AAKG

Arginine alpha-ketoglutarate ( AAKG for short) is a nutritional supplement used by bodybuilders and athletes to increase performance, reduce muscle fatigue and speed up recovery. However, AAKG supplementation may also have benefits for numerous diseases and conditions. In this article, we will describe how AAKG works and what health benefits are attributed to it.

What is arginine alpha-ketoglutarate (AAKG)?

Arginine alpha-ketoglutarate (AAKG) is a modified version of the amino acid arginine (1). Alpha-ketoglutarate is an intermediate compound in a series of reactions that produces energy for the body. To improve absorption in the stomach, many alpha-ketoglutarate supplements are available in the form of different salts. The most common variant of alpha-ketoglutarate compounds is the combination of ornithine and alpha-ketoglutarate (4, 5). Alpha-ketoglutarate also regulates amino acid synthesis, energy production and the formation of free radicals. It acts as a messenger molecule in many chemical reactions in the body (4). Arginine is a component of proteins and stimulates the release of hormones such as insulin, glucagon, prolactin and growth hormone. Arginine also plays a crucial role in maintaining blood pressure, heart function and immune system function. These functions are mediated by the production of nitric oxide, which dilates blood vessels, improving blood flow and circulation. Arginine is broken down in the body into ornithine and creatine. Ornithine is essential for cell growth and division, while creatine is important for muscle contractions (6). Arginine is supplied in the diet and can also be produced by the body itself. Arginine is referred to as a semi-essential amino acid. In healthy adults, dietary intake and endogenous synthesis are sufficient to meet the need for this amino acid. This requirement includes functions such as tissue repair, protein synthesis and maintenance of immune function (7). During periods of rapid growth, physical stress or injury, this normal arginine supply may be insufficient to meet the body's needs. During these periods, taking arginine as a supplement can help maintain muscle mass and improve a range of bodily functions (7). Arginine supplementation may also increase exercise capacity. Some of this improvement can be observed immediately after consuming arginine. In addition, long-term improvements may be observed due to increased protein synthesis in the muscles (7). In addition to its performance-enhancing effects, arginine appears to be a safe and effective treatment for high blood pressure, type 2 diabetes and erectile dysfunction (9, 10, 11, 12). Arginine reduces infection rates in situations such as post-surgery or severe illnesses where the body is susceptible to infection (9). Arginine is marketed in combination with alpha-ketoglutarate as arginine alpha-ketoglutarate primarily as a supplement for athletes due to its performance-enhancing potential (13, 14, 15). In the clinical setting, however, L-arginine is more commonly used on its own. (16, 6).

The composition of AAKG

Arginine alpha-ketoglutarate is formed when two arginine molecules are attached to an alpha-ketoglutarate. The combination of these two compounds improves the stability of arginine. This is said to improve the performance-enhancing capabilities of arginine and its role in energy production.

Natural sources of L-arginine and alpha-ketoglutarate

L-arginine is one of the 20 amino acids found in food and is considered a semi-essential amino acid, as it is both supplied through food and produced by the body itself. L-arginine is found in high concentrations in foods such as watermelon, nuts, seeds, algae, meat, seafood, beans, lentils, whole grains, rice protein concentrate and soy protein isolate (17).

In the body, L-arginine is synthesized from citruline. Although this synthesis can occur in many cells, most arginine is produced in the kidneys (18, 19), alpha-ketoglutarate is an intermediate in the cycle that converts food into energy. In this cycle it is formed from isocitrate. However, alpha-ketoglutarate can also be produced from glutamate (2).

Mechanisms of action

It is not known exactly how arginine alpha-ketoglutarate enhances performance, but this effect is most likely due to increased nitric oxide levels (15).

