Alpha-Lipoic Acid
A Simple Molecule Fuels Complex Processes in Cellular Metabolism
Oct 13, 2009 Stephen Allen Christensen
Alpha-lipoic acid (ALA) is a remarkable molecule whose reputation has grown over the past decade. Because of its unique structure and biochemical properties, ALA is being marketed as a cure for everything from Alzheimer’s disease to weight gain.
In truth, while ALA is essential for aerobic metabolism, many of the claims surrounding its benefits are probably derived from a little bit of science and a large dose of hyperbole.
However, what is already known about alpha-lipoic acid – and what is being learned – is sufficient to convince many people that supplemental ALA should be included in their daily routines.
Alpha-Lipoic Acid in Aerobic Metabolism
ALA is a co-factor in several enzyme complexes that regulate the metabolism of carbohydrates, proteins, and fats.
The final common pathway for the molecules produced by these enzyme complexes (acetyl-CoA, succinyl-CoA, etc.) is the citric acid cycle, a metabolic pathway where all aerobic organisms burn fuel molecules to produce water, carbon dioxide, and energy.
Without the citric acid cycle, aerobic cells would perish, and without ALA, the citric acid cycle would grind to a halt. Fortunately, humans manufacture sufficient amounts of ALA in their cells to meet their daily needs.
In fact, high oral doses of ALA only transiently increase plasma levels of ALA, and once it gets inside cells, exogenous ALA is quickly metabolized and excreted.
Alpha-Lipoic Acid as an Antioxidant
ALA has been called the “universal antioxidant” because of its wide distribution and putative effects in the body. Unlike many other antioxidants, ALA can function in both aqueous and lipid environments, thus allowing this molecule to maintain its integrity over a broad physiologic range.
However, ALA’s ability to scavenge free radicals independently has only been demonstrated in test tubes; it is not clear if this occurs in living cells. (Smith A, et al. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem 2004;11(9):1135-1146)
ALA’s antioxidant effects in living cells are probably due to its ability to “recycle” other antioxidant molecules like vitamins C and E, glutathione, and Coenzyme Q10. In this way, ALA acts synergistically to reduce free radicals that can damage DNA and other cell components.
Furthermore, ALA is apparently involved in the manufacture of glutathione, an important intracellular antioxidant that is responsible for the metabolism and elimination of potential carcinogens and other toxins. Glutathione levels fall in older animals, but ALA increases the expression of the enzyme that produces glutathione. (Suh J, 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;101(10):3381-3386)
One specialized antioxidant function that ALA may serve is in the chelation of certain free metal ions that, if left alone, would elicit destructive free radicals through the chemical reactions they catalyze. (Yamamoto H, et al. The antioxidant effect of DL-alpha-lipoic acid on copper-induced acute hepatitis in Long-Evans Cinnamon (LEC) rats. Free Radic Res 2001;34(1):69-80)
Alpha-Lipoic Acid as a Cellular Signaling Agent
At physiologic doses (i.e., those found within the cell), ALA appears to “turn on” certain cellular receptors that are involved in a number of important processes:
Insulin signaling: ALA increases the numbers of cell membrane receptors that respond to insulin, thus increasing the uptake of glucose in muscle and fat cells. (Yaworsky K, et al. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia 2000;43(3):294-303)
Protein kinase B (PKB) signaling: Addition of ALA to cultured cells increases PKB signaling, which affects a variety of metabolic, stress, survival, and growth functions. For example, ALA has been shown to improve survival in stressed neuronal cells in culture. (Zhang L, et al. Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett 2001;312(3):125-128)
Transcription factor signaling: ALA favorably affects the activity of cellular proteins that control the expression of specific genes, some of which play roles in the development of cancer, diabetes, or cardiovascular disease.
Alpha-Lipoic Acid: The Bottom Line
Although the benefits of ALA are often exaggerated, research has generated some interesting information about this molecule:
- Evidence shows that some conditions (e.g., diabetic neuropathy) may be ameliorated by ALA.
- Health benefits derived from ALA may be due to its ability to induce the production of glutathione, its capacity to recycle other antioxidant molecules, and its cellular signaling characteristics.
- There is insufficient evidence to support the use of ALA for prevention or treatment of neurodegenerative diseases like Alzheimer’s.
- ALA lowers blood sugars, which may make it useful in managing diabetes. (However, diabetics should consult their physicians before taking ALA.)
The precise mechanism of action and the full range of benefits that might be derived from ALA are not fully understood. For people who wish to take ALA, 200-400 mg daily are recommended for healthy individuals.
3-D Rendition of Lipoic Acid
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