulated glucose transport and metabolism in insulin-resistant rat skeletal muscle.8

arw R-Lipoic acid was more effective than racemic alpha-lipoic acid and S -alpha-lipoic acid in preventing cataracts in rats.9

arw R-Lipoic Acid increases cellular and mitochondrial antioxidant activity and prevents mitochondrial decay. This effectively attenuates the reported increase in oxidative stress with aging.10

arw R-Lipoic Acid improves memory, reverses cognitive dysfunction, and protects the brain from neurodegeneration associated with aging.10-12, 25

arw R-Lipoic Acid supplementation improves metabolic activity and lowers oxidative stress and damage evident in aging.12, 13

arw R-Lipoic Acid significantly increase insulin sensitivity, enhances glucose transport, increases metabolic rate and reduces the gain in body fat from aging.13, 14

arw R-Lipoic Acid has insulin-mimetic effects in glucose uptake in insulin resistant cells and may have therapeutic implications in restoring glucose availability in tissues such as the skeletal muscle.15, 16

arw R-Lipoic Acid significantly increases or maintain levels of other antioxidants including Coenzyme Q10, vitamin C, vitamin E and glutathione.16-18

arw R-Lipoic Acid prevents depletion of the glutathione pool within the cytoplasm and mitochondria. Pre-treatment of PC12 cells with R-Lipoic Acid leads to the preservation of mitochondrial complex I activity lost due to glutathione depletion.18

arw R-Lipoic Acid increases the activity of the crucial mitochondrial PDH enzyme, important for nutrient metabolism (inhibited by age-related diseases such as diabetes) whereas SLA inhibits it.19

arw R-Lipoic Acid , the natural enantiomer, is more effective than the S-(-) enantiomer at enhancing insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism.20

arw R-Lipoic Acid was reduced six to eight times more rapidly than S-lipoate in the rat heart.21

arw R-lipoic acid prevented hyperglycemia, reduced insulin levels, and increased free radical scavenging potential.22

arw R-Lipoic Acid, through its positive effects on cellular energy metabolism, attenuates metabolic dysfunction associated with advanced glycation endproducts (AGEs). AGEs accumulate on long-lived proteins, including beta-amyloid plaques in Alzheimer's disease and contributes to neuronal dysfunction and cell death.23, 24

arw R-Lipoic Acid, a membrane permeable antioxidant, prevents the up-regulation of the AGE -induced gene expression responsible for regulating nitric oxide (NO) production. NO oxidizes and nitrates proteins which are markers of a chronic neuroinflammatory condition. This mechanism is relevant for Alzheimer's disease and for many chronic inflammatory conditions.25

arw R-Lipoic Acid is the preferred substrate for the mitochondrial enzyme, dihydrolipoamide dehydrogenase, reacting 24 times faster than the S-enantiomer.26
Pro-oxidant Effects
It is now clear that many of the positive benefits and dangerous side effects of R-lipoic acid are the result of pro-oxidant effects. Since R-lipoic acid can interchange between a reduced form and an oxidized form, it displays reducing (antioxidant) and pro-oxidant properties related to dosage, 1/2 life and metabolism.

It is suggested that pro-oxidants produced by R-lipoic acid are involved in activation of insulin receptors and in elevated glucose uptake in muscle and fat cells. On the other hand, R-lipoic acid appears to protect the insulin-signaling cascade from oxidative stress-induced insulin resistance through its reducing capacities

R-lipoic acid and R-Dihydrolipoic acid can effectively induce apoptosis in human colon cancer cells by a prooxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria.

The ability of R-lipoic acid and/or R-Dihydrolipoic acid to function as either anti- or pro-oxidants, at least in part, is determined by the type of oxidative stress and the physiological circumstances.27-30

Stability, Absorption and Dissolution
R-Lipoic Acid, despite all its potential health benefits, when separated from the S form, is physically unstable. R-Lipoic Acid deteriorates relatively rapidly at slightly above room temperature into a sticky insoluble polymer.31 Moisture and the heat of friction during encapsulation and the compression of tablets are sufficient to initiate this process. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces the disintegration and dissolution of tablets or capsules, reduces GI absorption and lowers the bioavailability to less than 10%. Numerous factors affect absorption. Racemic-ALA has poor solubility and absorption from the GI tract, as 20- 30% reaches the plasma vs. an intra venous dose. R-Lipoic Acid is even less soluble and polymerizes on contact with the low pH environment of the stomach.32

GeroNova Research has 4 years of experience in producing and processing R-Lipoic Acid into stabilized, finished dietary ingredients for the nutritional supplement market. GeroNova stabilizes R-Lipoic Acid, creates highly bio-available dosage forms, introduced R-Dihydrolipoic Acid to the market and is constantly researching better ways to build these valuable molecules and make them affordable to health care practitioners and the public.
Pharmaceutical composition containing R-.alpha.-lipoic acid or S-.alpha.-lipoic acid as active ingredient. Ulrich H, Weischer CH, et al. US Patent 5,728,735, 1998.

