1.7mg

The potential for slow-acting pathology from "radicalized" antioxidants can be prevented through taking advantage of the unique synergistic interactions of an elite antioxidant strike force: the Networking Antioxidants.

When taken together, these specific, biologically essential nutrients form a dynamic team of synergistic "co antioxidants." Networking antioxidants can "recycle" one another from their "radicalized" forms back into their active, antioxidant forms. By this process of mutual regeneration, networking antioxidants enhance and extend one another's capacities, fueled by the fires of life in the body's cellular "power plants" (mitochondria). There are exactly five networking antioxidants: R (+)-lipoic acid, the vitamin E complex (including the four tocopherols and four tocotrienols), vitamin C, coenzyme Q10, and glutathione (GSH).

The cycle is ultimately kept going thanks to role played by R (+)-lipoic acid in the body's energy-production cycle. As food energy is converted into cellular energy by your cellular "power plants" (the mitochondria), supplemental R (+)-lipoic acid is "charged up" into its more potent antioxidant form, dihydrolipoic acid (DHLA). It is DHLA, rather than R (+)-lipoic acid itself, that "recycles" other networking antioxidants. And so, because the "charging-up" of R (+)-lipoic acid to DHLA piggybacks on the ongoing process of energy production, the mitochondria fuel a renewing cycle of co-regeneration amongst the networking antioxidants.

The "bird's eye view" of the antioxidant network recycling process looks like this. First, the original free radical attacker is neutralized by a networking antioxidant. Unfortunately, the result is that the networking antioxidant is degraded into its free radical form. To save the body from disaster, the networking antioxidant is rejuvenated by a co antioxidant from the antioxidant network team. A game of electron donating "hot potato" ensues, which ultimately results in rejuvenation by DHLA of the networking antioxidant free radical. And at this point, the "hot potato" game is halted when DHLA is restored through R (+)-lipoic acid's cycling through the mitochondrial energy-production process.

For the Antioxidant network to work optimally, it's critical to ensure that your lipoic acid supplement is in the form of R (+)-lipoic acid. Supplements labeled "alpha-lipoic acid" or simply "lipoic acid" contain up to 50% S (-)-lipoic acid, an unnatural molecule that hinders the ability of mitochondria to "charge up" R (+)-lipoic acid into DHLA. As a result, the S (-)-lipoic acid in conventional "lipoic acid" supplements actually interferes with the recycling activity of the Networking antioxidants.

The networking antioxidants have a genuine synergy with one another. The effects of each networking antioxidant support greater functionality of the antioxidant network as a whole. No other antioxidants participate in the interlocking cycles of the antioxidant network. In fact, the ability of other antioxidants to play a protective role in the body depends on having a functional Antioxidant network - but not vice-versa.

However, a few antioxidants do play a supporting role to networking antioxidants, without fully participating in the antioxidant network recycling system. The best understood of these Network "boosters" are bioflavonoids and the mineral selenium. Among bioflavonoids, carnosic acid - which is found in the herb rosemary - is especially interesting because of its ability to repeatedly rearrange itself into a "cascade" of new antioxidant "booster" forms before being exhausted. Selenium supports the network by maintaining the body's supply of two key enzymes: glutathione peroxidase (GSH-Px) and thioredoxin reductase (TrxR). Only very low doses of selenium are needed to maximize the levels and activity of these enzymes.

You'll want to ensure that you're taking the complete team of networking antioxidants, plus carnosic acid, resveratrol, and Se-methylselenocysteine, as proven "boosters" of the Network itself.

The days of throwaway "kitchen sink" antioxidant mishmashes are over. The recycling system of the Antioxidant Network is the path to cellular sustainability.

References

i. Packer L, Weber SU, Rimbach G. "Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling." J Nutr. 2001 Feb; 131(2): 369S-73S.

ii. Upston JM, Terentis AC, Stocker R. "Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement." FASEB J. 1999 Jun; 13(9): 977-94.

iii. Sen CK, Packer L. "Thiol homeostasis and supplements in physical exercise." Am J Clin Nutr. 2000 Aug; 72(2 Suppl): 653S-69S.

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

v. Packer L, Kraemer K, Rimbach G. "Molecular aspects of lipoic acid in the prevention of diabetes complications." Nutrition. 2001 Oct; 17(10): 888-95.

vi. Nordberg J, Arner ES. "Reactive oxygen species, antioxidants, and the mammalian thioredoxin system." Free Radic Biol Med. 2001 Dec 1; 31(11): 1287-312. 

Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling.
J Nutr 2001 Feb; 131(2): 369S-73S.
Packer L, Weber SU, Rimbach G.

Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922 in the laboratory of Herbert M. Evans (Science 1922, 55: 650). At least eight vitamin E isoforms with biological activity have been isolated from plant sources. Since its discovery, mainly antioxidant and recently also cell signaling aspects of tocopherols and tocotrienols have been studied. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles, which has been termed the antioxidant network. Although the antioxidant activity of tocotrienols is higher than that of tocopherols, tocotrienols have a lower bioavailability after oral ingestion. Tocotrienols penetrate rapidly through skin and efficiently combat oxidative stress induced by UV or ozone. Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation and by down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a key enzyme of the mevalonate pathway. Important novel antiproliferative and neuroprotective effects of tocotrienols, which may be independent of their antioxidant activity, have also been described.


Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement.
FASEB J 1999 Jun; 13(9): 977-94.
Upston JM, Terentis AC, Stocker R.

