Calcium alpha-ketoglutarate (CA-AKG): Therapeutic potential, clinical – QIDOSHA

Calcium alpha-ketoglutarate (CA-AKG): Therapeutic potential, clinical evidence and security profile

June 06/18/25, 2025from Patrick Linder

Calcium alpha-ketoglutarate (Ca-AKG) is a special form of alpha-ketoglutaric acid (AKG), a naturally occurring compound that plays a central role in the citric acid cycle and is involved in numerous metabolic processes in the body. As an intermediate in cellular energy metabolism, AKG functions not only as an energy source but also as a signaling molecule, a precursor of amino acid synthesis, and a regulator of epigenetic processes. The calcium form (Ca-AKG) was developed to improve the bioavailability and stability of AKG, making it particularly interesting for therapeutic applications.

It is noteworthy that AKG levels in the body decrease significantly with age – studies show that at age 80, the concentration is only about 10% of the level present at age 40. This age-related decline has sparked scientific interest in Ca-AKG as a potential agent for influencing age-related processes (“longevity”).

Biochemical principles and mechanisms of action

Metabolic functions

Ca-AKG plays a central role in several fundamental biochemical processes:

Energy metabolism: As a key intermediate in the citric acid cycle, AKG is directly involved in cellular energy production and supports the efficient conversion of macronutrients into cellular energy (ATP).
Nitrogen metabolism: AKG acts as a nitrogen acceptor in amino acid synthesis and helps regulate nitrogen and ammonia balance in the body, which is particularly relevant during metabolic stress.
Collagen synthesis: AKG is a cofactor for prolyl hydroxylases, which are essential for collagen formation and stabilization, which explains its importance for bone and skin health.
Epigenetic regulation: AKG serves as a substrate for DNA demethylases (TET enzymes), which contribute to DNA demethylation and can thus influence gene expression.

Molecular signaling pathways

At the molecular level, Ca-AKG influences several signaling pathways related to aging and health:

AMPK activation: Studies suggest that AKG can activate AMP-activated protein kinase (AMPK), a key energy sensor that regulates cellular metabolism.
mTOR inhibition: In some model organisms, AKG has been shown to inhibit the mTOR signaling pathway, which plays an important role in cell growth and aging.
Autophagy promotion: By influencing AMPK and mTOR, AKG can promote autophagy, a cellular cleaning process important for cell health and longevity.
Anti-inflammatory: Ca-AKG exhibits anti-inflammatory properties, particularly through the induction of interleukin-10 (IL-10) in T cells, which may contribute to the suppression of chronic inflammation.

Clinical studies and therapeutic applications

Bone health and osteoporosis

A randomized, double-blind, placebo-controlled study of 76 postmenopausal women with osteopenia investigated the effects of Ca-AKG (6 g AKG and 1.68 g Ca per day) over a period of 6 months. The results showed a significant decrease in serum levels of C-terminal cross-linked telopeptide of type I collagen (CTX), a marker of bone loss, by up to 37% after 24 weeks.

Kidney disease and hemodialysis

Clinical studies in hemodialysis patients have shown that Ca-AKG is safe at doses up to 4.5 g/day for up to three years and can lead to an increase in plasma arginine levels and a decrease in plasma urea levels.
A crossover study compared the phosphate-binding efficacy of calcium ketoglutarate with calcium carbonate in patients undergoing chronic hemodialysis and found comparable effects in controlling serum phosphate levels.
Ca-AKG has been shown to be effective in correcting secondary hyperparathyroidism in malnourished hemodialysis patients by regulating the phosphate to calcium ratio.

Aging and healthy longevity

Research on Ca-AKG in the context of aging and longevity has become increasingly important in recent years:

A retrospective analysis of 42 individuals taking Rejuvant® (a patented formulation containing Ca-AKG and sex-specific vitamins) for an average of 7 months showed a remarkable average reduction in biological age of approximately 8 years as measured by DNA methylation patterns (p-value = 6.538 × 10^-12).
A double-blind, placebo-controlled, randomized trial called ABLE (Alpha-ketoglutarate supplementation and BiologicaL agE) is currently investigating the effect of 1 g of Ca-AKG daily for 6 months in 120 healthy individuals aged 40-60 years with an increased DNA methylation age compared to their chronological age. The primary endpoint is a reduction in DNA methylation age, a biomarker of biological aging.

