Alpha Lipoic Acid

Alpha lipoic acid's antiaging properties stem from its ability to remodel the extracellular matrix by stimulating collagen production, as well as its numerous antioxidant effects that enable it to protect the skin from oxidative stress.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

B

Wrinkle treatment

Moderate

Reduces facial lines and ameliorates wrinkles around the eyes and mouth by increasing collagen production.

B

Skin lightening

Mild

Improves pigmentation and the overall colour of the skin.

B

Improved eye bags

Mild

Led to a statistically significant improvement in the appearance of under-eye bags in one study, based on photographic evaluation.

B

Smaller pores

Mild

Diminished the size of pores in 2 separate double-blinded, placebo-controlled studies.

C

Increased skin thickness

Moderate

Increased the thickness of the epidermis-dermis layer by nearly 9% after 3 months of treatment in one study.

C

Smoother skin

Mild

Reduced the roughness of the skin by an average of 51% in one study, compared to 41% for the placebo.

C

Less visible scars

Mild

2 out of 12 volunteers in one study reported improvements in facial scars after 3 months of treatment with alpha lipoic acid.

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Scientific Research


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Table of contents

1. Sources

Alpha lipoic acid, also known as lipoic acid and thiotic acid, is a naturally occurring compound that is produced in small amounts by both plants and animals, including humans.[1][2]

Because the structure of lipoic acid contains an asymmetric carbon, there are 2 optical isomers of alpha lipoic acid; however, only the R-isomer is endogenously synthesized. It is this R-isomer that is found in food, bound covalently to the amino acid lysine to form lipoyllysine. The liver, heart and kidney tissues of animals contain the highest amount of lipoyllysine,[3][4] while vegetables rich in lipoyllysine include broccoli and spinach.[5]

Functionally, alpha lipoic acid is an essential cofactor for several mitochondrial multienzyme complexes and plays a fundamental role in the breakdown of various alpha keto-acids and amino acids.[6][7][8]

2. Bioavailability

The distorted five-membered 1,2-dithiolane ring of alpha lipoic acid is quite vulnerable to UV radiation.[9][10] Upon photoirradiation, alpha lipoic acid is easily decomposed[11][12] and its degradation products possess an unpleasant odour,[13] which complicates the preparation of cosmetic formulations suitable for topical use.[14]

Studies indicate that the presence of retinyl palmitate, ascorbyl palmitate or butylhydroxytoluene favours the chemical stability of alpha lipoic acid, but tocopheryl acetate does not protect alpha lipoic acid from degradation.[15][16] The amino acid homocysteine has also been shown to protect against the degradation of alpha lipoic acid slightly and more importantly, to regenerate alpha lipoic acid after UV irradiation.[11]

Nanoencapsulation both increases the stability of alpha lipoic acid[14][17] and has the potential to enhance its delivery into the skin, without compromising its biological activity.[18] Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been shown to be suitable carriers for alpha lipoic acid.[13][18] Semisolid formulations of alpha lipoic acid nanocapsules appear to be suitable for topical use as well.[14]

Alpha lipoic acid is lipophilic[15] and has a low molecular weight,[19] characteristics that enable it to readily penetrate the stratum corneum. In a study on mice, the maximum concentration of alpha lipoic acid in the skin was reached 2 hours after application, with 95% in the stratum corneum, 1% in the epidermis and 4% in the dermis and subcutaneous layers.[20] 30-80% of alpha lipoic acid was also demonstrated to successfully penetrate pig skin in vitro, with formulations of water/oil emulsions and penetration promotors such as phytantriol aiding permeation.[21]

A study on cutaneous delivery using microemulsions found that microemulsions did not affect the penetration of alpha lipoic acid despite disrupting the skin barrier. Still, the amount of alpha lipoic acid delivered to the skin may be sufficient for enhanced protection.[22]

After its delivery into the skin, a proportion of alpha lipoic acid is reduced to dihydrolipoic acid.[20]

3. Effects on the skin

Studies indicate that topical treatment with alpha lipoic acid have beneficial effects on photoaged skin. In one randomized, double-blind and placebo-controlled trial, 33 women applied a 5% alpha lipoic acid-containing cream twice daily to one half of their face and a control cream to the other half. After 12 weeks, the roughness of the skin had declined by 51% on the side treated with alpha lipoic acid, compared with a 41% improvement on the placebo-treated side. Fine lines, pigmentation, under-eye bags, pore size and puffiness were also improved.[19]

Another double-blinded, placebo-controlled trial tested the efficacy of poloxamer gel as a vehicle for a novel lipid base particulate system (cubosome dispersions) of alpha lipoic acid. The results showed that topical 30% poloxamer gel loaded with alpha lipoic acid cubosomes reduced facial lines, diminished pores, almost completely resolved fine lines around the eye and the upper lip, and led to overall improvements in skin colour and texture in most volunteers. Further, 2 volunteers reported improvements in facial scars. There was also a significant increase in the thickness of the epidermis and dermis layers, implying an increase in the amount of collagen in the skin.[23]

