The Antioxidant of Antioxidants: A Compound You're Not Paying Attention To

In this episode of Daily Value, we look at the often overlooked yet potent nutrient, alpha lipoic acid, which is integral to mitochondrial energy metabolism and cellular health. Discovered in 1937, ALA acts as a primary antioxidant in the body. This episode covers the distinction(s) between supplemental and endogenous ALA. The latter is able to cross the blood-brain barrier and is used therapeutically for conditions like diabetic neuropathy, oxidative stress, and metal detoxification. I will also explain the importance of selecting the right form of ALA , recommended dosages for different formulations and their potential benefits in metabolic health.

00:00 Introduction to Alpha Lipoic Acid

00:53 Discovery and Biological Role

02:05 Antioxidant Properties and Functions

03:28 Supplemental Benefits and Research

06:28 Forms and Bioavailability

09:52 Therapeutic Threshold and Dosing

11:27 Safety and Efficacy

13:14 Conclusion and Recommendations

PMID: 39456481

PMID: 18069903

PMID: 29191830

PMID: 25971966

Chapters

• 0:00 Introduction to Lipoic Acid
• 1:32 Functions Within Mitochondria
• 4:22 Benefits of Supplemental Lipoic Acid
• 7:04 R vs S Forms: Choosing Effective Supplements
• 10:12 Therapeutic Dosing and Safety Guidelines
• 14:08 Conclusion and Recommendations

Transcript

Speaker 1: 0:00

Inside every cell of your body, hidden deep within the mitochondria, there is a powerful nutrient quietly fueling your energy, protecting your brain and supporting your metabolism. It's conditionally essential, yet often completely overlooked, even by many health enthusiasts. Today, we're looking at why lipoic acid might just be the most underrated compound that you're not paying attention to. Hello everyone, and welcome back to Daily Value. I'm William Wallace, and today we are looking at one of the most underrated compounds that you may not be paying attention to, that being alpha lipoic acid. Originally called thioctic acid, but also known simply as lipoic acid, is a uniquely potent compound with very important functions deeply embedded within our cellular machinery. First discovered in 1937, when scientists found a type of bacteria that uses potato juice for reproduction, this antioxidant is naturally occurring within our mitochondria, where it serves as a necessary cofactor from mitochondrial energy metabolism of all three major macronutrients proteins, carbs and fats. Essentially, cells cannot make energy at all without lipoic acid. Lipoic acid is a self-made primary antioxidant in the body, and what I mean by that is, of all the compounds our body makes. Lipoic acid sits in a class of primary antioxidant compounds that include carnitine, nadh, glutathione and coenzyme Q10. This class of compounds does not include enzymes or hormones. If we were including hormones, then something like melatonin would certainly join that group. This compound is also present in dietary sources like red meat, beets, carrots, potatoes, spinach, as well as broccoli. Structurally, lipoic acid is interesting. It exists in two forms inside the body. There is its oxidized form, alpha-lipoic acid, and its reduced form called dihydrolipoic acid. Alpha-lipoic acid and its reduced form, called dihydrolipoic acid. Together they form an antioxidant system capable of quenching a variety of reactive oxygen species and regenerating other necessary antioxidants like vitamins E and C and glutathione. Due to its multifunctional abilities, lipoic acid is commonly called the antioxidant of antioxidants. Again, endogenous lipoic acid is produced naturally within our mitochondria. When inside the mitochondria, it does, remain tightly bound to mitochondrial enzyme complexes, primarily proteins like pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. These enzyme-bound forms of lipoic acid facilitate important metabolic reactions, converting carbohydrates and amino acids into usable energy. Importantly, because endogenous lipoic acid is protein-bound, it generally remains within mitochondria, with limited ability to travel outside into other cellular compartments or extracellular spaces. In addition to all of that, lipoic acid's amphiphilic nature meaning it can dissolve in both water and fat theoretically enables penetration into diverse cellular environments. However, and again endogenous lipoic acid's protein-bound nature restricts its mobility, which contrasts a bit from the recorded effects with supplemental forms of lipoic mobility, which contrasts a bit from the recorded effects with supplemental forms of lipoic acid, which are freely available and can exert additional beneficial effects throughout the body, even crossing the blood-brain barrier, to provide neuroprotective benefits. Recent research has demonstrated the diverse therapeutic potentials of lipoic acid, ranging from neuroprotection to improved metabolic health, positioning itself not just as an antioxidant but as an essential regulator of cellular health and possibly longevity. This nuanced distinction between naturally occurring mitochondrial-bound lipoic acid and its supplemental counterpart will be important as we look at the broader implications and unique benefits of supplementation later in this episode.

