Alpha Ketoglutarate

• Lifespan extension
• Healthspan improvement
• Reduced frailty
• Cellular energy regulation

• Bone health
• Protein synthesis
• Wound healing
• Collagen production
• Immune function
• Gut health
• Muscle preservation

Alpha-ketoglutarate (AKG) is a key intermediate in the Krebs (tricarboxylic acid) cycle, serving as a crucial metabolite for cellular energy production and nitrogen metabolism. Its diverse biological effects stem from multiple mechanisms. As a TCA cycle intermediate, AKG plays a central role in cellular energy metabolism, influencing ATP production and overall metabolic rate. Research has shown that AKG extends lifespan in multiple organisms by inhibiting ATP synthase and the Target of Rapamycin (TOR) pathway, a master regulator of cellular growth, metabolism, and aging.

This TOR inhibition mimics aspects of caloric restriction, a well-established intervention that extends lifespan across species. AKG also activates AMP-activated protein kinase (AMPK), a cellular energy sensor that promotes longevity and metabolic health. In protein metabolism, AKG serves as a nitrogen scavenger, accepting amino groups from amino acids during transamination reactions to form glutamate, which can then form glutamine. This process is essential for protein synthesis and nitrogen balance, particularly important during stress, illness, or recovery.

AKG stimulates protein synthesis while inhibiting protein degradation in muscles, contributing to its anti-catabolic effects. For bone health, AKG enhances collagen synthesis by serving as a cofactor for prolyl-4-hydroxylase, an enzyme critical for collagen formation and stability. It also influences bone mineral density and may help prevent osteoporosis. AKG has significant immunomodulatory effects, particularly by inducing anti-inflammatory cytokines like IL-10 while reducing pro-inflammatory cytokines.

This anti-inflammatory action appears to be a key mechanism behind its ability to reduce age-related chronic inflammation and improve healthspan. In the gut, AKG serves as a preferred fuel for intestinal cells, supporting intestinal barrier function and reducing bacterial translocation. AKG also functions as an antioxidant, directly scavenging reactive oxygen species and supporting glutathione synthesis, thereby protecting cells from oxidative damage. Epigenetically, AKG serves as a cofactor for DNA and histone demethylases, influencing gene expression patterns related to aging and metabolism.

Recent research has demonstrated that AKG supplementation can reduce frailty in aging mice more dramatically than it extends lifespan, suggesting a compression of morbidity effect where the proportion of life spent in good health increases. This multi-faceted mechanism profile explains why AKG has such diverse physiological effects and potential applications in aging, metabolism, bone health, and immune function.

The optimal dosage of Alpha-Ketoglutarate (AKG) varies depending on the form used and the intended purpose. For general health and anti-aging benefits, dosages typically range from 1-3 grams per day of calcium AKG (CaAKG). Higher dosages of 3-6 grams per day may be used for specific therapeutic purposes.

AKG is typically taken in divided doses with meals to improve tolerance and absorption. For athletic performance, it may be taken 30-60 minutes before exercise. For general health and anti-aging benefits, consistent daily use appears to be more important than specific timing.

Alpha-Ketoglutarate (AKG) has moderate oral bioavailability, with studies suggesting approximately 25-40% of orally administered AKG reaches systemic circulation intact. First-pass metabolism in the intestinal cells and liver significantly reduces the amount of AKG that reaches the bloodstream unchanged.

When ingested orally, AKG undergoes significant first-pass metabolism in the intestinal mucosa. Intestinal cells can directly utilize AKG as an energy source, converting it to other metabolites. In the liver, AKG can enter the TCA cycle or be used for glutamine synthesis. Some AKG is converted to glutamate and glutamine in the intestinal cells before reaching systemic circulation.

Calcium salt form (CaAKG) may improve stability and bioavailability compared to the free acid form, Taking with meals may improve absorption and reduce potential gastrointestinal discomfort, Divided doses throughout the day may be more effective than a single large dose, Liposomal formulations may improve cellular delivery and reduce first-pass metabolism, Co-administration with vitamin B6 or vitamin C may enhance utilization, Buffered formulations may protect AKG from degradation in stomach acid

AKG is best taken with meals to improve tolerance and potentially enhance absorption. For general health and anti-aging benefits, consistent daily use appears more important than specific timing. For athletic performance, taking AKG 30-60 minutes before exercise may be beneficial.

