R-Lipoic Acid in Signal Transduction

Question: “I read with great interest your blog concerning the greatest discovery in lipoic acid research but not being a molecular biologist, I found a lot of it over my head. Is there any way to put some of this in lay terms?"

Answer:  You are not alone. I received a lot of similar feedback from others who also thought it was too technical. Unfortunately, “signal transduction” [i] is one of the most complicated areas of molecular biology research. I’ll soon be adding links to a glossary of terms to facilitate learning, but part of this will take some effort and mental gymnastics to understand. Don’t be afraid to “stretch the synapses”; the result is well worth the effort.

Basically, what I was talking about is how a chemical (hormone or nutrient) “signal” transmits its information to other parts of the cell. When I was in school we thought of food and its constituent nutrients as “building blocks” of proteins, fats and nucleic acids. While this is true it is now known that many nutrients and hormones act by altering or modifying the cell’s communication highways.

For example, R-lipoic acid, like insulin activates the insulin signaling pathway at the cell surface.  Insulin mediates all of it’s multitude of effects on metabolism by transducing a signal from the surface through the cytoplasm (the inner matrix of the cell) to the nucleus (containing the genetic material) which then alters the transcription[ii] of a specific set of insulin sensitive genes.

R-lipoic acid, after activating this pathway, is transported into the cytoplasm of the cell by a specific sodium dependent vitamin transporter. In the cytoplasm RLA interacts with Nrf2[iii], another transcription factor[iv] that when activated migrates to the nucleus and upregulates[v] or activates a set of protective genes, which provide the instructions to build new proteins or enzymes, some of which use glutathione as their co-factor. Glutathione is one the major compounds in the body involved in protecting the cell and is intimately connected to the benefits of RLA.

Up to 200 different genes may be activated by the interaction of Nrf2 by RLA. This protects the cell from toxic insults, induces cellular turnover and repair mechanisms and improves the antioxidant status of the cell. These are just two of the multiple signaling systems affected by RLA.

For a look at the beauty & complexity of signal transduction involved in aging, please see the colored diagram in the article by Greer & Brunet;  http://jcs.biologists.org/cgi/content/full/121/4/407. It is a free download through PubMed or the Journal of Cell Science.   

There is evidence that RLA can modulate many of these signaling systems by multiple mechanisms and offers a fruitful area for future research.

In addition, we have some preliminary evidence that the sodium in sodium R-lipoate (NaRLA) generates higher blood and tissue levels of RLA than other salt forms of RLA due to the dependency of the vitamin transporter on this ion.  These higher levels may be necessary to activate the protective mechanisms described above.

[i] Signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another.

[ii] Transcription is the synthesis of RNA under the direction of DNA.

[iii] Nrf2 (NF-E2-related factor 2) acts as a master regulator of the majority of antioxidant pathways and detoxifying enzymes for environmental pollutants.

[iv] A transcription factor is a protein that binds to specific DNA sequences and thereby controls the transfer (or transcription) of genetic information from DNA to RNA.

[v] Upregulation is the process by which a cell increases the quantity of a cellular component, such as RNA or protein, in response to an external variable.