Alpha Lipoic Acid

Alpha Lipoic Acid (ALA) is not classified as a vitamin, yet is synthesized by the body and is conditionally essential. Alpha lipoic acid benefits include supporting glucose metabolism, and this is perhaps it’s best-known feature.^1,2,3 As a chiral molecule, it can be found in both isomeric forms (S and R) while the majority of non-specified supplemental forms are a racemic mixture of both.

Paying attention to the form is important. For example, if your target is healthy glucose metabolism, all oxidized forms (S, R, and racemic) will affect glucose uptake; however, only the R form interacts with the insulin receptor itself.¹² It is also important to be watchful of dietary and nutrient interactions. Co-ingestion with medium-chain triglycerides inhibits the already limited bioavailability which is approximately 30%.^13,14 Conversely, acetyl-L-carnitine has been studied in combination with alpha lipoic acid and, when taken together, may support mitochondrial biogenesis and act upon the peroxisome proliferator-activated receptors (PPAR), gamma, and alpha.*^16,25

ALA essentially has two purposes. Primarily, it acts as a coenzyme in metabolic functions and secondarily to scavenge free radicals.* While it is a fatty acid by design, it is also water-soluble and suitable for both lipophilic and hydrophilic environments. It is also effective in both its oxidized and reduced forms.⁴ This unique motif equips ALA for the complex domain of the mitochondria and electron transport chain.*

In vivo, ALA’s cofactor role is to assist in the production of energy-originating biomolecules like acetyl-CoA and mitochondrial energy powerhouse enzymes like pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase.⁴  These enzymes seem to produce enough ALA endogenously and do not appear to respond to supplementation.⁴ Multiple basic science studies and clinical trials are aiming to fully understand the benefits of ALA.^{1,2,4,5,8,10,11,15,16,18,19,20,21,23}

Specifically, ALA has been studied in basic sciences with N-acetyl-cysteine (NAC).⁸ In mice, researchers observed the effects of doses of 20mg/kg on lipid peroxidation and dopamine levels.*^9,10 ALA is also of interest in its role in heavy mineral metabolism.* ^11,15

In the diet, ALA can be found in muscle meats,⁴ spinach,^5,6 kidney,^5,6 liver,^5,6 broccoli,^5,6, and tomatoes.^5,6 The amounts in foods are much less than in the dietary supplement form.

In addition, Alpha lipoic acid benefits include:

• ALA may act on AMP-activated protein kinase (AMPK).⁷
• Human clinical trials on ALA have emerged that are supportive of its use in heart, glucose metabolism, and nerve health.*^18,19,23

When considering ALA remember:

• Biotin and ALA have a similar structure, thus like with biotin, avoid avidin or the protein in raw egg whites as it can sequester the biomolecule.²²
• ALA acts on the Keap1-Nrf2 system. When this system is activated, genetic expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and UDP-glucuronosyltransferase (UGT) are regulated by the Keap1 sensor.^20,21
• The ALADIN (I, II, and III), SYDNEY (I and II), and ORPIL clinical trials all used divided oral dosages of up to 2400 mg per day with no apparent side effects; however, selenium levels in the serum, heart, brain, and muscle tissues were all lowered along with manganese levels also decreasing in the heart.⁴
• Use caution with ALA when there is evidence or suspicion of 21-hydroxylase and/or 17α-hydroxylase deficiencies. ALA is an inhibitor of NADPH-cytochrome-P450 reductase (POR) and can potentially have consequences for those with alterations in these genes.¹⁷
• Co-ingestion of monocarboxylic acids inhibits the absorption of ALA and there is a very limited amount of ALA coming from food. Mitochondria efficiently recycle ALA under normal circumstances.