Stomach acidity: Very acidic conditions may degrade some forms of AKG, Food intake: Taking with food may slow but improve overall absorption, Age: Older individuals may have reduced absorption efficiency, Intestinal health: Conditions affecting gut integrity may impact absorption, Salt form: Different salt forms (calcium, sodium, etc.) may have different absorption profiles, Dosage: Very high single doses may saturate absorption mechanisms

After absorption, AKG is distributed throughout the body, with particularly high uptake in metabolically active tissues such as liver, kidney, intestine, and muscle. AKG can cross the blood-brain barrier, though at a lower rate than some other metabolites.

The elimination half-life of AKG in humans is relatively short, estimated at 1-2 hours, as it is rapidly metabolized through various pathways including the TCA cycle and amino acid synthesis.

Alpha-Ketoglutarate (AKG) is generally recognized as safe when used at recommended dosages. It is an endogenous metabolite naturally present in the human body as part of normal metabolism. Clinical studies have shown good tolerability with few adverse effects at typical supplemental dosages.

• Gastrointestinal discomfort (mild nausea, bloating, or diarrhea) at higher doses
• Temporary fatigue or lethargy in some individuals (possibly related to metabolic adjustments)
• Headache (uncommon)
• Dry mouth (uncommon)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Children (unless under medical supervision)
• Severe kidney disease (AKG metabolism may be impaired)
• Severe liver disease (AKG metabolism may be impaired)

• Medications metabolized by the liver: Theoretical potential for interaction, though clinical significance is unclear
• Diabetes medications: AKG may affect glucose metabolism, potentially requiring adjustment of diabetes medications
• Immunosuppressants: Due to AKG’s effects on immune function, caution is advised when combining with immunosuppressive drugs
• Protein-synthesis inhibiting antibiotics: May theoretically counteract some of AKG’s protein synthesis effects

No official upper limit has been established. Studies have used up to 10 grams per day of various AKG forms (such as Ornithine-AKG) in clinical settings without serious adverse effects. However, for general supplementation, staying below 6 grams per day is recommended to minimize potential side effects.

Long-term safety data in humans is limited, though animal studies suggest good safety profiles even with extended use. The mouse studies showing lifespan extension used AKG supplementation throughout much of the animals’ lives without reported adverse effects. As an endogenous metabolite, AKG is unlikely to accumulate to toxic levels under normal physiological conditions.

Elderly: Generally well-tolerated and may be particularly beneficial for this population. Start with lower doses and monitor for effects.

Renal Impairment: Use with caution in moderate to severe renal impairment, as altered metabolism may occur.

Hepatic Impairment: Use with caution in moderate to severe hepatic impairment, as altered metabolism may occur.

Pregnant Women: Not recommended due to insufficient safety data.

Children: Not recommended without medical supervision due to insufficient safety data.

Overdose risk appears low. Very high doses may cause pronounced gastrointestinal discomfort, but serious toxicity has not been reported. As with any supplement, accidental overdose should be treated with appropriate medical attention.

No known withdrawal effects. As an endogenous metabolite, discontinuation should not produce dependence or withdrawal symptoms.

Alpha-Ketoglutarate (AKG) is generally recognized as safe (GRAS) in the United States when used as a food ingredient. As a dietary supplement, AKG falls under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Under this framework, AKG can be marketed as a supplement without pre-approval, provided no specific disease claims are made. The FDA has not approved AKG for the treatment, prevention, or cure of any disease.

Eu: In the European Union, AKG is regulated under food supplement directives. It is allowed for use in food supplements, though specific health claims must be authorized by the European Food Safety Authority (EFSA). To date, EFSA has not approved specific health claims for AKG supplements.

Canada: Health Canada allows AKG as a Natural Health Product (NHP) ingredient. Various forms including calcium AKG and ornithine AKG have monographs in the Natural Health Products Ingredients Database, permitting their use in supplements with appropriate labeling.

Australia: The Therapeutic Goods Administration (TGA) permits AKG in listed complementary medicines. It is considered a low-risk ingredient when used at appropriate dosages.

Japan: AKG is permitted as a food supplement ingredient in Japan, though it is not specifically listed as a Food for Specified Health Uses (FOSHU).

China: AKG is permitted in food supplements in China, subject to Chinese regulatory requirements for supplement ingredients.

AKG, particularly in the form of Ornithine Alpha-Ketoglutarate (OKG), has been used in clinical nutrition for patients recovering from trauma, burns, or surgery. In this context, it may be administered under medical supervision, sometimes as part of enteral or parenteral nutrition formulations. However, it is not approved as a pharmaceutical drug for specific indications in most countries.

