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Alpha-ketoglutarate Health Benefits and Side Effects

Alpha-ketoglutarate (AKG) has long been a popular sports supplement and is often used in the bodybuilding world, but interest in this molecule has now reached the aging research field due to its central role in metabolism.

What is alpha-ketoglutarate?

AKG is a naturally occurring endogenous intermediary metabolite and part of the Krebs cycle, which means that our own bodies create it. The supplement industry also produces a synthetic version which is chemically identical to naturally produced AKG.

History of alpha-ketoglutarate

Alpha-ketoglutarate (AKG) was discovered in 1937 by Hans Adolf Krebs and William Arthur Johnson at the University of Sheffield, with Krebs going on to receive the Nobel Prize for Physiology or Medicine in 1953. The discovery of AKG was part of the overall identification of the citric acid cycle, which is commonly known as the Krebs cycle due to its discoverer.

Collectively, the Krebs cycle is a series of chemical reactions that is used to generate energy via the oxidation of acetate, which is derived from carbohydrates, fats, and proteins, into carbon dioxide.

What does AKG do?

AKG is a molecule involved in a number of metabolic and cellular pathways. It works as an energy donor, a precursor in amino acid production, and a cellular signalling molecule, and it is a regulator of epigenetic processes. It is a critical molecule in the Krebs cycle and regulates the overall speed of the citric acid cycle of an organism. It works in various pathways in the body, to help build muscle, and to help heal wounds, this is one reason it has become popular in the bodybuilding community.

Sometimes healthcare providers administer alpha-ketoglutarate intravenously for preventing injury to the heart resulting from blood flow issues during heart surgery and for preventing muscle loss following surgery or trauma.

AKG also acts as a nitrogen scavenger and can prevent nitrogen overload and prevent the build-up of excessive ammonia. It is also a key source of glutamate and glutamine, which stimulates protein synthesis and inhibits protein degradation in the muscles.

Additionally, it regulates the ten-eleven translocation (TET) enzymes, which are involved in DNA demethylation and the Jumonji C domain containing lysine demethylases, which are the major histone demethylases. In this way, it is an important player in gene regulation and expression.

Can AKG slow aging?

There is evidence that AKG can influence aging, and a number of studies suggest that this is the case. A 2014 study showed that AKG extends the lifespan of adult C. elegans by roughly 50% by inhibiting ATP synthase and the target of rapamycin (TOR) [1].

During this study, it was found that AKG not only increased lifespan but also delayed certain age-related phenotypes, such as the loss of rapid coordinated body movement commonly seen in aged C. elegans. In order to understand how AKG influences aging, we will describe the mechanism by which AKG inhibits ATP synthase and TOR to extend lifespan in C. elegans and likely other species as well.

ATP synthase

Mitochondrial ATP synthase is a ubiquitous enzyme involved in the energy metabolism of most living cells. ATP is a membrane-bound enzyme that acts as an energy carrier facilitating cellular energy metabolism. The 2014 study showed that in order to increase lifespan in C. elegans, AKG needs ATP synthase subunit β and is dependent on downstream TOR.

The researchers found that ATP synthase subunit β is a binding protein of AKG. They discovered that AKG inhibits ATP synthase, which leads to a reduction of available ATP, decreased oxygen consumption, and an increase of autophagy in the cells of both C. elegans and mammals.

The direct binding of ATP-2 by AKG, the associated inhibition of enzymes, the reduction of ATP levels, reduction of oxygen consumption, and increased lifespan were almost the same as when ATP synthase 2 (ATP-2) is directly, genetically knocked out. From these findings, the researchers concluded that AKG likely increases lifespan by targeting ATP-2.

Essentially, what is happening here is that mitochondrial function is being somewhat suppressed, in particular the electron transport chain, and it is that partial suppression that is responsible for increased lifespans in C. elegans.

The key is to reduce mitochondrial function just enough without going too far and it becoming detrimental. So, the old saying “live fast, die young” is absolutely correct, only in this case, the worms are living slow and dying old thanks to ATP suppression.

Alpha-ketoglutarate and the target of rapamycin (TOR)

TOR is part of a group of serine/threonine kinases from the phosphatidylinositol kinase-related kinase (PIKK) family. It is a conserved pathway, meaning that it is common to multiple species, including C. elegans, mice, and humans, and its job is to regulate growth and metabolism. In mammals is it is called mammalian target of rapamycin or mTOR.

