Skip to content
What Exactly is AKG?
Alpha-ketoglutarate (AKG) has garnered considerable attention in the field of aging research, in addition to its longstanding use as a sports supplement in bodybuilding circles.
What exactly is alpha-ketoglutarate?
Alpha-ketoglutarate, or AKG, is a naturally occurring intermediary metabolite that is produced within our bodies. It is an integral part of the Krebs cycle, also known as the citric acid cycle. Synthetic versions of AKG, chemically identical to the naturally produced compound, are also available as supplements in the market.
A Brief History of Alpha-ketoglutarate
Alpha-ketoglutarate, or AKG, was discovered in 1937 by Hans Adolf Krebs and William Arthur Johnson at the University of Sheffield. Krebs was subsequently awarded the Nobel Prize for Physiology or Medicine in 1953 for his contributions to the field. The identification of AKG was part of the broader understanding of the citric acid cycle, which is commonly referred to as the Krebs cycle.
The Krebs cycle comprises a series of chemical reactions that generate energy through the oxidation of acetate derived from carbohydrates, fats, and proteins into carbon dioxide.
Functions and Benefits of AKG
AKG serves as a crucial molecule in various metabolic and cellular pathways. It acts as an energy donor, a precursor for amino acid production, a signaling molecule within cells, and a regulator of epigenetic processes. In the body, AKG plays a critical role in the Krebs cycle, regulating the overall speed of the citric acid cycle. It is involved in pathways that aid in muscle building and wound healing, which has contributed to its popularity in the bodybuilding community.
In certain medical scenarios, healthcare providers administer alpha-ketoglutarate intravenously to prevent heart damage resulting from blood flow issues during heart surgery, as well as to prevent muscle loss following surgery or trauma.
AKG also acts as a nitrogen scavenger, preventing nitrogen overload and the excessive buildup of ammonia. It is a significant source of glutamate and glutamine, which stimulate protein synthesis and inhibit protein degradation in muscles.
Furthermore, AKG regulates enzymes such as ten-eleven translocation (TET), which are involved in DNA demethylation, and Jumonji C domain-containing lysine demethylases, major histone demethylases. This positions AKG as an important player in gene regulation and expression.
Can AKG Slow Down Aging?
There is evidence to suggest that AKG can influence the aging process, with several studies supporting this claim. For instance, a study conducted in 2014 demonstrated that AKG extended the lifespan of adult C. elegans by approximately 50% by inhibiting ATP synthase and the target of rapamycin (TOR).
During this study, it was observed that AKG not only increased lifespan but also delayed certain age-related phenotypes in aged C. elegans, such as the loss of coordinated body movement. To understand how AKG affects aging, we will delve into the mechanism by which it inhibits ATP synthase and TOR to extend lifespan in C. elegans and potentially other species as well.
ATP Synthase
Mitochondrial ATP synthase is a widely distributed enzyme involved in the energy metabolism of most living cells. ATP synthase acts as a membrane-bound enzyme, functioning as an energy carrier that facilitates cellular energy metabolism. The 2014 study revealed that to increase lifespan in C. elegans, AKG requires the presence of ATP synthase subunit β and relies on downstream TOR.
The researchers discovered that ATP synthase subunit β serves as a binding protein for AKG. AKG inhibits ATP synthase, resulting in reduced available ATP, decreased oxygen consumption, and increased autophagy in both C.elegans and mammalian cells.
The direct binding of AKG to ATP synthase subunit β, the associated enzyme inhibition, the reduction in ATP levels, the decrease in oxygen consumption, and the increase in lifespan were similar to the effects observed when ATP synthase 2 (ATP-2) was genetically knocked out. Based on these findings, the researchers concluded that AKG likely extends lifespan by targeting ATP-2.
Essentially, this implies that mitochondrial function is partially suppressed, particularly the electron transport chain, which ultimately leads to increased lifespans in C. elegans. The key lies in reducing mitochondrial function to an optimal level without causing harm. Therefore, the saying "live fast, die young" is accurate in this context, as the worms live slowly and age gracefully due to ATP suppression.
Target of Rapamycin (TOR)
TOR belongs to a group of serine/threonine kinases from the phosphatidylinositol kinase-related kinase (PIKK) family. It is a conserved pathway found in multiple species, including C. elegans, mice, and humans, and its role is to regulate growth and metabolism. In mammals, it is known as mammalian target of rapamycin or mTOR.
Numerous studies have demonstrated that inhibiting TOR can impact aging in various species. It has been shown to slow down aging in yeast, C. elegans, fruit flies, and regulate lifespan in mice.
