What Is Alpha Ketoglutarate?
Introduction | What is alpha-ketoglutarate (AKG)? | Overview of Potential Health Benefits and Risks | How Does it Work? | Potential Health Benefits of AKG | Potential Risks and Side Effects of AKG | Can You Get AKG From Food? | Caloric Restriction | Supplementation and Dosage | Calcium Alpha-ketoglutarate (Ca-AKG) | Conclusion: AKG Supplements Are Promising, But More Clinical Trials Are Needed
Alpha-ketoglutarate is an essential compound that regulates energy metabolism, DNA expression, amino acid formation, and inflammation response. This multifaceted keto acid decreases about 10-fold between ages 40-80, making it a prime target for longevity supplements. Animal studies are promising and demonstrate shocking results from AKG supplementation, including life extension and a significant delay in the onset of age-related conditions and diseases.
What is alpha-ketoglutarate (AKG)?
Alpha-ketoglutarate (AKG) is a powerful compound that plays a significant role in many biological processes. As a Kreb’s Cycle metabolite, alpha-ketoglutarate is produced when cells break down food molecules for energy. It then flows in and between cells, enabling many life sustaining processes and signaling systems. It even plays a role in gene expression, acting as a regulatory mechanism that appears to prevent DNA transcription errors that often cause disease and illness, like cancer.
Alarmingly, natural levels of alpha-ketoglutarate decline about 10-fold between ages 40-80. Modern longevity researchers now correlate this decline with the aging process, age related disease, and morbidity.
Alpha-ketoglutarate is an endogenous chemical, meaning it is produced by the body. It cannot be obtained through food, but some studies indicate it can be preserved through fasting and following a ketogenic diet. Supplements are available over the counter, and they are likely the best option for individuals who want to maintain healthy levels as they age.
Here, we explore the impact of alpha-ketoglutarate on the aging process, the impact its decline has on health, and the science behind supplementing with this exciting new longevity tool.
Overview of Potential Health Benefits and Risks
Disclaimer: Always consult your health care professional prior to making changes in your diet or exercise regimen, including whether to use supplements like alpha-ketoglutarate. Pregnant women, women who are nursing, and children especially must always consult a physician prior to taking supplements or medications.
Potential AKG health benefits:
- Longevity/Extended Lifespan
- Compressed Morbidity (Greater Health Span)
- Regulates Energy and Metabolism
- Promotes Healthy Glutamine Levels
- Detoxifies Body
- Promotes Gut Health
- Healthy Weight Loss and Management
- Promotes Collagen Synthesis
- Promotes the Proliferation of Stem Cells
- May Prevent Osteoporosis
Potential risks and side effects of AKG:
Alpha-ketoglutarate is generally considered safe for oral consumption. However, more research is needed. Children and women who are pregnant, trying to become pregnant, or nursing should avoid this compound. See Potential Risks and Side Effects of AKG below.
How Does it Work?
Alpha-ketoglutarate is an alpha-keto acid that plays a significant role in several foundational biological processes. Longevity research on alpha-ketoglutarate is still in its early stages, but it appears to have at least four key mechanisms of action. These include maintaining healthy metabolism, facilitating the transamination of vital amino acids, protecting DNA, and suppressing chronic inflammation.
Maintains healthy metabolism
Alpha-ketoglutarate plays a key role in healthy metabolism. It is produced in response to the ingestion of macronutrients, namely fats, carbohydrates, and proteins. Following digestion, food molecules are broken down and eventually reach every cell in the body. This is where the story of AKG begins.
Inside the cell, food metabolism occurs inside tiny organelles called mitochondria. These structures are often referred to as the “power houses” of cells. Inside mitochondria, a process called the Kreb’s Cycle (also known as the Citric Acid Cycle) converts food molecules to energy that can be used by the cell, and by extension, the organism.
The Kreb’s Cycle also produces byproducts, however. This includes potentially harmful things, like reactive oxygen species, as well as beneficial metabolites, like alpha-ketoglutarate.
Modern longevity research indicates that alpha-ketoglutarate is among the most important byproducts of the Kreb’s Cycle. As authors Timothy Rhoads and Rozalyn Anderson note in a 2020 article published in Cell Metabolism, “Given its breadth of influence, AKG might be viewed as a fundamental metabolic intermediate” that ultimately affects many vital cellular processes beyond the walls of the mitochondria. According to the authors, these include things like amino transamination, DNA methylation, and reducing inflammation.
