Circadian Clock Normalization as Novel Mechanism Behind the Health Benefits of ALA in NAFLD & Diabesity | Plus: ALA For Athletes & the Obese - Yes/No + When to Take It?

Yes, you can buy alpha lipoic acid as bulk powder, but if you still have intact mucosa and want to keep it intact, I suggest you swallow pills.

Alpha lipoic acid aka "ALA" is a natural AMPK agonist that works similar to metformin. Developed by BASF and others as an anti-diabetes medication in the late 20th century, it's now a popular supplement that is prescribed as a "drug" to type II diabetics only rarely and only in Europe, yet not in the US.

Based on the currently available evidence its anti-diabetic effects are comparable but far inferior to metformin. In view of the fact that lipoic acid is also non-patentable and thus not exactly profitable, it's no wonder that it has disappeared from the radar of the medical establishment over the past decade.

Learn more about lipoic acid here at the SuppVersity

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A recent study from the Linus Pauling Institute may yet well put the naturally occurring power-antioxidant, which is found at higher levels in organ meats and leafy vegetables such as spinach and broccoli, back onto the research agenda of top scientists all around the world.

Lipoic acid appears to reset and synchronize circadian rhythms, or the "biological clock" found in most life forms. The ability of lipoic acid to help restore a more normal circadian rhythm to aging animals could explain its apparent value in so many important biological functions, ranging from stress resistance to cardiac function, hormonal balance, muscle performance, glucose metabolism and the aging process.

Figure 1: ALA had no direct weight loss effect, but it reduced the abnormal cortisol excursions and the increase in postprandial fatty acid synthesis in the old rodents (Keith. 2014)

The findings were made by biochemists from the Linus Pauling Institute at Oregon State University, and published in Biochemical and Biophysical Research Communications, a professional journal.

"This could be a breakthrough in our understanding of why lipoic acid is so important and how it functions. Circadian rhythms are day-night cycles that affect the daily ebb and flow of critical biological processes. The more we improve our understanding of them, the more we find them involved in so many aspects of life, "said Tory Hagen, the Helen P. Rumbel Professor for Healthy Aging Research in the Linus Pauling Institute, and a professor of biochemistry and biophysics in the OSU College of Science

Almost one-third of all genes are influenced by circadian rhythms, and when out of balance they can play roles in cancer, heart disease, inflammation, hormonal imbalance and many other areas, the OSU researchers said. Of particular importance is the dysfunction of circadian rhythms with age.

"In old animals, including elderly humans, it's well-known that circadian rhythms break down and certain enzymes don't function as efficiently, or as well as they should," said Dove Keith, a research associate in the Linus Pauling Institute and lead author on this study.

If lipoic acid offers a way to help synchronize and restore circadian rhythms, this could be a quite significant result. In that it is yet important to know if the effects, the researchers observed only in the liver, are mediated by effects that are independent of the anti-oxidant effects of lipoic acid - or, to put it differently, if lipoic acid has direct or just indirect effects which are mediated by the blockade of pro-oxidant disturbances of the "circadian clock" of the liver.

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2012), and implications (bottom)

I guess it would be pretty unsatisfying if I passed on this opportunity to review a handful of recent studies on the benefits of alpha lipoic acid, right? Well, then... I guess you will remember that I am skeptical about its usefulness as a nutrient partitioner, right? Although we have only rodent data to support this hypothesis the increase in AMPK expression that would come at a very unfavorable moment, if you take your "repartitioning supplement" shortly before or with a meal did after all leave the rodents in the previously discussed study by Prieto-Hontoria et al (2012) lighter and less muscular (see Figure 2, as well as previous article "Lean & Muscular W/ Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!" | read more).

That obviously doesn't mean that ALA was useless. In a different scenario - e.g. for someone with a high(er) baseline inflammation - alpha lipoic acid may well have beneficial "nutrient repartitioning effects". Examples? What about the seminal paper by Ko et al. (2011)?

In said study, 360 obese individuals (body mass index [BMI] ≥30 kg/m2 or BMI 27-30 kg/m2 plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The supplement was consumed in three doses of 600mg timed 30 minutes before a meal. Now in my past articles, I have often pointed out that supplement timing may be overrated. In the case of ALA, it does yet make perfect sense for diabetics and insulin resistant obese people (!) to take it before a meal, in order to benefit from the insulin sensitizing effects of the AMPK activator alpha lipoic acid.

