Alpha-ketoglutarate (AKG) is an important component of energy metabolism and is involved in many physiological functions and processes in our body. Since AKG levels decrease with age and we cannot obtain this molecule through food, it has been studied as a promising molecule in the context of longevity research. In animal studies alpha-ketoglutarate extended lifespan by up to 50% and also in humans AKG reduced biological age by up to 8 years in one study. Additionally, it has positive effects on bone metabolism and promotes muscle growth. You can find out how exactly AKG works in the body, what the current state of research is, and what forms of the molecule exist here.
Alpha-Ketoglutarate Overview
Alpha-ketoglutarate is a small molecule composed of five carbon, six hydrogen, and five oxygen atoms. In our body, AKG is continuously broken down and rebuilt, as it plays an important role in energy metabolism. Since the AKG levels decrease over time, the molecule has come into focus for aging researchers. They see good potential in using AKG for the prevention of age-related diseases such as diabetes, obesity, and cardiovascular diseases.
Let's take a look at how this can work.
Physiological function of alpha-ketoglutarate
Where does AKG actually occur in the body? For this, we need to take a closer look at the power plants of our cells. In the mitochondria , sugar from food is converted into energy, in the form of ATP. This is exactly where alpha-ketoglutarate plays an essential role. In the so-called citric acid cycle , the carbon framework of glucose is broken down. This occurs through the conversion of several molecules. One of them is alpha-ketoglutarate.
Furthermore, AKG is important for the nitrogen metabolism, i.e., u.a. in the utilization of proteins through diet.
As a precursor of glutamate and glutamine alpha-ketoglutarate also plays a key role in the energy metabolism of the digestive tract . There, AKG serves as a precursor of glutamine for the energy production of our intestinal cells.
But that's not all, alpha-ketoglutarate is also capable of minimizing the breakdown of endogenous proteins and increasing protein synthesis. The molecule is involved in the formation of bone mass and skeletal muscles. This effect provides, according to the latest scientific findings, a basis for clinical applications in the field of prevention of age-related diseases.
Hormones and Immune System
Another influence of alpha-ketoglutarate (AKG) is on the endocrine system. Glutamine and glutamate are metabolized to ornithine and arginine. These two amino acids stimulate the release of growth hormones. It is suspected that AKG has a direct influence on bone metabolism. Furthermore, the longevity shooting star is involved in converting pro-collagen into collagen. Accordingly, the molecule is a supplier for collagen production in our body.
More on the topic Collagen can be found in the corresponding article in our magazine.
Interesting facts: Alpha-ketoglutarate is a stronger radical scavenger than ascorbic acid (Vitamin C).The high antioxidant potential of AKG is another promising property of this molecule.
Healthy bones – important even in old age
As we age, our bones become weaker. The large network of bone components becomes thinner, leading to an ever-increasing probability of fractures. In 2010, in Europe alone, 22 million women and 5.5 million men met the diagnostic criteria of the WHO for osteoporosis, in English: bone loss. Trend is increasing.
Osteoporosis is estimated to be responsible for 80-90% of all fractures in old age and can thus significantly affect the quality of life.For this reason, healthy, strong bones are particularly important in old age.
So what can you do to minimize bone loss? The European guidelines recommend strength training, as this has been shown to increase bone density through the pull of muscles on the bones. Additionally, regular vitamin D supplementation is recommended, as this hormone also affects calcium metabolism.
Alpha-ketoglutarate can be another supporter for healthy bones in old age. In a 6-month study, 73 postmenopausal women took either calcium alone or in the form of calcium-alpha-ketoglutarate. Calcium alone did not bring any improvement – however, the regular intake of 1000 mg Ca-AKG increased bone density.Together with strength training, an adequate magnesium supply and vitamin D could therefore represent a good precaution for healthy bones. Milk ensures healthy bones? Myth or fact? This saying has been used for a long time by the advertising industry. The calcium in milk is supposed to ensure stronger bones. In this study, 96,000 older women and men were followed for 22 years. Interestingly, men with a higher milk consumption in their youth had more fractures in old age. When body height is accounted for, the effect is no longer significant.