Speaker 1: 4:07

While endogenous lipoic acid is tightly bound to mitochondrial proteins, restricting its antioxidant functions largely to mitochondrial environments, supplemental lipoic acid seems to unlock functions that your own body's supply cannot. Basically, supplemental lipoic acid is free to work beyond the mitochondria. When taken orally, ala rapidly achieves peak plasma levels within 30 to 60 minutes, traversing both lipidic that's fat-based and aqueous that's water-based cellular compartments efficiently. Due to its amphipathic properties, supplemental ALA is capable of neutralizing reactive oxygen species such as superoxide radicals, singlet oxygen and hydroxyl radicals. Specifically, in its reduced form, dihydrolipoate alpha-lipoic acid exhibits strong antioxidant actions, making it highly beneficial for conditions associated with oxidative stress, including ischemia, reperfusion, injury, radiation damage, etc.

Speaker 1: 5:09

The therapeutic potential of supplemental ALA extends beyond its antioxidant properties. It significantly enhances nitric oxide mediated endothelium-dependent vasodilation, which improves microcirculation, particularly valuable in managing something like diabetic neuropathy. Actually, there's pretty robust clinical data supporting its use for reducing neuropathic symptoms, which demonstrates its unique role in diabetic management. Another distinct advantage of supplemental ALA is its excellent metal chelation properties attributed to its theol groups. By increasing cellular glutathione levels, ala and dihydrolipoate facilitate the excretion of toxic metals, with dihydrolipoate specifically forming complexes with metals like iron, copper, lead and mercury. Thus it aids in detoxification. Thus it aids in detoxification. Lepoic acid also regenerates other antioxidant factors like vitamins C and E and glutathione, as I mentioned before. In addition to that, lepoic acid is actually needed to cleave a compound called cysteine. This is two cysteine amino acids bound together into individual cysteine units, which allows them to enter a cell and be used to make glutathione.

Speaker 1: 6:29

Supplemental lipoic acid does seem to offer health benefits, but selecting the right form is important for efficacy. Lipoic acid naturally occurs as the RN antimer called R-lipoic acid or RLA, which is the biologically active form that is utilized by your cells. Which is the biologically active form that is utilized by your cells. Actually, all known biological systems that utilize lipoic acid rely exclusively on the R form. However, most commercially available supplements contain what are called racemic mixtures, which is 50% R lipoic acid and 50% S lipoic acid. This mixture has traditionally been favored due to its simpler and cost-effective production. It also seems like the addition of S-lipoic acid, which is a natural byproduct of the chemical synthesis of lipoic acid, does make it more shelf-stable compared to RLA by itself. There have been binding studies that confirm the specific interaction between the biologically active R form and the human sodium multivitamin transporter. This transporter specifically recognizes and transports the RN antimer, reinforcing the importance of choosing the correct supplemental form for optimal absorption and systemic efficacy. Importantly, pharmacokinetic studies do show significant differences between these two forms. The S-form is thought to be biologically inactive and some researchers suggest that it may also interfere with the absorption and beneficial effects of the R-form. When taken together, the S-form might competitively inhibit the absorption of the R-form, reducing its bioavailability.

Speaker 1: 8:10

In addition, and again pure arlopoic acid itself faces stability challenges. It has a tendency to polymerize. Polymerize means to join small molecules together, called monomers together, to form a large chain or network of chemicals. This results in poor water solubility and significantly limited bioavailability. This instability has historically hindered its therapeutic application, despite its superior biological activity. To overcome these issues, a form of arlipoic acid stabilized by sodium was developed. This is known as sodium-stabilized arlipoic acid.