Many studies use 600 mg of oxidized alpha lipoic acid two to three times per day.  Chronic high dosages of approximately 5-10 g per day have been shown to increase oxidative damage.^4,24

By Christy Williamson, MS

Christy Williamson has a master’s degree in human nutrition from the University of Bridgeport and is a candidate for both the Certified Nutritional Specialist and Doctor of Clinical Nutrition. Christy is currently collaborating to create a database of genomic material to facilitate state-of-the-art research on rare diseases. Christy was active in the 2016 Virginia General Assembly in the passage of legislation that established a statutory definition of nutritional genomics. With a colleague, Christy developed a course in nutritional genomics for the Maryland University of Integrative Health.  Christy is the owner of Nutrigenomic Health Consulting, LLC. Her company focuses on functional nutrition as it relates to biochemical nuances within the genome and microbiome. Christy and her company are based in Midlothian, Virginia.

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8. Farr SA, Poon HF, Dogrukol-Ak D, et al. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem. 2003 Mar;84(5):1173-83.
9. Santos IM, Freitas RL, Saldanha GB, et al. Alterations on monoamines concentration in rat hippocampus produced by lipoic acid. Arq Neuropsiquiatr. 2010 Jun;68(3):362-6.
10. Ferreira PM, Militão GC, Freitas RM. Lipoic acid effects on lipid peroxidation level, superoxide dismutase activity, and monoamines concentration in rat hippocampus. Neurosci Lett. 2009 Oct 23;464(2):131-4.
11. Anuradha B, Varalakshmi P. Protective role of DL-alpha-lipoic acid against mercury-induced … Pharmacol Res. 1999 Jan;39(1):67-80.
12. Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys. 2002 Jan 15;397(2):384-91.
13. Takaishi N, Yoshida K, Satsu H, Shimizu M. Transepithelial transport of alpha-lipoic acid across human intestinal Caco-2 cell monolayers. J Agric Food Chem. 2007 Jun 27;55(13):5253-9.
14. Teichert J, Hermann R, Ruus P, Preiss R. Plasma kinetics, metabolism, and urinary excretion of alpha-lipoic acid following oral administration in healthy volunteers. J Clin Pharmacol. 2003 Nov;43(11):1257-67.
15. Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep. 2005;10(1):52-60.
16. Chou TC, Shih CY, Chen YT. Inhibitory effect of α-lipoic acid on platelet aggregation is mediated by PPARs. J Agric Food Chem. 2011 Apr 13;59(7):3050-9.
17. Slepneva IA, Sergeeva SV, Khramtsov VV. Reversible inhibition of NADPH-cytochrome P450 reductase by alpha-lipoic acid. Biochem Biophys Res Commun. 1995 Sep 25;214(3):1246-53.
18. McNeilly AM, Davison GW, Murphy MH, et al. Effect of α-lipoic acid and exercise training on cardiovascular … glucose tolerance. Lipids Health Dis. 2011 Nov 22;10:217.
19. Andrea Scaramuzza, Elisa Giani, Francesca Redaelli, et al. Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial ..: A Pilot Trial.  Journal of Diabetes Research. 2015;2015:474561 20. Akira U, Yoko Y, Masayuki Y. The Keap1–Nrf2 system and … Archives of Biochemistry and Biophysics. 2015; 566:76–84.
21. Kobayashi A, Kang M-I, Watai Y, et al. Oxidative and Electrophilic Stresses Activate Nrf2 through Inhibition of Ubiquitination Activity of Keap1. Molecular and Cellular Biology. 2006;26(1):221-9.
22. Hale G, Wallis NG, Perham RN. Interaction of avidin with the lipoyl domains in the pyruvate dehydrogenase multienzyme complex: three-dimensional location and similarity to biotinyl domains in carboxylases. Proc Biol Sci. 1992 Jun 22;248(1323):247-53.
23. Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of …: results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study.  Circulation. 2005; 111: 343-8
24. Cakatay U, Kayali R. Plasma protein oxidation in aging rats after alpha-lipoic acid administration. Biogerontology. 2005;6(2):87-93.
25. Shen W, Liu K, Tian C, et al. R-alpha-lipoic acid and acetyl-L-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes. Diabetologia. 2008 Jan;51(1):165-74                    

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