R-Dihydro-Lipoic Acid The Optimal Form of Lipoic Acid
By Jim English
R-Lipoic Acid May Boost Brain Function
Age-related declines in physical activity and mental function are partly the result of a drop in mitochondrial energy production. Mitochondria are known to lose efficiency with age due to the oxidation of proteins, lipids, DNA, and RNA.16 Researchers led by Bruce Ames, PhD, professor of biochemistry and molecular biology at the University of California, Berkeley, have shown that the age-related decay of mitochondrial function can be partially reversed in older animals following treatment with R-lipoic acid or a combination of R-lipoic acid and acetyl-L-carnitine. In their study, older rats receiving either R-lipoic acid or a combination of R-lipoic acid and acetyl-L-carnitine showed signs of reduced lipid peroxidation and improved memory.17
Over time, oxidative stress in brain cells damages mitochondria, proteins, and nucleic acids, particularly in the region of the hippocampus. Left unchecked, these changes can contribute to impaired memory and loss of cognitive functions. In a groundbreaking study designed to mimic age-related loss of cognitive function and memory in humans, Dr. Ames and his colleagues treated older rats with either R-lipoic acid or a combination of R-lipoic acid and acetyl-L-carnitine. Dietary supplementation with R-lipoic acid and/or acetyl-L-carnitine was shown to significantly improve both spatial and temporal memory performance. Additionally, both R-lipoic acid and R-lipoic acid/acetyl-L-carnitine were found to significantly reduce the extent of oxidized RNA. Follow-up electron microscopic studies in the hippocampus showed that R-lipoic acid and R-lipoic acid/acetyl-L-carnitine reversed age-associated mitochondrial structural decay. The study results suggest that R-lipoic acid, either alone or in combination with acetyl-L-carnitine, may aid in lowering oxidative damage and improving mitochondrial function, thus improving memory and cognitive functions in aging humans.18
A Better Form of R-Lipoic Acid
In the body, alpha-lipoic acid occurs in two forms: R-lipoic acid and R-dihydro-lipoic acid (R-DHLA). The two make up a “redox couple.” Oxidation reduction (redox reactions) involves the transfer of an electron from a donor to an acceptor. When the donor loses an electron, it is transformed from its reduced form to its oxidized form; conversely, when an acceptor gains an electron, it changes from its oxidized form to its reduced form. Together, the oxidized and reduced forms of a redox component are said to form a redox couple.
In the case of R-lipoic acid, when it donates an electron to R-dihydro-lipoic acid, the R-dihydro-lipoic acid is oxidized back into R-lipoic acid, and the R-lipoic acid is then reduced back into R-dihydro-lipoic acid. As the two forms swap electrons, they rapidly convert. Many of the properties of lipoic acid depend on this ability to rapidly swap electrons, and most health benefits are observed regardless of which form is used. As always, however, there are important exceptions.
R-Dihydro-Lipoic Acid’s Unique Effects
As researchers continued to study lipoic acid, they discovered that R-dihydro-lipoic acid exerts a number of antioxidant and neuroprotective actions that are not seen with alpha-lipoic acid. One important difference is that while both alpha-lipoic acid and R-dihydro-lipoic acid effectively scavenge a number of radical species (hydroxyl radicals, nitric oxide radicals, peroxynitrite, hydrogen peroxide, and hypochlorite), only R-dihydro-lipoic acid has been shown effective against superoxide and peroxyl reactive oxygen species.19
Moreover, whereas alpha-lipoic acid and R-dihydro-lipoic acid both regenerate endogenous antioxidants and prevent oxidative stress, only R-dihydro-lipoic acid has been shown capable of actually repairing oxidative damage. Alpha-1 antiprotease (alpha 1-AP) is a physiologically essential macromolecule that helps lung tissue remain elastic. Oxidized alpha 1-AP has been implicated in the etiology of certain lung diseases, such as cystic fibrosis. German researchers discovered that R-dihydro-lipoic acid was effective in reversing the oxidative damage to alpha 1-AP, leading them to conclude, “[R-]dihydro-lipoic acid may exert a curative effect in diseases accompanied by oxidative stress.”20
