Exploring AKG: From Energy Metabolism to Osteoarthritis, Immune Function and Anti-Ageing

What if there were a natural substance that could reverse our age by some 8 years, and by doing so reduce the probability of getting degenerative diseases, or even potentially reverse degenerative diseases that have recently started?

Well, there just might be such a substance…

AKG, also known as alpha-ketoglutarate, is a vital metabolite involved in the citric acid cycle within the mitochondria, playing a fundamental role in cellular energy metabolism. Beyond its energy-related functions, AKG has garnered attention for its diverse physiological roles. It acts as a nitrogen scavenger, preventing muscle degradation and providing amino acids like glutamine and glutamate. AKG has been found to activate protein synthesis, influence collagen synthesis, aid iron absorption, and exhibit antioxidant properties. Moreover, AKG has shown promising implications in osteoarthritis management and the ageing process. This article delves into the multifaceted functions of AKG, shedding light on its potential benefits for various aspects of health and exploring the mechanisms behind its effects.

What is AKG?

AKG, or alpha-ketoglutarate, is a metabolite that plays a crucial role in the citric acid cycle (Krebs cycle, Tricarboxylic cycle, or TCA cycle) within the mitochondria. It is essential for energy metabolism in cells and is associated with metabolic flexibility.

Another one of its key functions is acting as a nitrogen scavenger, helping to remove excess nitrogen and prevent the buildup of ammonia. Excessive nitrogen buildup can lead to muscle degradation, making AKG important for preventing muscle breakdown. Additionally, AKG is partially converted into amino acids like glutamate, making it a source of glutamine and glutamate, which are essential metabolic fuels for the gastrointestinal tract and proper gut barrier function (Hixt and Müller, 1996; Jones et al., 1999).

Moreover, AKG has been shown to activate protein synthesis, potentially through the activation of the mammalian target of rapamycin (mTOR) signalling pathway.

Interestingly, AKG levels decline with age, including a tenfold decrease in blood levels. In mice, supplemental AKG has been found to shorten the time they are sick before dying, suggesting an increase in health span. In humans it has, on average, been shown to set back the methylation clock 8 years in 7 months.

AKG also plays a role in collagen synthesis and provides relevant amino acids for the process (Kristensen et al., 2002; Tocaj et al., 2003). Additionally, it has been shown to assist in the absorption of iron (Fe+2) (Dąbek et al., 2005).

Furthermore, AKG appears to be particularly beneficial in osteoarthritis, as we will explore in more detail later in this article.

These are just a few examples of the roles AKG plays in the body.

Why does AKG decline with age?

The exact reason for the decline of AKG with age has not been established conclusively. One possibility is that it may be related to decreased mitochondrial function. It is also plausible that enzymes involved in AKG production could be a contributing factor. 

For instance, isocitrate dehydrogenase (IDG), the enzyme responsible for converting isocitrate to AKG, has been shown to decline with age. IDG and alpha-ketoglutarate dehydrogenase (α-KGDH) are NAD-dependent enzymes, and increasing NAD levels may potentially boost IDG and α-KGDH levels, leading to an increase in energy production (read about NAD, Nicotinamide dinucleotide and how to boost it here). However, it is important to note that these are currently speculative hypotheses and require further investigation.

The Role of Supplemental AKG in Energy Production

When alpha-ketoglutarate (AKG) is supplemented, it doesn’t directly participate in the tricarboxylic acid (TCA) cycle itself. Instead, AKG can affect the activity of enzymes within the TCA cycle, such as isocitrate dehydrogenase (IDH) and alpha-ketoglutarate dehydrogenase (α-KGDH).

AKG acts as a precursor or substrate for these enzymes, providing them with the necessary molecules to catalyze their reactions. 

By increasing the availability of AKG, it can potentially enhance the activity of IDH and α-KGDH, which are key regulatory enzymes in the TCA cycle. This, in turn, can positively influence the overall efficiency of the TCA cycle and energy production.

The effects of AKG supplementation on IDH and α-KGDH can lead to improved energy metabolism and ATP production within the mitochondria. AKG’s role is more indirect, providing the necessary components for these enzymes to function optimally and support energy production pathways.

In the picture we see how supplemental AKG affects IDH and α-KGDH, which are essential in the TCA cycle.

Also, AKG has been shown to have antioxidant properties, which can help reduce oxidative stress within mitochondria. By protecting mitochondria from excessive free radical damage, AKG may help maintain their function and energy production capacity.

Revitalizing Cartilage Health: The Role of AKG in Managing Osteoarthritis

Osteoarthritis is a metabolic disease that commonly occurs at an advanced age. It involves factors such as oxidative stress and chronic low-grade inflammation.

As osteoarthritis progresses, levels of reactive oxygen species (ROS) increase in the joints, leading to oxidative stress. It is known that mitochondrial metabolism disorder can contribute to elevated ROS levels. Therefore, it is worth investigating whether optimising mitochondrial function in these areas could be beneficial.