Muscle health and physical performance

Ca-AKG also shows potential to support muscle health and physical performance:

Preclinical studies have shown that AKG can promote muscle regeneration by stimulating muscle satellite cells (MuSCs) and influencing macrophage polarization, which contributes to muscle repair and reduces fibrosis.
AKG may potentially prevent muscle atrophy by improving protein synthesis, inhibiting degradation pathways, and modulating inflammatory responses, making it relevant for conditions such as sarcopenia, cachexia, and injury recovery.
For athletes and active individuals, AKG supplementation has been shown in some studies to improve endurance, reduce fatigue, and support faster recovery after exercise.

Metabolic health

Ca-AKG can also have positive effects on various aspects of metabolic health:

In animal models, Ca-AKG has been shown to support weight control and promote the conversion of white adipose tissue to brown adipose tissue, which may be beneficial for energy metabolism.
AKG plays an important role in regulating nitrogen metabolism and may help reduce ammonia buildup, which is important for overall metabolic health.
Preclinical studies suggest that AKG may be promising in diabetes by reducing hyperglycemia and preventing hepatic gluconeogenesis.

Safety profile and side effects

Ca-AKG is generally considered safe and is classified as "Generally Recognized As Safe" (GRAS) by the U.S. Food and Drug Administration (FDA).Clinical studies have confirmed the safety of Ca-AKG at different dosages:

Studies with daily dosages of 4.5 g for up to three years have shown no significant side effects from Ca-AKG supplementation.
In another study, a dosage of 6 g was considered safe for human use.

Although Ca-AKG is generally well tolerated, some mild side effects have been reported: mild gastrointestinal disturbances such as nausea, diarrhea, and stomach upset have occasionally been observed, especially at higher doses.

Special precautions and contraindications

Certain groups of people should exercise particular caution when taking Ca-AKG:

Pregnancy and breastfeeding: Due to insufficient research data, it is recommended that pregnant or breastfeeding women avoid Ca-AKG.
Kidney diseases: People with existing kidney problems should consult a doctor before taking Ca-AKG, although it was safe in controlled studies in hemodialysis patients.

Drug interactions

Although research on Ca-AKG interactions with medications is limited, there are some potential interactions that should be considered:

Calcium channel blockers: Ca-AKG should not be taken together with calcium channel blockers, as an unsafe interaction may occur that could impair the effectiveness of the medications for treating heart and blood pressure conditions.
Immunosuppressants: Due to the potential immunomodulatory effects of AKG, individuals taking immunosuppressants should consult a physician before supplementing with Ca-AKG.
Blood thinners: People with bleeding disorders or those taking blood thinning medication should seek medical advice before taking Ca-AKG.

Dosage and application recommendations

The optimal dosage of Ca-AKG may vary depending on the application and individual factors:

For general health and anti-aging purposes: Doses used in clinical studies range from 300 mg to 1000 mg Ca-AKG daily.
For bone health: In the study with postmenopausal women, 6 g of AKG (as calcium salt) per day was used for 6 months.
For kidney diseases: Doses up to 4.5 g/day have been found to be safe and effective in hemodialysis patients.
BioavailabilityThe bioavailability of Ca-AKG is higher than that of pure AKG, which may allow for lower dosages. Pharmacokinetic studies have shown that orally administered AKG is rapidly absorbed and distributed into various tissues, including bone, skin, and muscle.

Comparison with other AKG forms

Ca-AKG is not the only available form of alpha-ketoglutarate. Other forms include:

Sodium alpha-ketoglutarate (Na-AKG): This form has higher water solubility than Ca-AKG, but lower bioavailability.
Arginine alpha-ketoglutarate (AAKG): This combination of L-arginine and AKG is often used in sports to improve blood circulation and athletic performance.
Ornithine alpha-ketoglutarate (OAKG): This form combines AKG with the amino acid ornithine and is often used to support protein synthesis and muscle recovery.

Compared to these other forms, Ca-AKG is characterized by the following properties:

Higher bioavailability: The calcium form offers better stability and bioavailability than pure AKG.
Longevity and anti-aging benefits: Ca-AKG has shown particularly promising results in studies on longevity and biological age.

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Calcium alpha-ketoglutarate (CA-AKG): Therapeutic potential, clinical evidence and security profile

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