AKG is not on the World Anti-Doping Agency (WADA) Prohibited List. Athletes can use AKG supplements without concern for violating anti-doping regulations, though as with any supplement, contamination risks should be considered.

Us: In the US, AKG supplements must be labeled as dietary supplements and include a Supplement Facts panel. They cannot make claims to treat, cure, or prevent any disease.

Eu: EU regulations require clear labeling as food supplements with appropriate Recommended Daily Allowance (RDA) information where applicable. Health claims are strictly regulated.

Other: Most countries require supplement labeling that clearly identifies the product as a supplement, lists all ingredients and their amounts, and includes appropriate warning statements.

Regulatory interest in AKG may increase as research into its anti-aging effects continues to develop. As with other compounds being studied for effects on aging and longevity, there may be evolving regulatory frameworks to address these novel applications. Currently, no regulatory body has recognized claims related to anti-aging or lifespan extension for any supplement, including AKG.

Medium

Calcium AKG (CaAKG) typically costs $1-3 per day at effective doses (1-3 grams daily). Specialized forms like Ornithine Alpha-Ketoglutarate (OKG) or Arginine Alpha-Ketoglutarate (AAKG) may cost $2-5 per day at recommended dosages.

Low End: Generic AKG powder may cost as little as $0.50-1.00 per gram

Mid Range: Branded CaAKG supplements typically cost $1.00-2.00 per gram

High End: Specialized formulations, patented delivery systems, or pharmaceutical-grade products may cost $2.00-5.00 per gram

For general health and anti-aging purposes, AKG represents a moderate investment compared to other longevity supplements. While more expensive than basic vitamins and minerals, it is generally less costly than many specialized peptides or proprietary compounds marketed for anti-aging. The potential return on investment depends on the specific health goals:

– For anti-aging and healthspan: The value proposition is promising based on animal studies, but human data is still limited. Those seeking cutting-edge longevity interventions may find the cost justified by the research potential.

– For bone health: Compared to prescription medications for osteoporosis, AKG is relatively inexpensive and may offer a complementary approach with fewer side effects.

– For sports performance: AAKG is moderately priced compared to other performance supplements, with mixed evidence for effectiveness.

– For recovery from illness: In clinical contexts, the cost-effectiveness of OKG for recovery from trauma or surgery may be high given the potential to reduce complications and speed recovery.

Purchasing powder form rather than capsules typically offers significant savings, Buying in bulk can reduce per-gram costs substantially, Looking for sales or subscription discounts from reputable suppliers, Comparing different salt forms (calcium vs. sodium) for the best value, Considering the total formula – some products combine AKG with synergistic ingredients that may provide better overall value than taking multiple separate supplements

Vs Similar Supplements: AKG is moderately priced compared to other TCA cycle intermediates and metabolic enhancers. It is generally less expensive than specialized NAD+ precursors (NMN, NR) but more costly than basic amino acids or citric acid cycle supplements like malate or succinate.

Vs Conventional Treatments: For applications like bone health, AKG supplements are typically much less expensive than prescription medications for osteoporosis, though the evidence base is also less robust. For muscle preservation, AKG is less costly than medical interventions for sarcopenia or muscle wasting.

When considering AKG as a long-term supplement for anti-aging or healthspan, the cumulative cost becomes significant. At an average of $2 per day, the annual cost would be approximately $730. This should be weighed against the preliminary nature of human evidence for longevity benefits. However, if future human studies confirm the healthspan benefits seen in mice, this cost may be justified by potential reductions in age-related healthcare expenses and improved quality of life in later years.

Properly stored AKG supplements typically have a shelf life of 2-3 years, depending on the specific formulation and packaging. Calcium AKG (CaAKG) tends to have better stability than the free acid form.

Store in a cool, dry place away from direct sunlight, Keep container tightly closed when not in use, Avoid exposure to high humidity, Refrigeration is not necessary but may extend shelf life in very warm climates, Desiccant packets in the container should be maintained if provided

Heat: Elevated temperatures accelerate degradation, Moisture: Humidity can cause hydrolysis and degradation, particularly of powder forms, Light: Direct sunlight may contribute to degradation, Oxygen: Oxidation can occur over time, especially if containers are frequently opened, pH extremes: Very acidic or alkaline conditions can accelerate breakdown, Microbial contamination: Can occur if exposed to moisture or if containers are not properly sealed

AKG is moderately stable in aqueous solution at neutral pH, but degradation accelerates in very acidic or alkaline conditions. Once mixed in solution, it should ideally be used within 24 hours. Refrigeration of solutions can extend this period somewhat.