R-dihydro-lipoic acid has also been shown to interact with and enhance the antioxidant effects of CoQ10. By donating an electron to oxidized CoQ10, R-dihydro-lipoic acid has been demonstrated to prevent the formation of damaging pro-oxidants, while maintaining CoQ10 in its active antioxidant form to prevent peroxidation of susceptible biomembranes.21
R-Dihydro-Lipoic Acid and Alzheimer’s Disease
Alzheimer’s disease is a progressive neurodegenerative disorder that typically develops in people aged 50 or older. Its hallmarks include oxidative stress and energy depletion. German researchers theorized that alpha-lipoic acid’s positive effects on glucose metabolism might assist in treating Alzheimer’s. They administered 600 mg of alpha-lipoic acid daily to nine Alzheimer’s patients in an open study for periods lasting close to a year. Alpha-lipoic acid treatment led to a stabilization of cognitive functions in the study group, determined by constant scores in two neuropsychological tests. Despite the limited sample size, the research team reported that treatment with alpha-lipoic acid might be a successful neuroprotective therapy for Alzheimer’s disease and related dementias.22
In a second study, researchers at the Sanders-Brown Center on Aging at the University of Kentucky Chandler Medical Center have shown that R-dihydro-lipoic acid protects cortical neurons from the toxic effects of two oxidative substances implicated in Alzheimer’s disease. The researchers found that cortical neurons were significantly protected by R-dihydro-lipoic acid following exposure to iron/hydrogen peroxide and amyloid beta-peptide. Interestingly, whereas pretreatment with alpha-lipoic acid protected cells subsequently exposed to iron/hydrogen peroxide, there was no protection noticed in cells exposed to alpha-lipoic acid and iron/hydrogen peroxide at the same time. Reviewing the results of the study, the authors concluded, “Treatment of cortical neurons with [R-]dihydro-lipoic acid significantly protected glucose transport against [iron/hydrogen peroxide] or beta-mediated decreases, although treatment with alpha-lipoic acid did not provide protection. These data suggest that R-dihydro-lipoic acid, the reduced form of R-lipoic acid, significantly protects against both [amyloid beta] and [iron/hydrogen peroxide] mediated toxicity.”23
R-Dihydro-Lipoic Acid and Atherosclerosis
Atherosclerosis is theorized to begin when low-density lipoprotein (LDL) particles circulating in the blood are damaged by lipid peroxidation. When the oxidatively modified LDL particles become implanted beneath the endothelial layers lining arterial walls, they are recognized as foreign invaders. This triggers apoptosis, or the cellular suicide of artery cells. A build-up of foam cells later causes bulges in the artery wall and atherosclerotic plaque develops. In-vitro experiments have shown that R-dihydro-lipoic acid—but not alpha-lipoic acid—can counteract lipid peroxidation of LDL particles, demonstrating a potential therapeutic effect for the early prevention of atherosclerosis. In the same study, R-dihydro-lipoic acid—but not alpha-lipoic acid—was shown to readily reduce iron and scavenge free radicals in a model of atherosclerosis, demonstrating a potential therapeutic effect for the early prevention of inflammatory processes implicated in cardiovascular disease.24
R-Dihydro-Lipoic Acid Improves the Heart’s Energy Production
Heart attack and stroke are significant causes of mortality and disability. Therapeutics that can optimize healing from these events thus may be valuable aids in restoring health and function. When blood flow is restored following a heart attack or stroke, cells previously deprived of oxygen generate a flood of free radicals that inflict damage to surrounding tissues that is more severe than that caused by the original trauma. When researchers treated isolated rat hearts with lipoic acid (given in the form of R-dihydro-lipoic acid), mitochondrial function significantly improved. This resulted in significantly higher ATP levels in the heart tissue compared to untreated hearts.25
In one study, a combination of R-dihydro-lipoic acid and vitamin E was shown to synergistically improve cardiac functional recovery during post-ischemic reperfusion or post-hypoxic reoxygenation of working rat hearts. After 30 minutes of oxygen deprivation (hypoxia), hearts treated with R-dihydro-lipoic acid showed significantly higher levels of ATP following reoxygenation than did untreated hearts.26 R-dihydro-lipoic acid combined with vitamin E may therefore help guard against damage to heart tissue inflicted by cardiac events.