The 'oxidation theory' of atherosclerosis proposes that oxidation of low density lipoprotein (LDL) contributes to atherogenesis. Although little direct evidence for a causative role of 'oxidized LDL' in atherogenesis exists, several studies show that, in vitro, oxidized LDL exhibits potentially proatherogenic activities and lipoproteins isolated from atherosclerotic lesions are oxidized. As a consequence, the molecular mechanisms of LDL oxidation and the actions of alpha-tocopherol (alpha-TOH, vitamin E), the major lipid-soluble lipoprotein antioxidant, have been studied in detail. Based on the known antioxidant action of alpha-TOH and epidemiological evidence, vitamin E is generally considered to be beneficial in coronary artery disease. However, intervention studies overall show a null effect of vitamin E on atherosclerosis. This confounding outcome can be rationalized by the recently discovered diverse role for alpha-TOH in lipoprotein oxidation; that is, alpha-TOH displays neutral, anti-, or, indeed, pro-oxidant activity under various conditions. This review describes the latter, novel action of alpha-TOH, termed tocopherol-mediated peroxidation, and discusses the benefits of vitamin E supplementation alone or together with other antioxidants that work in concert with alpha-TOH in ameliorating lipoprotein lipid peroxidation in the artery wall and, hence, atherosclerosis.


Thiol homeostasis and supplements in physical exercise.
Am J Clin Nutr 2000 Aug; 72(2 Suppl): 653S-69S.
Sen CK, Packer L.

Thiols are a class of organic sulfur derivatives (mercaptans) characterized by the presence of sulfhydryl residues. In biological systems, thiols have numerous functions, including a central role in coordinating the antioxidant defense network. Physical exercise may induce oxidative stress. In humans, a consistent marker of exercise-induced oxidative stress is blood glutathione oxidation.Physical training programs have specific effects on tissue glutathione metabolism that depend on the work program and the type of tissue. Experimental studies show that glutathione metabolism in several tissues sensitively responds to an exhaustive bout of exercise. Study of glutathione-deficient animals clearly indicates the central importance of having adequate tissue glutathione to protect against exercise-induced oxidative stress. Among the various thiol supplements studied, N-acetyl-L-cysteine and alpha-lipoic acid hold the most promise. These agents may have antioxidant effects at the biochemical level but are also known to influence redox-sensitive cell signaling.


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

1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity.
2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein).
3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage.
4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage.
5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+.
6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA.
7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione.
8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease.
9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress.
10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.


Molecular aspects of lipoic acid in the prevention of diabetes complications.
Nutrition 2001 Oct; 17(10): 888-95.
Packer L, Kraemer K, Rimbach G.

Alpha-lipoic acid (LA) and its reduced form, dihydrolipoic acid, are powerful antioxidants. LA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen. Dihydrolipoic acid also scavenges superoxide and peroxyl radicals and can regenerate thioredoxin, vitamin C, and glutathione, which in turn can recycle vitamin E. There are several possible sources of oxidative stress in diabetes including glycation reactions, decompartmentalization of transition metals, and a shift in the reduced-oxygen status of the diabetic cells. Diabetics have increased levels of lipid hydroperoxides, DNA adducts, and protein carbonyls. Available data strongly suggest that LA, because of its antioxidant properties, is particularly suited to the prevention and/or treatment of diabetic complications that arise from an overproduction of reactive oxygen and nitrogen species. In addition to its antioxidant properties, LA increases glucose uptake through recruitment of the glucose transporter-4 to plasma membranes, a mechanism that is shared with insulin-stimulated glucose uptake. Further, recent trials have demonstrated that LA improves glucose disposal in patients with type II diabetes. In experimental and clinical studies, LA markedly reduced the symptoms of diabetic pathologies, including cataract formation, vascular damage, and polyneuropathy. To develop a better understanding of the preventative and therapeutic potentials of LA, much of the current interest is focused on elucidating its molecular mechanisms in redox dependent gene expression.


Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.
Free Radic Biol Med 2001 Dec 1; 31(11): 1287-312.
Nordberg J, Arner ES.

Reactive oxygen species (ROS) are known mediators of intracellular signaling cascades. Excessive production of ROS may, however, lead to oxidative stress, loss of cell function, and ultimately apoptosis or necrosis. A balance between oxidant and antioxidant intracellular systems is hence vital for cell function, regulation, and adaptation to diverse growth conditions. Thioredoxin reductase (TrxR) in conjunction with thioredoxin (Trx) is a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles. In mammals, extracellular forms of Trx also have cytokine-like effects. Mammalian TrxR has a highly reactive active site selenocysteine residue resulting in a profound reductive capacity, reducing several substrates in addition to Trx. Due to the reactivity of TrxR, the enzyme is inhibited by many clinically used electrophilic compounds including nitrosoureas, aurothioglucose, platinum compounds, and retinoic acid derivatives. The properties of TrxR in combination with the functions of Trx position this system at the core of cellular thiol redox control and antioxidant defense. In this review, we focus on the reactions of the Trx system with ROS molecules and different cellular antioxidant enzymes. We summarize the TrxR-catalyzed regeneration of several antioxidant compounds, including ascorbic acid (vitamin C), selenium-containing substances, lipoic acid, and ubiquinone (Q10). We also discuss the general cellular effects of TrxR inhibition. Dinitrohalobenzenes constitute a unique class of immunostimulatory TrxR inhibitors and we consider the immunomodulatory effects of dinitrohalobenzene compounds in view of their reactions with the Trx system.