AKG Supplement: Benefits, How It Works, and Potential Side Effects

Alpha-ketoglutarate has gained popularity in the longevity field after a couple of animal study results indicated that it increases lifespan. While the compound has some proposed beneficial effects on human health, it may not be as simple and impactful as the headlines want you to believe.

With my background in Biomedical Sciences and a goal to make scientific study results comprehensible for everyone, I dove into the available research on AKG to check whether any of the AKG marketing claims have scientific backing. Below, you will find a thorough overview of alpha-ketoglutarate, its potential benefits, currently available studies, and overall information about the supplement.

What is alpha-ketoglutarate (AKG)?

Alpha-ketoglutarate (AKG) is an essential molecule and one of the intermediates in the Krebs (also known as citric acid) cycle. In simple terms, this cycle is a chain of reactions that converts nutrients to energy to power our cells. Besides that, AKG also mediates numerous metabolic and cellular pathways that regulate our physiological functions.

Besides the Krebs cycle and energy production, AKG is also crucial for amino acid synthesis, namely glutamine, proline, arginine, and lysine — all of which are essential for protein synthesis. The compound also helps neutralize hazardous metabolites in the body (such as ammonia) and has antioxidant properties. In addition, alpha-ketoglutarate is involved in epigenetic and immune system regulation, mostly by participating in the processes related to cell metabolism, growth, and aging.

Are there any benefits of AKG supplementation?

The levels of AKG tend to decrease with age, and so it has been speculated that supplementing with the compound may extend lifespan. However, the evidence and understanding of how it works is very limited. Animal research has shown life span extension in worms, fruit flies, and mice, however, the same effects were not seen in human research. There is one study on 42 healthy individuals that reported reduced biological age after a 7-month AKG use, however, one study without a placebo-controlled group is not good enough to make longevity claims.

There is a bit more research to support other potential benefits, such as improved exercise performance and bone health. You will find a summary of the currently available research on the potential marketed benefits of alpha-ketoglutarate below.

AKG and exercise performance

Alpha-ketoglutarate is sometimes taken by bodybuilders and other fitness enthusiasts due to its role in amino acid metabolism and protein synthesis, as well as nitrogen and carbon balance. It is believed that supplementation may aid muscle building, thus helping with physical performance and recovery.

A randomized, double-blind, placebo-controlled trial looked at how alpha-ketoglutarate affects training tolerance in 33 untrained young male adults. All participants had five training sessions per week and received daily supplementation of either 0.2 g/kg (90 mg/lb) of AKG, branched-chain keto acids (BCKA), or a placebo. At the end of the study, the supplement groups showed significant improvements in training volume, maximum power output, and muscle force and performance when compared to the placebo. The researchers observed the most pronounced improvements in the AKG group.

A small placebo-controlled trial involved 35 resistance-trained adult 30–50-year-old men who received 4 g of L-arginine alpha-ketoglutarate (AAKG) or a placebo three times a day for eight weeks. All participants had four resistance training sessions each week throughout the study. The results showed that after eight weeks, AAKG groups had significantly higher maximum power output without significant changes in body composition or muscle endurance. Overall, the study suggests that supplementing with AAKG may improve strength and power output but not aerobic capacity.

Can AKG support muscle regeneration?

A narrative review of 112 peer-reviewed scientific articles summarized that alpha-ketoglutarate may help skeletal muscle regeneration after injuries caused by various factors, including physical activity. It was observed that in mice, alpha-ketoglutarate can promote muscle cell proliferation in cells responsible for muscle repair and maintenance.

The compound may also promote anti-inflammatory processes, which are thought to aid the muscle repair process. Furthermore, AKG may help reduce muscle loss and support growth because it is involved in amino acid synthesis and protein formation. Despite the extent of the review article, more animal and human research is still needed to confirm these hypotheses.

Considering the currently available in-human research, I would say that AKG has some scientific backing in potentially improving muscle tissue strength and recovery, power, training volume, and reducing exercise-related fatigue. Noting the limitations of the studies, these effects were only observed with specific training regimens, which may not reflect the real-world exercise routines. In addition, based on scientific research, alpha-ketoglutarate has little to no benefit for cardio-based training and does not seem to affect body composition.