Alpha-ketoglutarate and the skin: Better wound healing and skin moisture
Collagen is one of the most important structural proteins of the skin, whose concentration decreases with age. This is where AKG can help by stimulating the conversion of pro-collagen to collagen.
Alpha-ketoglutarate has been tested as a skin cream in humans and was able to lead to a study that resulted in a significant reduction of wrinkles . In addition, the administration of AKG increased skin moisture and improved its function. The antioxidant properties of alpha-ketoglutarate likely play a crucial role here.
Research has also been conducted on the effect of AKG on wound healing in humans , particularly in burn victims. Alpha-ketoglutarate was able to contribute to a faster wound healing and reduced scar formation.
AKG a booster for the immune system
As a precursor to glutamine , alpha-ketoglutarate, as mentioned at the beginning, also plays a role in the immune system. Glutamine is essential for the physiological function of lymphocytes, which include B cells, T cells, and natural killer cells (NK cells). All these cells fight pathogens day in and day out with their different weapons.
Additionally, glutamine is also needed for macrophages, which play an important role in our body's defense against pathogens as phagocytic cells.
AKG can also directly increase the ability of phagocytosis . This means that the phagocytic cells (macrophages) can "eat up" (phagocytize) potential enemies better. This is one of the possible ways AKG can boost the immune system.
Longevity insights on Alpha Ketoglutarate
There are actually already initial studies in the context of longevity research. These were conducted on roundworms, specifically nematodes. Studies with the model organism Caenorhabditis elegans show that alpha-ketoglutarate can extend the lifespan of these organisms by about 50%.This mechanism is triggered by an inhibition of ATP synthase and mTOR. mTOR has been the focus of longevity research for years in connection with autophagy and is also one of the four longevity pathways. Furthermore, the administration of alpha-ketoglutarate in another study with nematodes delayed the onset of age-related phenotypes associated with a decline in the coordination and mobility of the worms. The first investigations with alpha-ketoglutarate (AKG) were conducted on the nematode Caenorhabditis elegans - with promising results.
Alpha-Ketoglutarate (AKG) in Human Research
The world-renowned Buck Institute for Research on Aging – leading in the field of longevity research for years – published new research findings from a mouse study in September 2020. They found that the mice that were administered alpha-ketoglutarate were healthier and also exhibited a longer lifespan in part. Additionally, the administration of AKG reduced inflammatory markers. Chronic inflammation has been associated with age-related diseases for years and is recognized under the name Inflammaging as a hallmark of aging.
A clinical study is planned at the National University of Singapore (NUS) to investigate the effect of alpha-ketoglutarate on people aged 45 to 65 years . The results of this study are of great importance for research, and the rapid implementation of such studies shows that AKG is of great interest in the longevity community.
A study from 2021 was also able to show that the administration of alpha-ketoglutarate in a formulation with other substances (z.B. vitamins) could rejuvenate the biological age of 42 participants by a full 8 years. The DNA methylation level was measured to determine biological age. This confirmed the theory that alpha-ketoglutarate has a positive effect on epigenetics .
Did you know? A study from 2012 found that increased alpha-ketoglutarate levels were detectable after physical activity. Exercise may be a good strategy to increase AKG levels. However, further studies are needed to confirm this effect.
Alpha-ketoglutarate and its effect on cells
AKG has antioxidant effects and can subsequently increase fertility (at least in animals) according to studies. To understand this better, we need to take a brief look at the biochemistry behind it.
In our body, reactive oxygen species, known as ROS, are constantly being produced. Too many of these highly active substances damage our cells, which is why there always needs to be a balance between the number of ROS molecules and ROS scavengers. One of the most important ROS scavengers in our body is glutathione. Simply put, the more reactive oxygen species are produced, the more glutathione is consumed. AKG helps our body maintain healthy levels of glutathione.
