Life Extension Magazine®

A Better Form of Lipoic Acid

Scientifically reviewed by: Dr. Gary Gonzalez, MD, in January 2021. Written by: Life Extension Editorial Staff.

LE Magazine Special Edition, Winter 2004/2005
A Better Form of Lipoic Acid

Lipoic acid has become one of the most popular dietary supplements in the United States. The reason for this is a series of extraordinary scientific findings showing that lipoic acid possesses biological properties that exceed that of ordinary antioxidants.

For instance, lipoic acid is both water and fat-soluble. This unique property enables lipoic acid to reach parts of cells that other antioxidants cannot. Once inside cells, lipoic acid is able to regenerate vitamins C and E and increase levels of glutathione to help protect against age-induced mitochondrial decay.1-7

One study showed a combination of lipoic acid and acetyl-l-carnitine restored vitamin C levels in the liver cells of old rats to those seen in young rats.8 Another study showed that lipoic acid restored heart muscle cell structure in old rats to that of young rats after only two weeks of administration.9 In addition, lipoic acid was able to reverse the age-related increase in a dangerous pro-inflammatory cytokine, a natural bodily substance, called interleukin-1b.10

What impressed us the most were studies published in the Proceedings of the National Academy of Sciences showing that lipoic acid and acetyl-l-carnitine:8,11-15

  1. Improved ambulatory function in old rats, with a significantly greater degree of improvement in old rats compared to young ones.
  2. Partially reversed the decline in mitochondrial membrane function while inducing an increase in oxygen consumption, thereby improving cellular metabolic function in old rats.
  3. Improved memory and reversed age-associated neuronal mitochondrial decay in old rats.
  4. Restored an enzyme required for mitochondrial energy production (carnitine acetyltransferase), while simultaneously protecting against lipid peroxidation in old rats.

Alpha lipoic acid consists of two different forms (isomers) that have vastly different properties. The “R” form is the biologically active component (native to the body) that is responsible for lipoic acid’s phenomenal antioxidant effect. The “S” form is produced from chemical manufacture and is not very biologically active. Alpha lipoic acid supplements consist of the “R” and “S” form in a 50/50 ratio. That means a 100 mg alpha lipoic acid supplement is providing 50 mg of the biologically active “R” form.

The human body normally produces and uses R-lipoic acid, the active form. R-lipoic acid significantly reduces inflammatory reactions and has been shown to be more potent than the combined “R” and “S” form that comprise alpha lipoic acid.16-25 R-lipoic acid increases cellular and mitochondrial antioxidant activity and prevents mitochondrial decay associated with aging.26 Because of this, the increase in oxidative stress with aging is said to be reduced.27,28 R-lipoic acid is neuroprotective and has been shown to help improve poor memory, while slowing cognition deficits associated with aging.15,29-33 R-lipoic acid has also demonstrated its ability to reduce the gain in body fat from aging by improving metabolic function.34,35 Studies have also shown R-lipoic acid to reduce oxidative damage to fats in the body and to block damage to the heart from stress.36,37 R-lipoic acid can increase glucose uptake in insulin resistant cells because it can mimic insulin’s properties.38-45 This active “R” form of lipoic acid can regenerate the oxidized forms of antioxidants by recycling coenzyme Q10, vitamin C, vitamin E, and glutathione back into their active state.3,6,7,46-50

In the February 2005 issue of Life Extension magazine, there will be an in-depth article about the multiple benefits of R-dihydrolipoic acid, which is more effective than even R-lipoic acid. In the meantime, members will soon have access to R-dihydrolipoic acid. This new R-dihydrolipoic acid supplement will come in 150 mg liquid capsules that provide more biologically active ingredient compared to the 250 mg alpha lipoic acid members have previously used.


1. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997 Sep;29(3):315-31.

2. Smith AR, Shenvi SV, Widlansky M, et al. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem. 2004 May;11(9):1135-46.

3. Xu DP, Wells WW. Alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria. J Bioenerg Biomembr. 1996 Feb;28(1):77-85.

4. Arivazhagan P, Ramanathan K, Panneerselvam C. Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats. Exp Gerontol. 2001 Dec;37(1):81-7.

5. Suh JH, Wang H, Liu RM, et al. (R)-alpha-lipoic acid reverses the age-related loss in GSH redox status in post-mitotic tissues: evidence for increased cysteine requirement for GSH synthesis. Arch Biochem Biophys. 2004 Mar1; 423(1):126-35.

6. Kagan VE, Kuzmenko AI, Shvedova AA, et al. Direct evidence for recycling of myeloperoxidase-catalyzed phenoxyl radicals of a vitamin E homologue, 2,2,5,7,8-pentamethyl-6-hydroxy chromane, by ascorbate/dihydrolipoate in living HL-60 cells. Biochim Biophys Acta. 2003 Mar 17;1620(1-3):72-84.

7. Stoyanovsky DA, Goldman R, Darrow RM, et al. Endogenous ascorbate regenerates vitamin E in the retina directly and in combination with exogenous dihydrolipoic acid. Curr Eye Res. 1995 Mar;14(3):181-9.

8. Hagen TM, Liu J, Lykkesfeldt J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA. 2002 Feb 19;99(4):1870-5.

9. Suh JH, Shigeno ET, Morrow JD, 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.

10. McGahon BM, Martin DS, Horrobin DF, Lynch MA. Age-related changes in LTP and antioxidant defenses are reversed by an alpha-lipoic acid-enriched diet. Neurobiol Aging. 1999 Nov-Dec;20(6):655-64.