Alpha-ketoglutarate

Alpha-ketoglutarate is a product of the mitochondria and plays a crucial role in the conversion of food into energy. It is also a source of glutamine and glutamate, both of which can inhibit protein breakdown in muscle and increase the rate of protein synthesis (2). Alpha-ketoglutarate increases bone formation. It regulates the synthesis of collagen and collagen is a significant component of bone tissue. Alpha-ketoglutarate also stimulates the production of IGF-1 and growth hormones - hormones that regulate the formation of new bone tissue in addition to stimulating muscle growth (4). In addition, alpha-ketoglutarate also has immune function enhancing properties and is potentially useful in delaying the ageing process (2).

L-arginine

L-arginine is broken down into nitric oxide (NO) in different types of tissue in the body. Depending on where it is produced, nitric oxide plays a crucial role in regulating different functions in the body (17, 20):

• In the brain, it acts as a messenger to transmit messages between nerves.
• In the immune system, it regulates the activity of white blood cells.
• In the cardiovascular system, it has a protective effect by relaxing the blood vessels. This improves the blood supply and oxygen transport throughout the body and supports the removal of waste products.

L-arginine also stimulates the release of growth hormones, which results in increased production of IGF-1. IGF-1 increases protein synthesis and thus promotes muscle development (21). In addition, arginine is involved in the removal of toxins by forming urea, which is excreted from the body via the urine (22). In the liver, L-arginine is converted into glucose and alpha-ketoglutarate and can therefore act as a potential source of energy (23).

It is claimed that AAKG combines the potential benefits of L-arginine and alpha-ketoglutarate

There are few studies that have specifically looked at the combination of arginine with alpha-ketoglutarate. Most of the benefits of this combination that have been reported are anecdotal in nature. The few studies that can be found include only a small number of subjects and show contradictory results, which may also be partly related to the very low amount of AAGK, which in one study, for example, was just 300 mg (1). The effects of supplementation with arginine alpha-ketoglutarate for 7 days were studied in 24 physically active men after resistance training. Arginine alpha-ketoglutarate had no effect on heart rate, blood pressure, blood flow or nitric oxide levels, but the amount of L-arginine in the blood was increased (24). In another study of 35 men who regularly trained with weights, arginine was found to be safe and well tolerated and positively affected muscle strength and maximal power release, while no effect on body composition or aerobic capacity was observed (15). Another study of 12 trained men observed no effects of AAKG on endurance or blood pressure response to anaerobic exercise (25). However, although there is limited research on the effects and health benefits of AAGK, the individual molecules L-arginine and alpha-ketoglutarate have been studied for their health benefits:

Health Benefits of L-Arginine

L-arginine can increase training performance

A daily intake of L-arginine for 45 days reduced muscle fatigue and increased athletic performance in 56 male field hockey players (42). In 8 healthy volunteers, L-arginine supplementation before training improved strength and training capacity by reducing blood levels of lactate and ammonia, both of which are associated with the onset of muscle fatigue (43). Long-term L-arginine supplementation (3 weeks) reduced blood lactate levels and oxygen consumption during exercise in 16 healthy male volunteers (44). These effects can be attributed to the increased blood flow caused by arginine, which not only improves the supply of oxygen, nutrients and amino acids required for muscle growth, but also results in faster removal of toxic metabolic products that are increasingly produced during intensive muscle exertion. Strength athletes also appreciate arginine because of the increased muscle pump, which also results from the increased blood flow caused by nitric oxide. In addition to cosmetic effects, such a muscle pump can also directly stimulate muscle growth via various mechanisms. These include stretching of the fascia and increased muscle protein synthesis due to a temporary increase in muscle volume.

In a study of 11 postmenopausal women, L-arginine supplementation for 6 months improved muscle strength and muscle performance release (45). L-arginine can promote the health of blood vessels and the cardiovascular system A meta-analysis of 7 studies concluded that L-arginine can lower blood pressure in adults with high blood pressure (16). In a clinical study of 14 subjects with high cholesterol levels, arginine supplementation reduced platelet reactivity, which in turn reduced the risk of blood clots (46). In rabbits, arginine supplementation had positive effects on arteriosclerotic diseases by dilating blood vessels, thinning the walls of blood vessels and preventing the build-up of fat (47, 48, 49). Arginine supplementation for 45 days reduced blood glucose and blood lipid levels in a clinical study of 28 healthy men (50). In contrast, a meta-analysis with a total of 927 subjects was unable to observe any positive effects of arginine supplementation in patients with acute myocardial infarction (51). Furthermore, arginine did not improve the availability of nitric oxide in subjects with heart disease (52).