There have been various studies showing that the inhibition of TOR can influence aging in multiple species, including slowing aging in yeast [2], slowing down aging in C. elegans [3], slowing aging in fruit flies [4], and regulates lifespan in mice [5].

AKG does not directly interact with TOR, though it does influence it, mainly via the inhibition of ATP synthase. AKG depends at least partially on activated protein kinase (AMPK) and Forkhead box ‘Other’ (FoxO) proteins to influence longevity.

AMPK is a conserved cellular energy sensor found in multiple species, including humans. When the AMP/ATP ratio is too high, AMPK is activated, which inhibits TOR signaling by activating phosphorylation of the TOR suppressor TSC2. This process allows the cell to adjust its metabolism and balance its energy status effectively.

FoxO is a subgroup of the Forkhead transcription factor family and plays a critical role in regulating the impact of insulin and growth factors on a wide range of functions, including cell proliferation, cellular metabolism, and apoptosis. A study showed that in order to increase lifespan via the reduction of TOR signaling, the FoxO transcription factor PHA-4 is required [6].

Alpha-ketoglutarate and autophagy

Finally, autophagy, which is activated by caloric restriction and also the direct inhibition of TOR, is increased significantly in C. elegans given additional AKG. This means that AKG and TOR inhibition are increasing lifespan either via the same pathway or through independent/parallel pathways and mechanisms that ultimately converge on the same downstream target.

Further support for this has been shown in studies with starving yeast and bacteria [7] and in humans post-exercise [8], where AKG levels are shown to be elevated. This increase is believed to be a starvation response, in this case anaplerotic gluconeogenesis, which activates glutamate-associated transaminases in the liver to generate carbon derived from amino acid catabolism.

This is consistent with the findings of the 2014 C. elegans study [1], which showed that AKG levels are elevated in starving worms but that AKG did not increase the lifespan of calorically restricted animals. This suggests that AKG is a key metabolite and player in the regulation of lifespan via starvation and caloric restriction. It also suggests that AKG is a molecular link between cellular energy generation and dietary restriction in the context of lifespan regulation.

Finally, it means that AKG is a potential target for the delay of aging and the treatment of age-related diseases.

Building on these findings, recently, Dr. Brian Kennedy has published a new mouse study with AKG and demonstrated its potential to extend healthspan and lifespan [9]. Dr. Kennedy also gave a talk at our EARD 2020 conference about his work with AKG and its potential implications for the treatment of aging and age-related diseases.

Alpha-ketoglutarate side effects

No significant side effects caused by alpha-ketoglutarate have been reported in humans but as with any supplement, if you do experience any adverse effects you should cease taking it immediately and consult your doctor.

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Alpha-Ketoglutarate Decreases Biological Age in Human Study

This was determined by the TruAge methylation clock

A commercially available alpha-ketoglutarate-based supplement has been shown to roll back biological age by 7 years on average in a retrospective human study [1].

Live slower, die later

Though metformin and rapamycin are getting most of the attention in the longevity field today, alpha-ketoglutarate (AKG) has emerged as another candidate longevity drug.

These three molecules have something in common: their mechanisms of action, at least partly, mimic caloric restriction. In other words, one of our best anti-aging strategies today is to override the “live fast, die young” paradigm installed in our species by evolution. From what we know, people might be able to live longer if they just live a bit “slower”.

On the technical side, AKG is an intermediary metabolite of the Krebs cycle – a complex chain of reactions that generates energy from nutrients. In addition to regulating the speed of the Krebs cycle, AKG has multiple other functions, including amino acid production and cellular signaling. AKG levels generally decrease with aging. AKG supplementation has been shown to improve lifespan and healthspan in various model animals, but human studies are scarce.

An epigenetic clock you can buy online

For this trial, the researchers recruited 42 healthy people. The participants were given a multi-month supply of Rejuvant, an AKG-based dietary supplement produced by Ponce De Leon Health (Juan Ponce de León was a Spanish explorer who allegedly searched for the Fountain of Youth).

The median self-reported length of use was 7 months, with individual values varying from 4 to 10 months. At the baseline (beginning of the study) and at the end, the biological age of the participants was measured using another consumer product – TruAge, a commercially available epigenetic test produced by TruMe Labs.