Speaker 1: 8:49

Clinical pharmacokinetic data do show compelling advantages for sodium RLA. Firstly, sodium arlipoic acid significantly reduces the polymerization tendency, ensuring superior stability and water solubility compared to pure RLA. A study published by Carlson et al in 2007 showed that sodium arlipoic acid achieves dramatically higher plasma concentrations and total absorption, measured by area under the curve, compared to pure RLA or racemic lipoic acid, meaning the S and R combination form. Specifically, when 600 milligrams of sodium arlopoic acid was given to participants who, a few weeks later, were given pure arlopoic acid, the peak values in plasma were approximately 10-25% greater compared to standard RLA, and it reached peak plasma concentrations within 10-20 minutes after ingestion. Availability of sodium RLA was 2.7 to 3.3 times greater than standard RLA.

Speaker 1: 9:52

Now, an important factor that needs to be considered for the therapeutic efficacy of lipoic acid is the concept of a therapeutic threshold, defined as the minimum plasma concentration that's required to initiate the chain of protective biochemical reactions that lipoic acid has been documented to perform. Basically, you may need to spike ALA in your system to trigger beneficial metabolic cascades. Research does indicate that maintaining plasma concentrations above this therapeutic threshold, that's approximately 4 to 5 micrograms per milliliter, might be necessary for triggering antioxidant and anti-inflammatory pathways, enhancing glucose uptake and improving overall metabolic health. Sodium RLA has been shown to be uniquely suited to consistently surpass this threshold at practical dosing levels. An oral dose of approximately 150 milligrams of sodium RLA is, on average, capable of achieving plasma concentrations that breach for micrograms per milliliter. A 300 milligram dose has been shown to put nearly everyone over the therapeutic threshold. In contrast, internal data by a company that supplies the main form of sodium allopoic acid on the market suggests that even 1,000 milligrams of standard RLA cannot breach the therapeutic threshold of 4 micrograms per milliliter. According to the FDA, ala is safe and effective.

Speaker 1: 11:21

Alpha-lipoic acid is widely available as an oral supplement and in intravenous formulations. Now, while the data that was referenced does suggest the superiority of stabilized arlopoic acid, it is important to recognize that significant clinical research has been conducted using racemic mixtures of R and S-lipoic acid, which still show therapeutic potential. Clinical studies typically administer ALA orally in doses ranging from 300 milligrams to 1,800 milligrams daily. Oral supplementation at 300 milligrams over three months has been demonstrated to maintain and improve functional vision in patients with type 1 and type 2 diabetes. There have been other studies conducted showing that 600 to 1,800 milligrams administered daily for up to six months may be particularly effective in managing diabetic neuropathy and improving insulin sensitivity. Clinical trials have shown IV administration of 600 milligrams per day can significantly improve neuropathic symptoms and deficits, suggesting that IV therapy may be particularly effective for rapid symptom relief and significant neuropathic improvements. Available research does indicate that ALA supplementation during pregnancy is safe, although more data is needed to clearly define its role and optimal dosing parameters for that particular demographic. Studies report that adults can tolerate oral doses of up to 2,400 milligrams daily without adverse reactions. Beyond that, there is a risk of adverse reactions, including headache, heartburn, nausea and possibly vomiting.

Speaker 1: 12:55

While racemic forms of ALA have been demonstrated to show beneficial clinical outcomes, selection of appropriate dosages, forms, attention to specific patient populations and adherence to recommended dosing guidelines are important to ensure both safety and efficacy of taking ALA. In conclusion, when selecting lipoic acid supplements, understanding dosing and the differences between formulations is key to achieving benefit. Recommended daily oral doses of stabilized arlipoic acid are generally 150 to 300 milligrams per day. This form is unique in that it has higher bioavailability, superior stability and consistent achievement of therapeutic plasma concentrations. Recommended daily oral doses of S and R combination forms are between 300 and 1,800 milligrams per day. This is what has typically been used in clinical studies. Advantages here are established safety and efficacy profiles. Also, this form of ALA is widely available and it's pretty cost-effective. Supplementation can generally support neuroprotection, antioxidant defense, metabolic improvements and diabetic neuropathy. Thank you for joining me today on Daily Value. Don't forget to subscribe, share with friends and family and stay tuned for our next episode, where we continue to explore nutrients that fuel your body and mind. As always, stay healthy.