Arginine could have a positive effect on infertility and sexual dysfunction

L-arginine supplementation for 6 weeks in 29 male subjects improved symptoms of erectile dysfunction in 31% of the subjects (53). In a study of 34 women who did not respond to artificial insemination, oral supplementation with L-arginine improved the pregnancy rate. This effect was based on an improvement in the response of the ovaries and an improvement in the environment in the uterus (54). In goat spermatozoa, L-arginine increased the vitality of the sperm by increasing the production of nitric oxide. This effect could promote an improvement in fertility (55).

Arginine could be beneficial for diabetes

Diabetes is associated with low arginine levels and vascular dysfunction. Several animal studies suggest that arginine supplementation may be an effective way to improve blood vessel function in diabetes. Acute L-arginine injections can also increase insulin levels in the blood, which reduces the amount of glucose secreted by the liver (56). In addition, oral arginine supplementation for 21 to 31 days in 26 patients with type 2 diabetes improved insulin sensitivity and blood vessel function and reduced blood glucose levels (10, 11).

Arginine could improve immune function in cancer patients and healthy people

In a clinical trial with patients with advanced breast cancer, arginine supplementation for 3 days before chemotherapy reduced the suppression of the immune system by chemotherapy (57). In a clinical study with 13 healthy volunteers, oral intake of arginine increased the activity of immune cells involved in fighting tumor growth (C56+, natural killer cells, lymphocyte-activated killer cells) (58). In human and mouse cells, L-arginine increased the survival and anti-tumor activity of immune cells (59).

Arginine could increase exercise capacity in people with heart disease

Arginine supplementation was shown to increase exercise capacity in a study of 16 elderly people with heart disease (60).

In another study, arginine improved exercise capacity in 22 patients with angina pectoris who were recovering from a heart attack by increasing oxygen availability during exercise (61).

Arginine and alpha-ketoglutarate could improve wound healing

In a study of 36 healthy volunteers, arginine supplementation for 2 weeks improved wound healing and immune response (62). In guinea pigs, oral arginine improved immune function and increased burn survival (63). In mice, arginine reduced airway injuries caused by allergic inflammation (64). A significant improvement in the healing of burns was also observed with alpha-ketoglutarate supplementation in clinical and animal studies (26, 27, 28).

Arginine could increase fat burning

In a study, long-term use of arginine in combination with diet and exercise improved blood sugar and insulin levels. It also reduced abdominal fat in 33 overweight subjects with type 2 diabetes (10). In pigs, oral supplementation with L-arginine reduced fat deposits and promoted body-wide muscle growth (65).

Arginine could reduce pain in the digestive tract

Oral L-arginine supplementation significantly reduced the frequency and intensity of pain attacks and the use of painkillers in a study of 8 patients with digestive tract movement disorders (66). In rats, L-arginine accelerated the healing of gastric ulcers by improving blood flow and the formation of new blood vessels (67).

Arginine could improve cognitive function in dementia patients

1.6 grams of L-arginine per day was able to improve the subjects' intellectual function in a study of 16 elderly patients with dementia (68).

Arginine could have anti-ageing effects

Ageing was associated with reduced levels of nitric oxide in an observational study of over 200 people. Arginine supplementation could help to maintain normal nitric oxide levels and thus counteract the ageing process (69).

Interestingly, alpha-ketoglutarate supplementation has also been shown to delay the aging process in Caenorhabditis elegans worms (37).