AKG and gut health

Although scarce, some animal research on AKG supplementation suggests that it may support the gut microbiome and reduce gut inflammation, which in turn sparked the marketing claims. However, the evidence stems from only a few animal studies, and no trials explored whether these effects are observable in humans.

A study in mice observed that drinking water with 1% AKG decreased the symptoms of induced colitis, a condition described by inflammation in the large intestine. The overall results of the study suggest that alpha-ketoglutarate may offer some protection from developing colitis in mice.

A placebo-controlled two-part mice study looked at the effects of AKG in drinking water (10 g/l or 1.34 oz per gallon) on the gut of mice. The first part looked at AKG supplementation, and the second part at the disrupted mice microbiota model. The combined results suggest that AKG has the potential to support the gut and its immunity by mediating the composition of the gut microbiota, but fails to do so if microbiota is disrupted.

Despite alpha-ketoglutarate being marketed for gut health, after analyzing currently available animal research and noting the lack of research on the human gut, I would say that AKG supplementation is unlikely to benefit human gut health.

AKG and bone health

A six-month, parallel-group, double-blind study on post-menopausal women with osteopenia, a condition of low bone mineral density, administered calcium alpha-ketoglutarate (Ca-AKG) or calcium alone daily. The results showed that the Ca-AKG group had a 1.6% increase in bone mineral density and had lower blood concentrations of bone breakdown markers. These results suggest that Ca-AKG supplementation may help maintain bone density and reduce bone breakdown. However, the study supplemented women with alpha-ketoglutarate alongside calcium, which is known to be beneficial for bone health, not AKG alone. It is unclear whether the same effects would be observed if AKG was supplemented without calcium.

While this human study looks promising and suggests AKG administered with calcium may reduce bone breakdown and age-related bone loss, there is currently too little evidence to draw a firm conclusion. However, I am excited to see more research into the topic in the future.

AKG salts and formulations

Alpha-ketoglutarate has low cell permeability, meaning it has trouble getting through the cell membranes and has poor bioavailability. However, AKG can be administered in combination with other compounds, usually calcium, arginine, magnesium, glutamine, or ornithine.

Calcium alpha-ketoglutarate (Ca-AKG)

Ca-AKG combines calcium with alpha-ketoglutarate. The combination has been primarily used and studied for bone health, with some proof that it may increase bone mass density by 1.6% from baseline in post-menopausal women.

Calcium alpha-ketoglutarate administration is typically oral, with the only currently available human study using a 6 g daily dose for six months.

Other AKG salts: arginine, magnesium, glutamine, and ornithine

While most studies mostly administered alpha-ketoglutarate alone or in combination with calcium, other AKG salts are also available.

AKG can be combined with arginine to increase nitric oxide production, which would, in theory, support blood flow and aid resistance training. However, few studies are looking at arginine-AKG (AAKG). One study involving 24 active men administered 12 g of AAKG daily for 7 days around resistance training time but found no significant improvements in blood flow. This means that AAKG is unlikely to have any specific benefits.

The combination of ornithine and AKG, known as ornithine alpha-ketoglutarate (O-AKG) is one of the best studied. Ornithine is a non-essential amino acid but is involved in several crucial metabolic reactions, such as ammonia removal. Some early studies from the 80s and early 90s have shown that it may improve brain function after stroke, help with burn wound healing, reduce muscle mass loss after injury or surgery, improve appetite in older individuals with chronic disease, and reduce ammonia levels. While both human and animal research on O-AKG looks promising, there is still too little proof to conclude on the actual effects.

AKG may also be combined with magnesium or glutamine; however, no studies have explored these combinations.

Potential risks and side effects of AKG

AKG is one of the major metabolites naturally present in the body and involved in numerous metabolic reactions, thus, it is not a foreign compound to our body. However, as a supplement, it may cause some side effects, especially if taken in large doses.

Common side effects and adverse reactions

One of the main issues with taking AKG as a supplement is no established dosage guidelines, and there is a lack of studies on long-term supplementation.