According to Dr. Packer, “Just 10 years ago, scientists had a simplistic view of free radicals and antioxidants. Today, knowledge of a global antioxidant network has emerged which is linked to the metabolic energy-producing process—a new perspective that is leading to an explosion of basic research and therapeutic studies.”3
R-dihydro-lipoic acid is a powerful new supplement that sits at the forefront of this new wave of antioxidant research. As a powerful biological antioxidant involved in cellular metabolism and the recycling of endogenous antioxidants, R-dihydro-lipoic acid has been shown to aid in the prevention of numerous disorders associated with aging and oxidative stress, including diabetes, Alzheimer’s disease, and atherosclerosis.
1. Reed LJ, DeBusk BG, Gunsalus IC, Hornberger CS Jr. Crystalline alpha-lipoic acid; a catalytic agent associated with pyruvate dehydrogenase. Science. 1951 Aug 27;114(2952):93-4.
2. Bast A, Haenen GR. Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation. Biochim Biophys Acta. 1988 16;963(3):558-61.
3. Available at: http://www.berkeley.edu/news/media/releases/96legacy/releases.96/14316.html. Accessed October 22, 2004.
4. Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995 Sep;19(2):227-50.
5. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1-2):359-78.
6. Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001 Nov;17(10):888-95.
7. Evans JL, Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000 Autumn;2(3):401-13.
8. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes. 1996;104(3):284-8.
9. Kahler W, Kuklinski B, Ruhlmann C, Plotz C. Diabetes mellitus — a free radical-associated disease. Results of adjuvant antioxidant supplementation. Z Gesamte Inn Med. 1993 Jun;48(5):223-32.
10. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 Dec;38(12):1425-33.
11. Suzuki YJ, Aggarwal BB, Packer L. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15.
12. Merin JP, Matsuyama M, Kira T, Baba M, Okamoto T. Alpha-lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants. FEBS Lett. 1996 Oct 23;394(1):9-13.
13. Hofmann M, Mainka P, Tritschler H, Fuchs J, Zimmer G. Decrease of red cell membrane fluidity and -SH groups due to hyperglycemic conditions is counteracted by alpha-lipoic acid. Arch Biochem Biophys. 1995 Dec 1;324(1):85-92.
14. Kilic F, Handelman GJ, Serbinova E, Packer L, Trevithick JR. Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis. Biochem Mol Biol Int. 1995 Nov;37(2):361-70.
15. Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione concentrations in lens in model diabetic cataractogenesis. Biochem Mol Biol Int. 1998 Nov;46(3):585-95.
16. Liu J, Atamna H, Kuratsune H, Ames BN. Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci. 2002 May;959:133-66.
17. Liu J, Killilea DW, Ames BN. 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 Natl Acad Sci USA. 2002 Mar 19;99(4):1876-81.
18. 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 Mar 19;99(4):2356-61.
19. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997 Oct;29(3):315-31.
20. Biewenga GP, Veening-Griffioen DH, Nicastia AJ, Haenen GR, Bast A. Effects of dihydro-lipoic acid on peptide methionine sulfoxide reductase. Implications for antioxidant drugs. Arzneimittelforschung. 1998 Mar;48(2):144-8.
21. Kozlov AV, Gille L, Staniek K, Nohl H. Dihydro-lipoic acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone. Arch Biochem Biophys. 1999 Apr 1;363(1):148-54.
22. Hager K, Marahrens A, Kenklies M, Riederer P, Munch G. Alpha-lipoic acid as a new treatment option for Alzheimer type dementia. Arch Gerontol Geriatr. 2001 Jul;32(3):275-82.
23. Lovell MA, Xie C, Xiong S, Markesbery WR. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. J Alzheimers Dis. 2003 Jul;5(3):229-39.
24. Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Cuccurullo F. Dihydro-lipoic acid inhibits 15-lipoxygenase-dependent lipid peroxidation. Free Radic Biol Med. 2003 Dec 15;35(10):1203-9.
25. Haramaki N, Assadnazari H, Zimmer G, Schepkin V, Packer L. The influence of vitamin E and dihydro-lipoic acid on cardiac energy and glutathione status under hypoxia-reoxygenation. Biochem Mol Biol Int. 1995 Nov;37(3):591-7.
26. Haramaki N, Packer L, Assadnazari H, Zimmer G. Cardiac recovery during post-ischemic reperfusion is improved by combination of vitamin E with dihydro-lipoic acid. Biochem Biophys Res Commun. 1993 Dec 15;196(3):1101-7.