Health benefits of alpha-ketoglutarate

Alpha-ketoglutarate could prevent muscle wasting

In 21 patients who underwent surgical trauma, an alpha-ketoglutarate supplement prevented muscle breakdown and increased protein synthesis in a clinical trial (29). Gastric surgery reduces muscle protein synthesis. In 22 adults who had undergone gastric surgery, alpha-ketoglutarate supplementation improved muscle glutamine supply and prevented muscle loss (30).

Alpha-ketoglutarate could promote bone health

Alpha-ketoglutarate increases collagen production and enhances iron absorption, which could improve bone density and stability (2).

In 76 postmenopausal women with bone weakness, alpha-ketoglutarate supplementation over a 24-week period prevented bone loss and reduced symptoms of menopause while strengthening bone tissue (31). A number of animal studies also suggest that alpha-ketoglutarate supplementation may increase bone density (32, 33).

Alpha-ketoglutarate could improve immune function

In the body, alpha-ketoglutarate is converted into glutamine. Glutamine can increase the levels of white blood cells (macrophages and neutrophils) (34). In elderly patients suffering from nutrient deficiencies, supplementation with ornithine alpha-ketoglutarate has been shown to improve overall health and shorten recovery time from serious illness and surgery (35). In mice, the addition of alpha-ketoglutarate to drinking water led to improved immune function in the stomach and also reduced body weight (36).

Alpha-ketoglutarate could help against cyanide poisoning

In rats, oral alpha-ketoglutarate supplementation blocked the effects of cyanide poisoning - a potent toxin that can be fatal (38).

Alpha-ketoglutarate may have anti-cancer effects

In several animal studies, alpha-ketoglutarate has been shown to reduce the blood supply to tumors, resulting in tumor cell death (39). In studies on cell cultures, alpha-ketoglutarate was able to prevent the proliferation of cancer cells (40, 41). These are only the results of studies at a very early stage. Under no circumstances should alpha-ketoglutarate be used as a substitute for cancer therapy.

Possible side effects of arginine alpha-ketoglutarate

Supplementation with arginine alpha-ketoglutarate (AAKG) for 8 weeks had no serious side effects in a study of 45 healthy men (15). However, there are 3 case reports of people who were hospitalized after AAKG supplementation with symptoms such as drowsiness, vomiting, palpitations and fainting 70).

Possible side effects of alpha-ketoglutarate

No serious side effects of alpha-ketoglutarate have been reported in humans (71). However, based on studies conducted in rats, there may be a potential for toxicity with repeated use. Observed side effects included diarrhea and reduced body weight. Cases of anemia were also observed in female rats, but were reversible after cessation of supplementation (72).

Possible side effects of arginine

Arginine is not associated with serious side effects (6). Doses of up to 30 grams per day are usually well tolerated. The most common side effects occasionally reported with doses between 15 and 30 grams include nausea and diarrhea (18). A meta-analysis of 11 studies involving a total of 387 healthy volunteers suggests that arginine can significantly lower blood pressure (73). Higher doses of arginine may cause a bitter taste in the mouth.

Contraindications

Arginine alpha-ketoglutarate supplements should not be used by people with a history of heart attacks (70).

Not enough is known about the use of AAKG during pregnancy and lactation, so its use by pregnant or breastfeeding women is not recommended. Arginine supplementation should be used with caution and preferably in consultation with a doctor in children and people with viral infections, serious kidney dysfunction, asthma or cancer (18, 13).

Herpes patients should be cautious with arginine as it may exacerbate the symptoms of this infection, although this has not yet been validated by clinical trials (6). In patients with impaired liver or kidney function, the use of L-arginine supplements can lead to low potassium levels and high urea nitrogen levels (75).

Interactions with medications

L-arginine may interact with insulin- and cholesterol-lowering medications. L-arginine increases nitric oxide levels in the body, so patients taking nitric oxide donors should be cautious with arginine supplementation. These drugs include isosorbide mononitrate, sodium nitroprusside and glycerol trinitrate.

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