And what is the connection to fertility? As we age, oxygen radicals increase, and this seems to be one of the factors why the egg cells in the ovaries are increasingly affected by damage. AKG was able to ensure that the egg cells remained healthy for a longer time, at least in animal studies.
Did you know? Glutathione is extremely important for our cells. In the liver, it helps us break down harmful substances. However, glutathione levels decrease with age. The obvious idea of simply substituting glutathione is not always effective.Another molecule, GlyNAC, was significantly more effective in the studies and was also able to positively influence various Hallmarks of Aging in humans.
Alpha-ketoglutarate and heart function
In 2023, researchers made a potentially revolutionary discovery involving alpha-ketoglutarate in mouse hearts.
Our heart loses the ability to regenerate after birth. This is the reason why z.B. after a heart attack, the heart can never fully recover. Instead of new heart muscle cells, scar tissue forms. The researchers from the Max Planck Institute for Heart and Lung Research wanted to change this and blocked a gene named Cpt1b. This is important for fatty acid metabolism. In a second step, the researchers simulated a heart attack and compared the two groups of mice. The group with the blocked gene recovered significantly better after the heart attack, new heart muscle cells began to grow, and the regenerative ability returned. The scientists found that in this group, the levels of alpha-ketoglutarate were 20 times higher than in the control group.
New heart muscle cells through altered epigenetics?
The results of the study are impressive and offer hope for new therapeutic approaches.But how exactly did the result come about? It is suspected that alpha-ketoglutarate activates the enzyme KDM5. This, in turn, leads to the activation of other genes. The exact mechanism is complicated, but KDM5 removes methyl groups from histones. This frees up sites on the DNA, allowing other genes to be read. Due to the increased activity of KDM5, the heart muscle cells seem to become younger again and regain their regenerative ability. Instead of the expected scar, the mice regained their normal heart function after just a few weeks.
Ca-AKG, Na-AKG, O-AKG, A-AKG – what the abbreviations stand for
We have already encountered several abbreviations for alpha-ketoglutarate. AKG, Ca-AKG, Calcium-AKG or sometimes also in the English spelling as Alpha-ketoglutarate. Depending on which molecule alpha-ketoglutarate is combined with, new abbreviations are created. From calcium and alpha-ketoglutarate, Ca-AKG is formed. To avoid too much confusion, we show you what the abbreviations mean:
- Na-AKG: Alpha-ketoglutarate together with sodium
- O-AKG: Stands for the combination of alpha-ketoglutarate with the amino acid L-ornithine
- A-AKG: The combination of the amino acid arginine and alpha-ketoglutarate results in A-AKG.Arginine as a precursor to NO synthesis has been shown in studies to dilate blood vessels
Which forms of alpha-ketoglutarate are well suited for supplementation?
Alpha-ketoglutarate is produced in the body and is not found in foods. However, studies show that fasting and exercise can increase the alpha-ketoglutarate level in the blood. Another way to take AKG is through dietary supplements.
A particularly well-suited form for alpha-ketoglutarate is calcium alpha-ketoglutarate. The calcium combination ensures better bioavailability compared to the pure form. It is also known that AKG is better absorbed in the small intestine and at a low pH value and in the presence of iron and sulfur oxide ions.
In general, one should ensure that calcium alpha-ketoglutarate is free from unwanted additives and fillers.
Conclusion on calcium alpha-ketoglutarate
Alpha-ketoglutarate is an exciting molecule in aging research. Studies have shown that it not only can reverse biological age, but also contributed to a better bone density and stronger stem cells . Particularly interesting is the fact that we do not naturally obtain alpha-ketoglutarate through food and that levels decrease with age. Supplementation in animals has led to sometimes drastic increases in lifespan. Whether this will also be the case for us remains (to be) seen.