11. 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 USA. 2002. 99(4):2356-61

12. 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 Feb 19;99(4):1876-81.

13. Arivazhagan P, Ramanathan K, Panneerselvam C. Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. Chem Biol Interact. 2001 Nov 28;138(2):189-98.

14. Thirunavukkarasu V, Anuradha CV. Influence of alpha-lipoic acid on lipid peroxidation and antioxidant defense system in blood of insulin-resistant rats. Diabetes Obes Metab. 2004 May;6(3):200-7.

15. Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med. 1996;21(5):631-9.

16. Breithaupt-Grogler K, Niebch G, Schneider E, et al. Dose-proportionality of oral thioctic acid—coincidence of assessments via pooled plasma and individual data. Eur J Pharm Sci. 1999 Apr;8(1):57-65.

17. Hong YS, Jacobia SJ, Packer L, Patel MS. The inhibitory effects of lipoic compounds on mammalian pyruvate dehydrogenase complex and its catalytic components. Free Radic Biol Med. 1999 Mar;26(5-6):685-94.

18. Kilic F, Handelman GJ, Traber K, et al. Modeling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione concentrations in lens in model diabetic cataractogenesis. Biochem Mol Biol Int. 1998 Oct;46(3):585-95.

19. Streeper RS, Henriksen EJ, Jacob S, 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.

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

21. Maitra I, Serbinova E, Tritschler HJ, Packer L. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9.

22. Biewenga GP, Dorstijn MA, Verhagen JV, et al. Reduction of lipoic acid by lipoamide dehydrogenase. Biochem Pharmacol. 1996 Feb 9;51(3):233-8.

23. Zimmer G, Beikler TK, Schneider M, et al. Dose/response curves of lipoic acid R- and S-forms in the working rat heart during reoxygenation: superiority of the R-enantiomer in enhancement of aortic flow. J Mol Cell Cardiol. 1995 Sep;27(9):1895-903.

24. Fuchs J, Milbradt R. Antioxidant inhibition of skin inflammation induced by reactive oxidants: evaluation of the redox couple dihydrolipoate/lipoate. Skin Pharmacol. 1994; 7(5):278-84.

25. Schempp H, Ulrich H, Elstner EF. Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/ diaphorase. Z Naturforsch [C]. 1994 Sep-Oct; 49(9-10):691-2.

26. 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 Apr;959:133-66.

27. Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal. 2000 Fall;2(3):473-83.

28. Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-8.

29. Packer L, Tritschler H Wessel K. Neuroprotec-tion by the metabolic antioxidant alpha lipoic acid. Free Radic Biol Med. 1997 22(1-2):359-78.

30. Wolz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology. 1996 Mar; 35(3):369-75.

31. Arivazhagan P, Panneerselvam C. Effect of DL-alpha-lipoic acid on neural antioxidants in aged rats. Pharmacol Res. 2000 Sep;42(3):219-22.

32. Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995 Aug;18(8):1160-7.

33. Greenamyre JT, Garcia-Osuna M, Greene JG. The endogenous cofactors, thioctic acid and dihydrolipoic acid, are neuroprotective against NMDA and malonic acid lesions of striatum. Neurosci Lett. 1994 Apr 25;171(1-2):17-20.

34. Jacob S, Rues P, Hermann R, et al. 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.

35. Bustamante J, Lodge JK, Marcocci L, et al. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med. 1998 Apr;24(6):1023-39.

36. 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.

37. Ko KM, Yiu HY. Schisandrin B modulates the ischemia-reperfusion induced changes in non-enzymatic antioxidant levels in isolated-perfused rat hearts. Mol Cell Biochem. 2001 Apr;220(1-2):141-7.

38. Borcea V, Nourooz-Zadeh J, Wolff SP, et al. alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Free Radic Biol Med. 1999 Jun;26(11-12):1495-500.

39. Jacob S, Henriksen EJ, Schiemann AL, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung. 1995 Aug;45(8):872-4.

40. Konrad T, Vicini P, Kusterer K, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care. 1999 Feb;22(2):280-7.

41. Streeper RS, Henriksen EJ, Jacob S, et al. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol. 1997 Jul;27;3(1 Pt 1):E185-91.

42. Estrada DE, Ewart HS, Tsakiridis T, et al. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996 Dec;4(12):1798-804.

43. 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.

44. Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV. Alpha Lipoic acid restores antioxidant system in tissues of hyperinsulinaemic rats. Indian J Med Res. 2003 Sep;118:134-40.

45. Walgren JL, Amani Z, McMillan JM, et al. Effect of R(+)alpha-lipoic acid on pyruvate metabolism and fatty acid oxidation in rat hepatocytes. Metabolism. 2004 Feb;53(2):165-73.

46. Gotz ME, Dirr A, Burger R, et al. Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate. Eur J Pharmacol. 1994 Feb 15;266(3):291-300.

47. Lykkesfeldt J, Hagen TM, Vinarsky V, 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.

48. Suh JH, Shenvi SV, Dixon BM, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3381-6.

49. Kozlov AV, Gille L, Staniek K, Nohl H. Dihydrolipoic acid maintains ubiquinone in the antioxidant active form by two-electron reduction of ubiquinone and one-electron reduction of ubisemiquinone. Arch Biochem Biophys. 1999 Mar 1;363(1):148-54.

50. Schneider D, Elstner EF. Coenzyme Q10, vitamin E, and dihydrothioctic acid cooperatively prevent diene conjugation in isolated low-density lipoprotein. Antioxid Redox Signal. 2000 Summer;2(2):327-3.