Greatest Recent Finding in Lipoic Acid Research

June 6, 2013 Science Blog By

Recently, Professor Lester Packer asked me what I thought was the greatest discovery in lipoic acid research in the last 10 years.

This is an important question and the answer has significant ramifications. It has been known since the 50’s that lipoic acid has antioxidant activities.1 This property was advanced by Lester’s group throughout the 90’s 2 at a time when oxidative stress research was booming which resulted in the unfortunate “branding” or “type casting” of lipoic acid as an “antioxidant.” I consider this “label” unfortunate because it doesn’t consider the differences in the mechanisms of action of lipoic acid from compounds like vitamin C or vitamin E. Many people have told me that they don’t take alpha lipoic acid or R-lipoic acid because they consume plenty of fruits and vegetables in their diets or antioxidants by supplementation. It is now clear they are missing out an important nutrient that cannot be derived from food in sufficient concentrations to induce a beneficial response.
At the first International Symposium on Thioctic Acid (University of Naples, November 28-29, 1955) several researchers reported a potent and surprising anti-toxin effect of lipoic acid that could not be explained by its “vitamin-like” action as a substrate for pyruvate dehydrogenase or its antioxidant effects. In various animal models, lipoic acid protected against arsenic, cadmium, lead, carbon tetrachloride, mercury and an assortment of other noxious chemicals.3

It took another 47 years to begin to unravel the protective mechanisms involved. In 1995, the Nrf2 transcription factor was discovered and was found to be a major activator of a battery of cytoprotective genes protecting the cell from environmental and endogenous carcinogens through up-regulation (activation) of detoxifying phase II enzymes.4

In addition, induction of Nrf2-dependent genes is involved in the recognition and repair/removal of damaged proteins which expands the role of this signaling pathway beyond primary control of cellular electrophilic5 and oxidative stresses6 into secondary protective actions that enhance cell survival7. Recent research has indicated that phase II induction in the lungs could protect against the carcinogenic effects of cigarette smoke.8
In 2002, Flier et al 1st demonstrated that lipoic acid, like the structurally related dithiolethiones induced phase two detoxification enzymes in cultured astroglial cells.9

In 2004, Hagen’s group at the Linus Pauling Institute at Oregon State University discovered that R-lipoic acid is an in vivo inducer of Nrf2 10. Then in 2008, Hagen’s group reported that ALL of the ability of lipoic acid to induce the Nrf2 pathway is mediated by R-(+)-lipoic acid, ie; activation is completely stereospecific for RLA. S-(-)-lipoic acid is completely inactive.11

In other words, R-(+)-lipoic acid and other phase II enzyme inducers found in food (curcumin from tumeric, sulforaphane from broccoli, catechins from green tea, resveratrol from grapes) are far more than antioxidants; they are “hormetic” molecules that induce innate protective capacities of cells by acting as mild stessors. R-lipoic acid has the advantage over the other phytochemicals mentioned because it is possible achieve sufficient intracellular concentrations to induce these beneficial effects (50-100 ?M) by consumption of 600 mg up to 1 gram of RLA as sodium R-lipoate (Na-RLA) 12. While the other nutrients have been shown to be effective in in vitro models, it is almost impossible to achieve the levels necessary to induce the phase II enzymes by consuming them.

In summary and in my opinion the fact that R-lipoic acid is a phase II inducer and that all of this ability is attributed to the R-enantiomer is the greatest discovery in the last ten years of lipoic acid research and indicates a promising future for RLA in health maintenance and increasing the health-span.


1. Rosenberg HR, Culik R. Effect of a-lipoic acid on vitamin
C and vitamin E deficiencies. Archiv Biochem Biophys (1959) 80 86-93.
2. Packer L, Witt EH, Tritschler HJ.alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med (1995) 19(2):227-50.
3. Segre A; Symposium on Thioctic Acid. Nature (1956) 4498. Braude EA, Proceedings of Symposium su l’ acido tioctico. Chem & Ind (1955) 508. Chemical Abstracts (1956) 51:8153-5.
4. Yu X and Kensler TW. Nrf2 as a target for cancer chemo-prevention. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis (2005) 591(1-2) 11: 93-102.
5. Electrophilic: In chemistry, an electrophile (literally electron-lover) is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. These frequently include toxic aldehydes such as formaldehyde, acetaldehyde, acrolein etc. formed via metabolism.
6. Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system’s ability to readily detoxify the reactive intermediates or easily repair the resulting damage.
7. Osburn WO, Kensler TW. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res (2008) 659(1-2) 31-9.…
Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW. Modulation of gene expression by cancer chemo-preventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem (2003) 278(10) 8135-45.
8. Singh A, Ling G, Suhasini AN, Zhang P, Yamamoto M, Navas-Acien A, Cosgrove G, Tuder RM, Kensler TW, Watson WH, Biswal S.
Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free Radic Biol Med (2009) 46(3) 376-86.
Osburn WO, Kensler TW. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res (2008) 659(1-2) 31-9.
9. Flier J, Van Muiswinkel FL, Jongenelen CA, Drukarch B. The neuroprotective antioxidant alpha-lipoic acid induces detoxication enzymes in cultured astroglial cells. Free Radic Res (2002) 36(6) 695-9.
10. Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM. 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) 101(10) 3381-6.
11. Petersen-Shay K, Shenvi S, Hagen TM. Lipoic acid as an inducer of phase II detoxification enzymes through activation of Nr-f2 dependent gene expression. Chapter 14 in. Alpha Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects. Packer L, Patel M, eds. Boca Raton, New York, London: Taylor & Francis Publishers (2008) 349-371.
12. Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L.
The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects. Altern Med Rev (2007) 12(4) 343-51.

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