May form precipitates when mixed with certain minerals in high concentrations, Can degrade when combined with strong oxidizing agents, May interact with certain proteins or amino acids in solution

Powder: Generally most stable form, especially when kept dry

Capsules: Good stability when properly manufactured and stored

Tablets: Stability depends on binders and manufacturing process; generally stable

Liquid: Least stable form; typically requires preservatives and has shorter shelf life

Change in color (yellowing or browning), Development of unusual odor, Clumping or caking of powder (indicates moisture exposure), Visible mold or contamination, Significant change in taste (if normally consumed directly)

Antioxidants may be added to some formulations to prevent oxidation, Desiccants in packaging to control moisture, Buffering agents to maintain optimal pH in some formulations, Chelating agents in some liquid formulations

Synthesis Methods

Natural Sources

Quality Considerations

Commercial Forms

Sustainability

Ethical Considerations

Alpha-Ketoglutarate (AKG) has a relatively recent history of use as a supplement compared to many traditional herbs and nutrients. As a key intermediate in the Krebs cycle, AKG was first identified and characterized in the early 20th century as scientists elucidated the biochemical pathways of cellular energy production. However, its use as a therapeutic agent or supplement began much later.

The earliest clinical applications of AKG emerged in the 1980s and 1990s, primarily in the form of Ornithine Alpha-Ketoglutarate (OKG) for patients recovering from trauma, surgery, or severe illness. Medical researchers discovered that OKG could help preserve muscle mass and improve nitrogen balance in catabolic states, making it valuable in clinical nutrition for critically ill patients.

In sports nutrition, AKG gained popularity in the 1990s and early 2000s, particularly in the form of Arginine Alpha-Ketoglutarate (AAKG). It was marketed as a supplement to enhance nitric oxide production, improve blood flow to muscles, and support exercise performance and recovery. This application became widespread in pre-workout formulations and bodybuilding supplements.

The use of AKG for bone health began to emerge in the early 2000s, with studies showing potential benefits for bone mineral density and osteoporosis prevention. Research in both animals and humans suggested that AKG could support collagen synthesis and bone formation, leading to its consideration as a supplement for skeletal health, particularly in aging populations.

The most recent chapter in AKG’s history began in the 2010s with research into its potential anti-aging effects. The groundbreaking 2014 study in C. elegans showing that AKG could extend lifespan by inhibiting ATP synthase and TOR signaling sparked new interest in this molecule for longevity applications. This was followed by studies in fruit flies and, most notably, the 2020 research demonstrating lifespan extension and healthspan improvement in mice supplemented with calcium AKG.

Unlike many traditional supplements with centuries of folk use, AKG’s applications have been driven primarily by scientific research rather than traditional medicine. Its emergence as a supplement of interest for healthy aging is very recent, with most key discoveries occurring within the past decade. This represents a modern, research-driven approach to supplement development, where understanding of biochemical mechanisms precedes widespread use.

Today, AKG is increasingly being studied and marketed for its potential to support healthy aging, with particular emphasis on its ability to reduce biological age markers and improve healthspan. This application represents the cutting edge of nutritional science, where endogenous metabolites are being explored for their potential to modulate fundamental processes of aging and metabolism.

Alpha-Ketoglutarate (AKG) has moderate to strong evidence supporting its biological effects in animal models, particularly for lifespan extension, healthspan improvement, and metabolic benefits. Human clinical evidence is more limited but growing, with strongest support for applications in bone health, recovery from trauma or surgery, and sports performance. The mechanisms of action are well-established from biochemical and cellular studies.

No comprehensive meta-analyses specifically on AKG supplementation have been published to date, reflecting the relatively early stage of clinical research on this compound.

Several clinical trials are investigating AKG for applications in aging, bone health, and recovery from illness or surgery., Research on AKG’s effects on human healthspan and biomarkers of aging is ongoing at multiple institutions.

Long-term human clinical trials on AKG for anti-aging effects, Optimal dosing strategies for different applications, Comparative effectiveness of different AKG forms (calcium, sodium, ornithine, arginine), Effects on specific age-related diseases beyond general healthspan, Potential synergies with other anti-aging interventions, Biomarkers to identify individuals most likely to benefit from AKG supplementation

Researchers in the field of aging, including those who conducted the mouse lifespan studies, consider AKG a promising compound for healthspan extension. The fact that it is an endogenous metabolite with well-understood biochemistry provides a strong theoretical foundation for its applications. However, most experts emphasize the need for more human clinical data before making definitive claims about anti-aging benefits in humans.