Epigenetic clocks have been around for about a decade and are now into their second generation. They work by measuring DNA methylation patterns that regulate transcription and tend to change with age. Although methylation-based clocks are considered the gold standard for measuring biological age, we do not have much information about TruAge and how it stacks up against well-known clocks such as GrimAge and PhenoAge.

The researchers tried to control for as many confounding variables as possible, such as diet, alcohol intake, smoking, overall health, weight, sleep duration, and physical activity, though the sample size was small: for instance, only one participant was an active smoker, and just six reported a history of smoking.

Seven months of treatment, seven years of results

Based on the questionnaires, the researchers identified a group of 13 participants who did not report any changes over the study period in diet type, drinking frequency, additional dietary supplement intake, sleep duration, and exercise frequency. The scientists used this homogenous subset to initially assess the independent effect of AKG. At baseline, people in this group were, on average, 2.06 years biologically younger than their chronological age, but by the end of the treatment, this gap grew to 9.74 years. This means, epigenetically, these 13 participants became 7.69 years younger over a period of several months.

The results in the entire cohort of 42 patients were even more impressive. At baseline, the participants were on average 0.35 years biologically younger than their chronological age. By the end of the study, this increased to 8.31 years, with a mean difference of 7.96 years. Importantly, the effect was highly uniform, with just two of the 42 participants having their biological age slightly increased. The effect in males and females was also largely the same, with females receiving a somewhat smaller boost (6.98 years compared to 8.44 in males). This might be due to the fact that at baseline, the female participants had, on average, better biological and chronological age comparisons.

In general, people with higher biological age relative to their chronological age, and who were chronologically older, experienced the strongest effects. In other words, AKG seems to work best for the people who need it more: the older and the sicker. Interestingly, the duration of the treatment hardly correlated with the magnitude of the effect. According to the researchers, this indicates that the median treatment duration in this study, or approximately 7 months, may be sufficient to get the maximum out of AKG supplementation.

Conclusion

This exciting study had quite a few limitations. First, the sample size was relatively small. Second, it was built around a commercially available supplement and a commercially available epigenetic age clock that we know little about. Third, it was not placebo-controlled, though the results are probably too definitive to be explained by a placebo effect. Finally, the researchers note that AKG is a known substrate for DNA demethylases, which is why a methylation clock might not be the best way to gauge the effect of AKG on longevity. Despite all those caveats, the results are too spectacular to be ignored. Surely, more data on AKG and aging will be coming in soon, and we will keep you informed.

SIIM’s THOUGHTS

Now there is exciting Research about longevity drugs like Metformin and rapamycin that have the potential to Extend lifespan and improve Health span in humans.

But, they are very hard to get and have a lot of negative side effects. Fortunately, there is a more natural and more easily accessible supplement that has been shown to have lifespan extending effects in multiple animal models and in humans. The supplement is Alpha ketoglutarate or AKG. The biggest reason I’m interested in alpha ketoglutarate is because of this study published in 2021.

This study found that seven months of using a supplement that had Calcium AKG was able to Reverse the biological age of these Humans by eight years.

Alpha Ketoglutarate works by Inhibiting mtor, has many positive effects on aging, longevity, and immunity.

Your body has Alpha-ketoglutarate, which is one of the key molecules in the Krebs cycle that’s involved in energy production.

However, you don’t get it from diet. There’s no dietary source of Alpha-ketoglutarate.

You can make it with exercise, but with age, your Alpha-ketoglutarate levels do decrease.

So, overall, I’m not saying that this is some sort of magic pill. There is no magic pill.

There is no magic supplement when it comes to longevity. There are stacking effects if you stack certain supplements. They will have a physiological effect on your body.

And, of course, it all requires the addition of a healthy lifestyle and the regular exercise and sleep and all those other things. But taking compounds may have different effects, like mimicking calorie restriction, or helping with energy metabolism and energy performance or exercise performance.

The links above are affiliate links, so I receive a small commission every time you use them to purchase a product. The content contained in this video, and its accompanying description, is not intended to replace viewers’ relationships with their own medical practitioner. Always speak with your doctor regarding the content of this channel, and especially before using any products, services, or devices discussed on this channel or website.