Although AKG does not directly interact with TOR, it influences it mainly through the inhibition of ATP synthase. AKG's influence on longevity depends, at least partially, on activated protein kinase (AMPK) and Forkhead box 'Other' (FoxO) proteins.
AMPK is a cellular energy sensor found in multiple species, including humans. When the AMP/ATP ratio is high, AMPK is activated, inhibiting TOR signaling by phosphorylating the TOR suppressor TSC2. This process allows cells to adjust their metabolism and effectively balance their energy status.
FoxO is a subgroup of the Forkhead transcription factor family that plays a critical role in regulating the impact of insulin and growth factors on various functions, including cell proliferation, cellular metabolism, and apoptosis. A study showed that increasing lifespan through TOR signaling reduction requires the FoxO transcription factor PHA-4.
Furthermore, autophagy, which is activated by caloric restriction and TOR inhibition, significantly increases in C. elegans given additional AKG. This indicates that AKG and TOR inhibition may increase lifespan through either the same pathway or independent/parallel pathways that converge on the same downstream target.
Further evidence supporting this notion comes from studies involving starving yeast and bacteria, as well as post-exercise studies in humans, where AKG levels were found to be elevated. This increase is believed to be a response to starvation, specifically anaplerotic gluconeogenesis, which activates glutamate-associated transaminases in the liver to generate carbon derived from amino acid catabolism.
These findings align with the 2014 C. elegans study, which demonstrated elevated AKG levels in starving worms but found that AKG did not increase the lifespan of calorically restricted animals. This suggests that AKG is a crucial metabolite and regulator of lifespan in the context of starvation and caloric restriction. It also indicates that AKG may serve as a molecular link between cellular energy generation and dietary restriction in lifespan regulation.
Based on these discoveries, Dr. Brian Kennedy recently conducted a new mouse study with AKG, demonstrating its potential to extend healthspan and lifespan.
Side Effects of Alpha-ketoglutarate
No significant side effects associated with alpha-ketoglutarate have been reported in humans. Some consumers of AKG report gastric reflux due to the acidic nature of the compound. However, the risk of gastric reflux and other minor gastrointestinal issues can be reduced by taking the calcium salt form of AKG (CaAKG) and by utilizing a controlled release delivery format (for example an enteric coated capsule).
What exactly is alpha-ketoglutarate?
Alpha-ketoglutarate, or AKG, is a naturally occurring intermediary metabolite that is produced within our bodies. It is an integral part of the Krebs cycle, also known as the citric acid cycle. Synthetic versions of AKG, chemically identical to the naturally produced compound, are also available as supplements in the market.
A Brief History of Alpha-ketoglutarate
Alpha-ketoglutarate, or AKG, was discovered in 1937 by Hans Adolf Krebs and William Arthur Johnson at the University of Sheffield. Krebs was subsequently awarded the Nobel Prize for Physiology or Medicine in 1953 for his contributions to the field. The identification of AKG was part of the broader understanding of the citric acid cycle, which is commonly referred to as the Krebs cycle.
The Krebs cycle comprises a series of chemical reactions that generate energy through the oxidation of acetate derived from carbohydrates, fats, and proteins into carbon dioxide.
Functions and Benefits of AKG
AKG serves as a crucial molecule in various metabolic and cellular pathways. It acts as an energy donor, a precursor for amino acid production, a signaling molecule within cells, and a regulator of epigenetic processes. In the body, AKG plays a critical role in the Krebs cycle, regulating the overall speed of the citric acid cycle. It is involved in pathways that aid in muscle building and wound healing, which has contributed to its popularity in the bodybuilding community.
In certain medical scenarios, healthcare providers administer alpha-ketoglutarate intravenously to prevent heart damage resulting from blood flow issues during heart surgery, as well as to prevent muscle loss following surgery or trauma.
AKG also acts as a nitrogen scavenger, preventing nitrogen overload and the excessive buildup of ammonia. It is a significant source of glutamate and glutamine, which stimulate protein synthesis and inhibit protein degradation in muscles.
Furthermore, AKG regulates enzymes such as ten-eleven translocation (TET), which are involved in DNA demethylation, and Jumonji C domain-containing lysine demethylases, major histone demethylases. This positions AKG as an important player in gene regulation and expression.
Can AKG Slow Down Aging?