Figure 3: Weight loss during 4-week induction and 16-week follow up in the placebo, 1,200mg and 1,800mg ALA groups (left) and relative weight loss at the end of the study in all "completers" (Koh. 2011)

As you can see in Figure 3, the timely use of 600mg of alpha lipoic acid before each of the meals lead to significantly increased weight loss, specifically in the latter phase of the 20 week trial, in the course of which the subjects had to consume 600kcal less - but at least 1,200kcal/day - than their habitual diet would provide. Quite an impressive result of which the researchers from the University of Ulsan College of Medicine in Seoul say that its efficacy and safety (compared to other anti-obesity drugs) would "suggest that alpha-lipoic acid may be effective as an adjunctive medication for obesity" (Koh. 2011) - a medication, and you can see that in Figure 3, that helps with both: weight and fat loss!

Whether ALA is or isn't for hard-training athletes / gymrats remains to be seen

Unfortunately, studies on athlete subjects are quasi-non-existent. What we know is that alpha-lipoic acid can be used to increase the accumulation of creatine in the muscle (learn more | baking soda is probably more effective, though) and that it diminishes the exercise induced oxidative damage without having significant beneficial (or negative) effects on exercise performance in the short run (Zembron-Lacny. 2009).

ALA or R-ALA? There is no reliable evidence that R-ALA would produce superior effects in vivo studies. The often cited study by Streeper et al. (1997), for example, was conducted on isolated, insulin resistant rat muscle in the Petri dish and is thus hardly representative of trained athletes. In fact, the vast majority of studies reporting metabolic benefits from the use of alpha lipoic acid used the racemic mixture of the R- and the allegedly "toxic" S- isomer of alpha lipoic acid. If you still insist on R-ALA make sure it's bound to sodium (Na), because the unbound version won't even make it into your bloodstream (Carlson. 2007).

Otherwise, you will find patent after patent with hilarious, scientifically unverified claims about "muscle building", "body recompositioning" and "performance enhancing" effects of ALA in athletes.

Reliable evidence that any of these effects exist in athletes who follow a clean, whole foods based high(er) protein diet, however, is absent. If anything, one could cite a relatively exotic rodent study that was published in the Journal of Shaanxi Normal University (Natural Science Edition) in 2006. In said study, the Chinese scientists observed a glycogen preserving effect of ALA in rats who were trained to exhaustion (Xiong. 2006). Whether or not these or other benefits outweigh a potentially reduced adaptive response to exercise as it was observed for n-acetyl-cysteine (NAC) by Michailidis et al. in 2013 remains questionable, though.

Figure 3: Highly significant increases in PPAR-alpha are partly responsible for the reduced hepatic fatty liver synthesis and should help prevent NALD (Keith. 2014)

Let's get back to the "clock issue": It remains to be seen if similar effects on the clock genes in the liver can be observed in older humans, as they have now been reported for rodents with the standard 600mg/day servings of alpha lipoic acid of which previous studies show that it can help with diabetes and non-alcoholic fatty liver disease.

Until we don't know the exact mechanism by which alpha lipoic acid works its restorative magic on the clock genes of your liver, we cannot tell if it has to be timed appropriately, either. For melatonin, which is a cyclically produced hormone correct timing is a must. For lipoic acid it's probably irrelevant... at least if its effects are in fact mediated by the powerful antioxidant effects of lipoic acid | Comment!

References:

• Carlson, David A., et al. "The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects." Alternative Medicine Review 12.4 (2007): 343.
• Dove Keith, Liam Finlay, Judy Butler, Luis Gómez, Eric Smith, Régis Moreau, Tory Hagen. Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age. Biochemical and Biophysical Research Communications, 2014
• Koh, Eun Hee, et al. "Effects of alpha-lipoic acid on body weight in obese subjects." The American journal of medicine 124.1 (2011): 85-e1.
• Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2012 Jun 5. [Epub ahead of print]
• Streeper, Ryan S., et al. "Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle." American Journal of Physiology-Endocrinology And Metabolism 273.1 (1997): E185-E191.
• Xiong, Zheng-ying, and Hai-bin LIU. "Effects of alpha-lipoic acid on glucose reserve and moving capacity of training rats [J]." 
• Zembron-Lacny, A., et al. "Assessment of the antioxidant effectiveness of alpha-lipoic acid in healthy men exposed to muscle-damaging exercise." J Physiol Pharmacol 60.2 (2009): 139-43.