A cosmetic formulation containing a dispersion of liposome with magnesium ascorbyl phosphate, alpha lipoic acid and kinetin also enhanced the moisture of the stratum corneum and also hydrated deeper layers of the skin, although it is not certain whether these effects are attributable to alpha lipoic acid or the other active compounds in the formulation.[24]

Photoaging, the appearance of prematurely aged skin due to chronic sun exposure, is characterized by progressive alteration of the dermal extracellular matrix.[25] The amount of collagen and glycosaminoglycans decline, and their chemical structure and 3D organization also undergo changes.[26]

Alpha lipoic acid has been demonstrated to reverse some of these changes. A cosmetic formulation with 0.5% alpha lipoic acid, 0.3% proanthocyanidin and a mixture of essential amino acids significantly enhanced the synthesis and deposition of collagen in the dermis, when administrated transdermally. Importantly, alpha lipoic acid alone at lower concentrations was also shown to stimulate collagen production.[26] A later study confirmed these observations, demonstrating that alpha lipoic acid effectively increased the expression and deposition of type I collagen in human dermal fibroblasts, possibly via activating Smad signalling.[27] Therefore, the ability of alpha lipoic acid to efface wrinkles is very likely due to its stimulatory effect on collagen biosynthesis.

3.2 Antioxidant effect

Alpha lipoic acid is a known antioxidant[28] with multiple antioxidant properties.[29]

Firstly, it has the capacity to chelate metal ions such as iron and copper,[8][30][31] which can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals.[32]

Secondly, it is a powerful scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including hypochlorous acid and OH* free radicals.[28][33][34]

When an antioxidant scavenges a free radical, it becomes oxidized and needs to be reduced in order to continue scavenging other ROS or RNS. Dihydrolipoic acid (DHLA), the reduced form of lipoic acid, is a potent reducing agent.[35] In other words, it has the ability to regenerate endogenous antioxidants, such as ascorbic acid (vitamin C) and glutathione.[36] It may also regenerate alpha-tocopherol (vitamin E) directly or indirectly by reducing the oxidized forms of ascorbic acid and coenzyme Q10.[37][38]

Finally, alpha lipoic acid also increases the synthesis of glutathione,[39] another important intracellular antioxidant, by upregulating the expression of gamma-glutamylcysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis [40] and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis.[41]

An evaluation of the antioxidative capacity of commonly used antioxidants in cosmetics revealed that lipoic acid possesses moderate antioxidative capability, less powerful than ascorbic acid and alpha-tocopherol, but more powerful than vitamin C derivates like ascorbyl palmitate and ascorbic acid-2-glucoside.[42] Moreover, nanoencapusulation appears to improve the antioxidant effect of alpha lipoic acid.[43]

These help to explain why alpha lipoic acid protects against oxidative stress in the skin.[44] It counteracts the changes induced by PUVA therapy, such as the increase in ROS generation, disruption of the integrity of cellular membranes and the impairment of the function of the cellular antioxidant system. It also rescues fibroblasts from ROS-dependent changes such as cytoplasmic enlargement and enhanced expression of senescence-associated-beta-galactosidase and matrix-metalloproteinase-1, which are hallmarks of both extrinsic and intrinsic aging.[45]

However, alpha lipoic acid does not seem to be effective in photoprotection of the skin, as alpha lipoic acid alone (Perricone MD Advanced Face Firming Activator) did not provide any protection against solar-simulated radiation, nor did it augment the protective effects of a commercial formulation containing vitamins C and E (Skinceuticals Primacy C+E).[46]

3.3 Wound healing

Evidence that topical application of alpha lipoic acid aids wound healing is accumulating. The combination of gold nanoparticles, the green tea catechin epigallocatechin gallate and alpha lipoic acid has been shown to significantly accelerate the healing of cutaneous wounds in mice through its anti-inflammatory and antioxidant effects,[47] and possibly also by regulating angiogenesis and through blocking the receptor for advanced glycation end-products.[48]

Topical application of free alpha lipoic acid alone also increased the healing rate of surgical wounds on rat skin, though nanoencapsulation seemed to hinder the healing activity.[49]

4. Side Effects

The safety of alpha lipoic acid consumption has been well-studied, with results showing no significant toxic effects including mutagenicity or genotoxicity.[50][51][52]

However, we were unable to find similar studies on the safety and tolerability of topically applied alpha lipoic acid, save for a few case reports of contact dermatitis to alpha lipoic acid in an anti-wrinkle cream.[53] The human studies conducted so far have reported mainly mild adverse events such as a burning sensation and occasionally a rash. However, these were transient and resolved within a few weeks, which would seem to indicate that topical alpha lipoic acid is generally well-tolerated.[19][23][24] Theoretically, an individual weighing 65 kg applying 2 g of a 5% alpha lipoic acid cream to the entire face daily corresponds to 1.5 mg/kg/day, which represents a dose of approximately 100 mg/day.[19] This is below even the lower range of doses used for systemic treatment, and hence bodes well safety-wise, but actual studies are clearly needed in order to make a definitive statement.

Scientific References


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