There is evidence to suggest that AKG can influence the aging process, with several studies supporting this claim. For instance, a study conducted in 2014 demonstrated that AKG extended the lifespan of adult C. elegans by approximately 50% by inhibiting ATP synthase and the target of rapamycin (TOR).
During this study, it was observed that AKG not only increased lifespan but also delayed certain age-related phenotypes in aged C. elegans, such as the loss of coordinated body movement. To understand how AKG affects aging, we will delve into the mechanism by which it inhibits ATP synthase and TOR to extend lifespan in C. elegans and potentially other species as well.
ATP Synthase
Mitochondrial ATP synthase is a widely distributed enzyme involved in the energy metabolism of most living cells. ATP synthase acts as a membrane-bound enzyme, functioning as an energy carrier that facilitates cellular energy metabolism. The 2014 study revealed that to increase lifespan in C. elegans, AKG requires the presence of ATP synthase subunit β and relies on downstream TOR.
The researchers discovered that ATP synthase subunit β serves as a binding protein for AKG. AKG inhibits ATP synthase, resulting in reduced available ATP, decreased oxygen consumption, and increased autophagy in both C.elegans and mammalian cells.
The direct binding of AKG to ATP synthase subunit β, the associated enzyme inhibition, the reduction in ATP levels, the decrease in oxygen consumption, and the increase in lifespan were similar to the effects observed when ATP synthase 2 (ATP-2) was genetically knocked out. Based on these findings, the researchers concluded that AKG likely extends lifespan by targeting ATP-2.
Essentially, this implies that mitochondrial function is partially suppressed, particularly the electron transport chain, which ultimately leads to increased lifespans in C. elegans. The key lies in reducing mitochondrial function to an optimal level without causing harm. Therefore, the saying "live fast, die young" is accurate in this context, as the worms live slowly and age gracefully due to ATP suppression.
Target of Rapamycin (TOR)
TOR belongs to a group of serine/threonine kinases from the phosphatidylinositol kinase-related kinase (PIKK) family. It is a conserved pathway found in multiple species, including C. elegans, mice, and humans, and its role is to regulate growth and metabolism. In mammals, it is known as mammalian target of rapamycin or mTOR.
Numerous studies have demonstrated that inhibiting TOR can impact aging in various species. It has been shown to slow down aging in yeast, C. elegans, fruit flies, and regulate lifespan in mice.
Although AKG does not directly interact with TOR, it influences it mainly through the inhibition of ATP synthase. AKG's influence on longevity depends, at least partially, on activated protein kinase (AMPK) and Forkhead box 'Other' (FoxO) proteins.
AMPK is a cellular energy sensor found in multiple species, including humans. When the AMP/ATP ratio is high, AMPK is activated, inhibiting TOR signaling by phosphorylating the TOR suppressor TSC2. This process allows cells to adjust their metabolism and effectively balance their energy status.
FoxO is a subgroup of the Forkhead transcription factor family that plays a critical role in regulating the impact of insulin and growth factors on various functions, including cell proliferation, cellular metabolism, and apoptosis. A study showed that increasing lifespan through TOR signaling reduction requires the FoxO transcription factor PHA-4.
Furthermore, autophagy, which is activated by caloric restriction and TOR inhibition, significantly increases in C. elegans given additional AKG. This indicates that AKG and TOR inhibition may increase lifespan through either the same pathway or independent/parallel pathways that converge on the same downstream target.
Further evidence supporting this notion comes from studies involving starving yeast and bacteria, as well as post-exercise studies in humans, where AKG levels were found to be elevated. This increase is believed to be a response to starvation, specifically anaplerotic gluconeogenesis, which activates glutamate-associated transaminases in the liver to generate carbon derived from amino acid catabolism.
These findings align with the 2014 C. elegans study, which demonstrated elevated AKG levels in starving worms but found that AKG did not increase the lifespan of calorically restricted animals. This suggests that AKG is a crucial metabolite and regulator of lifespan in the context of starvation and caloric restriction. It also indicates that AKG may serve as a molecular link between cellular energy generation and dietary restriction in lifespan regulation.
Based on these discoveries, Dr. Brian Kennedy recently conducted a new mouse study with AKG, demonstrating its potential to extend healthspan and lifespan.
Side Effects of Alpha-ketoglutarate
No significant side effects associated with alpha-ketoglutarate have been reported in humans. Some consumers of AKG report gastric reflux due to the acidic nature of the compound. However, the risk of gastric reflux and other minor gastrointestinal issues can be reduced by taking the calcium salt form of AKG (CaAKG) and by utilizing a controlled release delivery format (for example an enteric coated capsule).