Enantioselective pharmacokinetics and bioavailability of different racemic a-lipoic acid formulations in healthy volunteers. Hermann R, Niebch G, Borbe HO, et al. Eur J Pharm Sci. 1996;4:167-174.

arw Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. Suh JH, Shigeno ET, et al. FASEB J 2001 Mar; 15(3): 700-6.

Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Ou P, Tritschler HJ, Wolff SP. Biochem Pharmacol 1995; 50:123-126.

Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Haramaki N, Han D, Handelman GJ, et al., Free Radic Biol Med.1997;22(3):535-42.

Incorporation of the enantiomers of lipoic acid into the pyruvate dehydrogenase complex from Escherichia coli in vivo. Oehring R, Bisswanger H. Biol Chem Hoppe Seyler. 1992 Jun;373(6):333-5.

Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. Freisleben HJ, Neeb A, et al. Arzneimittelforschung 1997 Jun; 47(6): 776-80.

Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Streeper RS, Henriksen EJ, et al .Am J Physiol. 1997;273(1 Pt 1):E185-191.

Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Maitra I, Serbinova E, Tritschler HJ, Packer L. Biochem Biophys Res Commun. 1996;221(2):422-429.

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, Head E, et al. Proc Natl Acad Sci U S A 2002 Feb 19; 99(4): 2356-61.

Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Hagen TM, Moreau R, et al. Ann N Y Acad Sci. 2002 Apr;959:491-507.

Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. Suh JH, Shigeno ET, et al. FASEB J 2001 Mar; 15(3): 700-6.

(R)-alpha-Lipoic acid-supplemented Old Rats Have Improved Mitochondrial Function, Decreased Oxidative Damage, and Increased Metabolic Rate. Hagen TM, Ingersoll RT, et al. FASEB J 1999 13:411-418.

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, et al. Free Rad Biol Med 1999 Aug;27(3-4):309-14.

R-alpha-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes. Moines H, Trios O, et al. Arch Biochem Biophys 2002 Jan 15; 397(2): 384-91.

Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Khanna S, Packer L, et al. Am J Physiol. 1999 May;276(5 Pt 2):R1327-33.

Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes--reversal with (R)-alpha-lipoic acid supplementation. Lykkesfeldt J, Ames BN et al. FASEB J 1998 Sep; 12(12): 1183-9.

Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson's disease therapy. Bharat S, Cochran BC, et al. Neurotoxicology. 2002 Oct;23(4-5):479-86.

Stereospecific effects of lipoic acids on mammalian pyruvate dehydrogenase complex. Hong YS, Jacobia SJ, et al. Free Radic Biol Med. 1999 Mar;26(5-6):685-94.

Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A. Diabetes. 1996 Dec;45(12):1798-804.

Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Haramaki N, Han D, et al. Free Radic Biol Med 1997; 22(3): 535-42

ALS/Lt: a new type 2 diabetes mouse model associated with low free radical scavenging potential. Mathews CE, Bagley R, Leiter EH. Diabetes. 2004 Apr;53(4):1177-8.

Advanced glycation endproducts induce changes in glucose consumption, lactate production, and ATP levels in SH-SY5Y neuroblastoma cells by a redox-sensitive mechanism. de Arriba SG, Loske C, et al. J Cereb Blood Flow Metab. 2003 Nov;23(11):1307-13.

Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. Wong A, Dukic-Stefanovic S, et al. Eur J Neurosci . 2001 Dec;14(12):1961-7.

arw Neuroprotection by the metabolic Antioxidant alpha Lipoic Acid. Packer, L, Tritschler, H; Wessel K, 1997 Free Rad Biol Med 22, Nos 1/2, 359-378.

Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex. Loffelhardt S, Bonaventura C, et al. Biochem Pharmacol. 1995 Aug 25;50(5):637-46.

Cho KJ, Moini H, et al. Alpha-lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes. Biochem Pharmacol. 2003 Sep 1;66(5):849-58.

Wenzel U, Nickel A, et al. alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis. 2005 Mar;10(2):359-68.

Utilization of the Insulin-Signaling Network in the Metabolic Actions of alpha-Lipoic Acid-Reduction or Oxidation? Antioxid Redox Signal. Konrad D. 2005 Jul-Aug;7(7-8):1032-9.

Prooxidant activities of alpha-lipoic acid on oxidative protein damage in the aging rat heart muscle. Cakatay U, Kayali R et al. Arch Gerontol Geriatr. 2005 May-Jun;40(3):231-40.

Disulfide Polymers of DL-alpha-lipoic Acid, Thomas and Reed (JACS 78, 6148 (1956).

Asta Medica, US Patent 6,348,490.