Transamination of amino acids
One of the most important jobs alpha-ketoglutarate performs is acting as a catalyst for amino acid transformation. Called transamination, this process is perhaps best understood by imagining a child playing with a set of Lego building blocks.
In this analogy, alpha-ketoglutarate is like the foundational Lego blocks. These pieces form the base of whatever is being built, like the first floor of a house or the chassis of a car. When dietary protein is digested, it is broken down into its own fundamental compounds called amino acids. These are comparable to the rest of the Lego blocks in the set.
With alpha-ketoglutarate as the foundation and amino acids as additional building blocks, transamination can now occur. The process of transamination begins with a keto acid, like alpha-ketoglutarate, and blends it with additional amino acids to create a unique set of end products. Typically, these end products are things like enzymes or new amino acids—effectively “helper molecules” that trigger important biological activities.
Perhaps the most important example of this process in action is the transamination of alpha-ketoglutarate and aspartate, which results in two new compounds: Glutamate, and oxaloacetate. This reaction is vital because glutamate is needed to form various members of the “glutamine family” of amino acids. Together, this family of chemicals accounts for about 25% of total amino acids used by the human body, and they are necessary building blocks for things like cell growth, detoxification, nervous system function, movement, and learning.
In this way, alpha-ketoglutarate acts as a foundational molecule that sets the stage for amino acid metabolism and optimal cellular function. Without it, cells would not be able to metabolize food molecules for energy, build vital amino acids, conduct protein synthesis, or even create the neurotransmitters needed for everything from brain function to digestion and motor movement.
Protects DNA via methylation
DNA is like a set of blueprints that contains specific information on how an organism develops, functions, grows, and reproduces throughout its life cycle. These instructions set the foundation for genetic expression—that is, the ways in which DNA is converted into the proteins and other chemicals that ultimately build the organism. Everything from height to eye color and cancer are thought to be end products of genetic expression, as encoded by an organism’s DNA.
Over the past decade, however, scientists have discovered another piece to this complex and fascinating equation: The epigenome. Though originally discovered in the early 1900s, the profound effect of the epigenome on DNA and longevity has only recently been understood. According to the National Genome Research Institute, the epigenome is a set of chemicals that can modify DNA and therefore change the way it is expressed. Environmental stress and disease are two common examples of external factors that can influence the epigenome, thereby affecting DNA expression.
This creates a dangerous and potentially fatal risk for aging organisms. Over time, environmental stressors may cause epigenetic changes to DNA. Such changes may result in physiological dysfunction and a significant increase in the risk of age-related diseases like cancer.
Fortunately, there is a built-in process that protects DNA from such damage called DNA methylation. And this is where alpha-ketoglutarate comes in.
DNA methylation is a process in which chemicals are attached to specific genes to ensure they remain “on” or “off”. This process is effective in young and healthy organisms, but it loses function over time. As DNA methylation loses control of the epigenome, studies indicate the risk of cancer significantly increases.
However, alpha-ketoglutarate appears to promote DNA methylation and maintain healthy DNA expression. As a result, longevity scientists now believe many age-related diseases can be prevented simply by maintaining adequate levels of alpha-ketoglutarate throughout the latter half of life.
Promotes anti-inflammatory cytokines
In addition to promoting healthy metabolism and protecting DNA, alpha-ketoglutarate also appears to confer substantial anti-inflammatory benefits. This is a hallmark sign of a legitimate longevity compound, as chronic inflammation is strongly correlated with aging and the development of age-related disease. Inflammation can also worsen certain illnesses and disease. For example, inflammation is often cited as a “critical driver” of cancer progression.
Fortunately, the human immune system has a built-in mechanism for mediating inflammation. Using special anti-inflammatory proteins called cytokines, the immune system can calm irritation and attenuate the symptoms of inflammation. Alpha-ketoglutarate has been shown to promote these cytokines and reduce inflammation in mice, which will be explored in more detail in the Potential Health Benefits of AKG – Compressed Morbidity section below.
Mammals have another critical defense system that can be leveraged to prevent chronic inflammation and age-related disease: A powerful protein called nuclear-factor-kappa-B, or NF-KB. This protein acts as a transcription factor, meaning it is involved in the process of transcribing DNA into RNA. Specifically, NF-KB activation triggers the creation of pro-inflammatory cytokines. NF-KB inhibition, on the other hand, reduces systemic inflammation and is associated with disease prevention.