Due to being understudied, AKG does not have a lot of data on its side effects, but gastrointestinal issues have been reported in a few studies. These typically involved nausea, bloating, vomiting, and diarrhea.

Interactions with medications and health conditions

The following groups should avoid taking AKG:

• Older adults
• Individuals with chronic disease
• Individuals taking medication
• Pregnant or breastfeeding individuals
• Individuals about to have or fresh after surgery
• Children

There is little to no information about AKG's interaction with medication or its adverse effects. The compound is involved in many metabolic pathways, thus, you should carefully discuss taking AKG as a supplement with your doctor if you are on prescription medication or have underlying health conditions.

Practical considerations

1. There is no dosage guidance. The doses used in studies mostly range from 3.6 g to 6 g daily, but they can go up to 30 g in some cases.
2. Form of AKG. AKG is available alone or in combination with other compounds, however, there is a lack of research on their pharmacokinetic differences.
3. Cellular permeability and bioavailability. AKG is unable to cross cell membranes. Also, around 80% of the compound received from diet is rapidly removed from the bloodstream, making its ability to reach cells complicated.
4. Short half-life. AKG has a half-life of about 5 minutes. The issue may be addressed with sustained-release technologies. However, there is currently minimal research and use of such technologies for AKG.

AKG supplementation and dosage

There is currently no medical consensus on alpha-ketoglutarate supplementation. The doses vary greatly between studies, and so do the lengths of the studies. Thus, there are no established recommendations for AKG dosage or length of use. If you decide to use the compound, consult your doctor who will take your needs, health status, and other relevant factors into consideration.

There are several routes of administration for alpha-ketoglutarate:

• Oral. The most straightforward way, however, 80% of the compound gets removed from the bloodstream, thus, not entirely efficient in increasing AKG levels.
• Intravenous. Intravenous AKG administration has been used in some clinical studies and may be more efficient in increasing AKG levels than oral administration by bypassing the gastrointestinal tract; however, not much is known about this administration route.
• Topical. One study has used topical alpha-ketoglutarate application to reduce the appearance of wrinkles and increase collagen production, however, this method is not popular and is understudied.

Similar to dosage, timing, and effects on the human body, the routes of administration also lack consensus and vary among studies. Still, the oral route is the most common one due to its simplicity.

Can you get AKG from food?

It is known that AKG is naturally present in numerous foods; however, the exact amounts are not yet analyzed and known like it is for other nutrients, vitamins, and minerals. Since AKG is a precursor for amino acids and protein and is involved in fatty acid oxidation and the Krebs cycle, you can mainly find AKG in high-protein animal sources, but it is also present in some plants.

However, because the exact amounts of AKG in foods are unknown and the compound has a poor absorption rate and short half-life, it is unknown whether food sources would significantly boost AKG levels in the human body.

Bottom line

Despite AKG being a crucial mediator and metabolite of essential cellular processes, the research on the benefits of AKG for human health is still in its infancy.

After researching the available scientific information on AKG, I noted that there is a clear mismatch between the marketing claims and the actual evidence. AKG is marketed mostly for longevity, exercise performance, muscle mass, and bone health benefits. After doing some thorough research, I did not find sufficient evidence to support many of these claims.

A similar comment was made by Linas Černiauskas, PhD candidate in medicine:

Scientific evidence points out that AKG may provide some support for physically active individuals, provided they manage other factors such as diet, recovery, and exercise. I also found research on Ca-AKG supporting bone health compelling, but I would like to see more consistent research with more definite conclusions. On the other hand, I did not see any convincing evidence for the claims regarding gut health and longevity in human trials and thus am skeptical.

The main risk of AKG is how understudied as a supplement it is. There is no clear guidance on dosage or usage, nor is there sufficient information on its interaction with medications. Thus, you should consult with your doctor before implementing AKG into your routine. Overall, AKG is involved in numerous biochemical pathways; however, that does not mean that it is as great and versatile a supplement as marketing suggests.

Future directions for AKG research and supplementation

To successfully scope AKG's utility as a supplement, more human studies involving various demographic groups are needed. These would allow us to determine AKG’s safety profile, devise dosage recommendations, and better understand whether AKG has benefits for human health.