The elevated ROS levels further contribute to a state of low-grade inflammation, which triggers the production of enzymes that degrade cartilage and disrupt the synthesis of new cartilage. Specifically, these enzymes downregulate cartilage-specific anabolic genes and the expression of collagen type II alpha 1 gene.

By targeting mitochondrial function and reducing oxidative stress, it is possible to mitigate the inflammatory response and preserve cartilage integrity in osteoarthritis. Strategies aimed at enhancing mitochondrial metabolism and reducing ROS levels may hold promise as potential therapeutic approaches for managing osteoarthritis.

Indeed, a recent article  suggests this in detail. The researchers quantified AKG levels in human cartilage tissue and chondrocytes, finding decreased levels in damaged cartilage and osteoarthritic chondrocytes. They then treated osteoarthritic chondrocytes with AKG and observed its impact on various cellular processes.

AKG supplementation reversed chondrocyte inhibition and apoptosis, increased the expression of important cartilage components, and reduced the expression of inflammatory mediators. The researchers also explored the underlying mechanism and found that AKG promoted mitophagy (a process for removing damaged mitochondria) and inhibited the generation of ROS. These effects were prevented when a mitophagy inhibitor was used. The study suggests that AKG supplementation may have therapeutic potential in ameliorating osteoarthritis by regulating mitophagy and oxidative stress.

AKG: Fueling the Immune System for Optimal Defense

AKG, also known as the immune nutrient factor, plays a significant role in immune metabolism. It serves as an important source of glutamine and glutamate, which are essential fuels for lymphocytes and macrophages. Macrophages and neutrophils, which are involved in early defense responses and protection against sepsis, rely on glutamine for their function. During inflammatory conditions like sepsis and injury, the consumption of glutamine by immune cells increases. Studies have shown that supplementing with glutamine can enhance the bactericidal activity of neutrophils and improve phagocytosis. Depressed glutamine levels have been associated with reduced phagocytosis by macrophages, while oral glutamine supplementation has been shown to decrease bacterial translocation in sepsis.

Overall, AKG, as a glutamine homologue, possesses immunoenhancing properties, helps maintain gut barrier function, increases immune cell activity, and improves neutrophil function and phagocytosis.

Delaying Aging and Prolonging Healthspan: The Potential of Calcium-AKG Supplementation

It has been shown in worms and mice that supplemental Calcium-AKG (Ca-AKG) delays aging and thus prolongs the healthspan, which refers to the period of time when an individual remains in good health throughout their lifetime. This is significant because aging is associated with an increased risk of degenerative diseases. By delaying the onset of these diseases, the overall healthspan is extended. Mechanisms underlying this effect have been investigated, and some suggest the activation of pathways similar to those triggered by fasting.

Recently, a human study was conducted to evaluate the impact of Ca-AKG supplementation on biological age, as measured by methylation clocks (for more information, refer to the article on methylation clocks). The study involved 42 participants who took two 1g tablets of Ca-AKG daily for an average duration of 7 months.

The results showed that, on average, the participants were measured to be 8 years younger in terms of biological age. It should be noted that the benefits of AKG supplementation appear to reach a saturation point around this time. In other words, the rate at which individuals become younger does not continue to accelerate with prolonged AKG intake. Additionally, the study participants also received supplemental vitamin A and D alongside AKG.

Overall, these findings suggest that Ca-AKG supplementation holds promise as a strategy to delay ageing and potentially extend the period of good health, as supported by both animal studies and human research.

Who Uses AKG for anti-ageing?

 The current world record holder in “age reversal”, Bryan Johnson, takes 1g of AKG twice a day as part of his longevity protocol. When he was 44 years old his biological age, based on several different methylation clocks was 36 year. Read about his protocol here.

Also, the company Tally Health, which has recently come out with a new version of methylation clock measurements (read here about methylation clocks) suggests a supplement, based on, you guessed it, Ca-AKG. Their supplement also contains some resveratrol, quercetin, fisetin, and spermadine.

Tapping into the Potential of AKG as a Versatile Metabolite for Health and Longevity

In conclusion, alpha-ketoglutarate (AKG) emerges as a fascinating metabolite with a wide range of physiological functions. Its role in energy metabolism, immune modulation, osteoarthritis management, and even potential anti-aging effects make it a subject of great interest in scientific research. AKG’s ability to influence key enzymes, promote mitophagy, reduce oxidative stress, and regulate important signaling pathways like TOR and AMPK underscores its potential therapeutic value.

Understanding the decline of AKG with age and exploring strategies to boost its levels may open new avenues for combating age-related decline and promoting healthy aging. AKG supplementation holds promise in mitigating muscle degradation, enhancing immune function, and potentially extending health span. While further research is needed to uncover the full extent of AKG’s benefits and its precise mechanisms of action, the current findings highlight its multifaceted nature and its potential as a valuable therapeutic target.

As scientific knowledge advances, continued exploration of AKG’s effects and its interactions with cellular processes will deepen our understanding of its therapeutic potential. Harnessing the power of AKG may pave the way for novel interventions and strategies in promoting overall health and well-being.

Links to related anti-ageing articles

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