In addition to promoting anti-inflammatory cytokines, alpha-ketoglutarate also appears to prevent chronic and systemic inflammation by acting as an NF-KB pathway inhibitor.
Potential Health Benefits of AKG
There are at least 3 things to consider when researching the potential health benefits of alpha-ketoglutarate. First, research is still in its early stages. Although the compound is generally considered safe for human consumption, more studies are needed to better understand the role it plays in promoting health and longevity.
Second, alpha-ketoglutarate supplements often contain a proprietary blend of AKG with other compounds. Calcium (Ca) and Arginine are among the most popular. As such, specific health benefits may differ depending on the formulation used. These are explored in more detail in the AKG Salts (Formulations), Supplements, and Dosages section below.
Natural alpha-ketoglutarate levels may also differ based on individual genetics, diet, and even fasting. As a result, potential health benefits may vary based on individual differences in diet and lifestyle.
As cited above, it is well documented that AKG levels decrease significantly after age 40. It is therefore unsurprising that preventing AKG decline may provide a wide range of health benefits, given the central role the compound plays in metabolism, cell signaling, and DNA maintenance.
The most well-documented health benefits of AKG are listed below. Potential health benefits of additional formulations—like Ca AKG, Arginine AKG, and others—are listed in the AKG Salts (Formulations), Supplements, and Dosages section that follows.
In some studies, alpha-ketoglutarate has been shown to extend lifespan. That’s not surprising, given the central role the compound plays in things like metabolism and amino acid formation.
In a 2019 paper published by the peer reviewed journal Aging, alpha-ketoglutarate was shown to extend the lifespan of nematodes, also known as roundworms. Authors speculate the extended lifespan is a result of the compound’s ability to reduce activity along the mTOR pathway.
Modern research indicates that mTOR inhibition is associated with several beneficial effects on health. Specifically, mTOR inhibition seems to promote cellular longevity and reduce the risk of age-related disease by increasing cellular autophagy.
However, these results are limited to nematodes and fruit flies—two relatively simple organisms with which human beings share little genetic common ground. Mice are a much closer proxy to human beings, and in such studies, alpha-ketoglutarate appears to compress morbidity without significantly extending lifespan (see below).
Compressed Morbidity (Greater Health Span)
By far, the most promising study on alpha-ketoglutarate was conducted in 2020 and published in the journal Cell Metabolism. Researchers studied the effects of calcium alpha-ketoglutarate (Ca-AKG) on aging mice. The results were shocking. According to the study, calcium alpha-ketoglutarate:
- Extended lifespan
- Compressed morbidity (significantly delayed the onset of age-related conditions and diseases)
- Reduced frailty
- Reduced chronic inflammation
Interestingly, researchers observed a difference in outcome based on sex. Observing females, the authors saw a significant decrease in the expression of age-dependent phenotypes like fur color, piloerection (involuntary bristling of hair), poor coat, dermatitis, gait disorder, and kyphosis (excessive curvature of the spine).
Researchers observed slightly different outcomes among males, including decreased expression of “severity of body condition, dermatitis, gait disorder, eye discharge, kyphosis, and tumors”.
A few other highlights of this study include:
- Results were achieved by giving mice calcium alpha-ketoglutarate at middle age, suggesting that even middle aged or elderly individuals may benefit of supplementing with AKG to combat the diseases and dysfunction associated with its natural decline.
- Researchers mapped the levels of 24 known inflammatory cytokines. Ca-AKG treated mice exhibited low levels of these cytokines, while the control group did not. This indicates Ca-AKG may prevent chronic inflammation by down-regulating the cytokines that cause it.
- In female mice, researchers also noticed an increase in the anti-inflammatory cytokine IL-10. This was not observed in males and may explain the aforementioned discrepancy in age-dependent phenotype expression.
The importance of this study, and the excitement it evoked among longevity scientists, cannot be understated. However, clinical trials are needed to better understand how similar results may or may not be achieved in human subjects.
Regulates Energy and Metabolism
It is well known that alpha-ketoglutarate plays a key role in regulating and maintaining healthy metabolism. Specifically, the rate at which cells can extract energy from food molecules is determined by the level of alpha-ketoglutarate that is present. As levels of AKG decrease, so too does the cell’s ability to produce energy via the Kreb’s Cycle. By the same token, healthy levels of AKG may promote normal metabolism and energy levels as humans age.
