Follow-up to R-Lipoic Acid Discussion Paper by David A. Carlson.
There were only a small handful of questions, below is a response to them from David Carlson. Huge thanks go to David, and the GeroNova folks for making the time and effort to provide this information to us, I imagine he has some sleep to catch up on!
"As my professor used to say; "there are no stupid questions as long as you prove to me you've taken the time to explore the question yourself... otherwise you're wasting my time. If one reads the papers cited by AOR that "prove" that only RLA can alter the NADH/NAD+ ratio they might question this argument.
This was actually one of AOR's weaker contentions. If one studies the papers cited by AOR, they see that the concentration used was 0.5 mM, sustained in culture for 24 hours. Do you think you can achieve that with an AOR RLA containing product? You can't even hit this level by injection.
One of the main purposes of my paper was to provide interested parties with the tools they'd need to read the studies, consider the concentrations used in them and evaluate the likelihood of whether or not they had any in vivo relevance . This is absolutely essential in order to determine before trying to make definitive statements concerning in vivo mechanisms. This was the main problem with and the criticism of the piece by AOR. I think it is also safe to say that the anonymous AOR author has no idea how much RLA you'd have to inject to obtain a level of 0.5 mM. If you consumed RLA by the spoon full all day long you would still not see this concentration level in your tissues.
Referring to my chart you'll see that 0.5mM ~=103,000 ng/ml whereas the amount you see in plasma is ~1154 ng/ml after consumption of 1 gram of either pure RLA or R-DHLA. I've measured a "walloping" (not!) 30-40ng/ml RLA in plasma from a commercial 150 mg RLA product, so the amount used in this paper are 2475-3433 times greater than you can get from AOR's RLA.
Therefore, under real life conditions no one can say whether or not RLA can have any significant and direct effect on these ratios. There are quite complex networks within the cell to store and shuttle reducing equivalents, rather than just effluxing the R-DHLA after RLA is reduced as AOR suggested.
We also do not know how much R-DHLA itself can be taken up by the cell or how much RLA actually traverses the cytosol and gets actively transported into the mitochondria when the cell is exposed to these low concentrations. It is possible that R-DHLA can be taken up by the cell and modulate the intracellular redox status directly or through interaction with the thioredoxin and glutaredoxin systems. It is apparent that there is cross talk between the plasma redox status and the intracellular redox state although they exist on separate circuits, so our approach to modulating the plasma redox itself may be even more practically viable than trying to load your cell with so much RLA.
Regarding MCT-RALA plasma levels versus the RG, R+, R+ASTA and MG products: there is no contradiction. I did not say that R-DHLA was the ONLY way to improve plasma stability and concentrations. The levels were significantly higher than raw RLA and I believe this was due to the competitive inhibition of RLA uptake in the presence of MCFA. Unfortunately, this was originally an R&D product done for a specific international customer but it proved to have long term stability problems, as well as too low an active load of RLA to use in formulations, so we are no longer offering it. With some more development work, it could be improved upon, which is why we still had it on the website. The problem is that it was significantly more difficult and expensive to make and really offers no advantages over the other products.
David A. Carlson
Director R&D GeroNova Research