AKG’s role in metabolism and energy production makes it a natural target for sports supplementation. To date, there are dozens of AKG supplements that claim to improve energy, vascularity, and strength. These claims are largely supported by anecdotal evidence only. In laboratory settings, many studies have failed to provide evidence to support this claim.
For example, a landmark study published by the Journal of the International Society of Sports Nutrition, arginine alpha-ketoglutarate failed to demonstrate any significant differences in muscular strength or endurance compared to a placebo.
Nevertheless, it is well established that alpha-ketoglutarate helps to regulate one of the human body’s most important amino acids: Glutamine.
Promotes Healthy Glutamine Levels
As described above, adequate levels of alpha-ketoglutarate are needed to form glutamate, which then can be used to form glutamine. Healthy glutamine levels are critical for normal biological function. Things like cellular homeostasis, protein synthesis, fat metabolism, and insulin secretion are all made possible by this all-important amino acid.
There is a lot of talk about “detox” in modern culture. Yoga poses, herbal teas, and infrared light therapy are just a few common examples of practices and products that claim to help the body detoxify itself. Some are backed by more scientific evidence than others. But one thing is certain: Without the alpha-ketoglutarate to glutamine transamination process described above, humans would likely die from the toxic side effects of metabolism.
Take the transamination process as an example. This special kind of amino acid metabolism happens continuously as cells try to keep up with the almost ceaseless demand for new proteins. The process also produces ammonia, however, which is a toxic and potentially fatal byproduct. If left unchecked, the accumulation of excess ammonia may cause irritability, headaches, vomiting, seizures, encephalopathy, and death.
However, the process of converting alpha-ketoglutarate to glutamine actually requires the use of free-floating ammonia. In this way, alpha-ketoglutarate plays a vital role in the detoxification of one of the human body’s most prevalent and potentially harmful toxins.
Promotes Gut Health
Alpha-ketoglutarate’s ability to produce glutamine has far reaching health benefits. In addition to its essential role in cellular homeostasis, protein synthesis, and fat metabolism, glutamine is also required to create and maintain a healthy gut.
Specifically, glutamine helps to balance the microbiome, strengthen the lining of the intestinal wall, and protect against inflammation. Together, these effects ensure the gastrointestinal tract (GI) functions optimally. This sets the stage for healthy aging by improving the absorption and availability of macronutrients, vitamins, minerals, and even longevity supplements.
Healthy Weight Loss and Management
In 2020, an animal study published in the journal Aging Cell showed alpha-ketoglutarate to decrease body weight and improve certain obesity and morbidity factors. Key takeaways include:
- Lower fat mass
- Improved glucose tolerance
- Increased brown adipose tissue (fat)
Interestingly, an increase in brown adipose tissue helps to maintain a low body fat percentage. That’s because brown adipose tissue actually burns stored fat from white adipose tissues. In doing so, brown fat creates a net loss in total body fat.
Promotes Collagen Synthesis
Collagen is sometimes considered a “beauty supplement”, but it is actually a critical component of a long and healthy life. In addition to being the most abundant protein in the human body, collagen is also responsible for creating and fortifying essential connective tissues like tendons, ligaments, muscles, and skin. The latter is particularly important, as skin is the first line of defense against radiation, germs, bacteria, viruses, and communicable diseases.
Alpha-ketoglutarate appears to increase collagen production, perhaps in part because of its central role as a metabolic mediator in the Kreb’s Cycle. To date, more research is needed to better understand this relationship.
Promotes the Proliferation of Stem Cells
Alpha-ketoglutarate may also promote stem cell proliferation. In a 2014 article published in the journal Nature, authors explain “AKG [alpha-ketoglutarate] levels can contribute to the maintenance of cellular identity and have a mechanistic role in the transcriptional and epigenetic state of stem cells“. Authors emphasized, however, the exact processes governing such cell proliferation was “poorly understood”.
Two years later, a 2016 article published by Cell Metabolism identified alpha-ketoglutarate’s role in early stem cell differentiation as the key mechanism by which it promotes cell proliferation.
May Prevent Osteoporosis
Osteoporosis is disease that causes bones to become weak and brittle over time. As the disease progresses, bones may become so compromised that they break easily. According to a meta-analysis published by Therapeutics and Clinical Risk Management, osteoporosis is a “major public health problem” that, in the case of slips and falls, often leads to increased rates of hospitalization, subsequent fractures, and death in elderly populations.
However, alpha-ketoglutarate may help. As described above, alpha-ketoglutarate is a powerful precursor to the amino acid glutamine. As such, it has been shown to increase protein synthesis and enhance bone tissue formation Although it plays a causal role in bone tissue formation, more research is needed to understand if alpha-ketoglutarate can help to treat or reverse osteoporosis specifically.
Potential Risks and Side Effects of AKG
Important: Due to limited research, children and women who are pregnant, trying to become pregnant, or breastfeeding should avoid alpha-ketoglutarate and associated supplements.
At the time of this writing, there are no known side effects of alpha-ketoglutarate. It is an endogenous compound, meaning it is naturally produced by the body. Therefore, supplementing with alpha-ketoglutarate should not cause any unwanted side effects.
However, care must be taken if supplementing with a formulation that contains more than just alpha-ketoglutarate. Additional compounds may cause unique side effects and/or interactions. For more information, see AKG Salts (Formulations), Supplements, and Dosage section below.
Can You Get AKG From Food?
As an endogenous chemical, alpha-ketoglutarate is not available from food sources. However, studies indicate that diet and lifestyle may influence its production.
A ketogenic diet consists primarily of fats and proteins. Carbohydrates are extremely limited and mostly consumed as fiber. This forces the body to burn fat as its primary fuel source, which creates an abundance of alpha-ketoglutarate in the Kreb’s Cycle.
More research is needed to determine the long-term effects of ketogenic diet on alpha-ketoglutarate levels.
Caloric restriction is an eating strategy that significantly limits daily caloric intake without compromising essential vitamin and mineral needs. It is estimated that adults may require anywhere from 1,600 to 3,800 calories every day depending on age, activity level, and body composition goals. According to the National Institute on Aging, caloric restriction in animal studies typically involves reducing daily calories by 10-40%.
In one animal study, caloric restriction appeared to preserve alpha-ketoglutarate levels in aging mice. However, more studies are needed to determine if similar results can be achieved in humans.
AKG Salts (Formulations), Supplements, and Dosage
Disclaimer: Always consult your health care professional prior to making changes in your diet or exercise regimen, including whether to use supplements containing alpha-ketoglutarate.
Calcium Alpha-ketoglutarate (Ca-AKG)
Calcium Alpha-ketoglutarate (Ca-AKG) is a calcium salt. Most notably, this is the form of alpha-ketoglutarate used in the landmark mouse study detailed in the Potential Health Benefits – Compressed Morbidity section above. It is reported to have a wide range of health benefits, including:
- Delayed onset of age-related disease
- Compressed morbidity
- Reduced inflammation
- Reduced frailty
Potential side effects may include:
Ca-AKG is potentially safe when taken orally for up to 3 years. More research is needed.
Arginine Alpha-ketoglutarate (A-AKG)
Arginine Alpha-ketoglutarate (A-AKG) is a sports performance supplement designed to promote strength and cardiovascular endurance. Reported benefits include:
Potential side effects may include:
- Arginine-AKG is potentially safe when taken orally. More research is needed.
Important note: Claims that A-AKG boosts nitric oxide levels and oxygen delivery to muscle tissue are largely unproven in clinical trials.
Magnesium Alpha-ketoglutarate is a wellness and longevity supplement that aims to promote metabolism by combining these two compounds, both of which are essential in the Kreb’s Cycle. Although magnesium and alpha-ketoglutarate are generally regarded as safe, more research is needed to determine potential health benefits.
Potential side effects may include:
- Magnesium alpha-ketoglutarate is potentially safe when taken orally. More research is needed.
Glutamine Alpha-ketoglutarate is a sports supplement designed to improve strength, cardiovascular endurance, and muscle recovery. Although glutamine and alpha-ketoglutarate are both generally regarded as safe, more research is needed to determine potential health benefits.
Potential side effects may include:
- Glutamine alpha-ketoglutarate is potentially safe when taken orally. More research is needed.
Ornithine Alpha-ketoglutarate is an amino acid salt. Most commonly, this supplement is used as a medical intervention for healing wounds, ulcers, burns, and treating individuals with HIV/AIDS. Potential health benefits include:
Potential side effects may include:
Conclusion: AKG Supplements Are Promising, But More Clinical Trials Are Needed
It is easy to see why longevity experts and consumers are so excited about alpha-ketoglutarate research and supplements. The compound is vital for so many fundamental biological processes, yet it decreases at an astonishing rate beginning at age 40. Moreover, a clear correlation exists between alpha-ketoglutarate decline and the onset of various age-related conditions and diseases.