Calcium Alpha Ketoglutarate

Calcium Alpha-Ketoglutarate (CA-AKG) exerts its biological effects through multiple interconnected pathways that collectively contribute to its anti-aging, metabolic, and physiological benefits. As a calcium salt of alpha-ketoglutarate (AKG), it provides a stable and bioavailable form of this critical Krebs cycle intermediate, addressing the natural decline in endogenous AKG levels that occurs with aging.

1. Metabolic Regulation via the Krebs Cycle
AKG serves as a pivotal intermediate in the Krebs cycle (also known as the tricarboxylic acid or TCA cycle), the central metabolic pathway that generates energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. By supplementing with CA-AKG, cellular energy production is supported, particularly in tissues with high energy demands such as muscle, brain, and heart. This metabolic support becomes increasingly important with age as mitochondrial efficiency naturally declines.

Specifically, AKG is converted to succinyl-CoA in the Krebs cycle by the alpha-ketoglutarate dehydrogenase complex, generating NADH that feeds into the electron transport chain for ATP production. By maintaining optimal AKG levels, this critical energy-producing pathway functions more efficiently, potentially counteracting age-related metabolic decline.

2. Epigenetic Regulation and DNA Demethylation
One of the most significant mechanisms underlying CA-AKG’s anti-aging effects involves its role as a cofactor for ten-eleven translocation (TET) enzymes and Jumonji C domain-containing histone demethylases (JHDMs). These enzymes regulate DNA and histone methylation patterns, which are critical epigenetic marks that control gene expression.

AKG serves as an essential co-substrate for TET enzymes that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, ultimately leading to DNA demethylation. This process helps maintain appropriate DNA methylation patterns, which tend to become dysregulated with aging. By supporting proper epigenetic regulation, CA-AKG may help maintain a more youthful gene expression profile.

Similarly, AKG is required for the activity of JHDMs that remove methyl groups from histones, further contributing to epigenetic regulation. These epigenetic effects may explain the observed reduction in biological age (as measured by DNA methylation clocks) in humans supplementing with CA-AKG.

3. Nitrogen Metabolism and Detoxification
AKG plays a crucial role in nitrogen metabolism by serving as a carbon skeleton for amino acid synthesis and as an ammonia scavenger. It can accept amino groups from other amino acids through transamination reactions, forming glutamate, which can further detoxify ammonia by forming glutamine.

This ammonia-scavenging function is particularly important in tissues like the brain, where ammonia toxicity can impair function. By enhancing the body’s capacity to detoxify ammonia, CA-AKG may help maintain cellular health and function, especially in the context of age-related declines in detoxification capacity.

4. Protein Synthesis and Muscle Preservation
CA-AKG supports protein synthesis while inhibiting protein degradation, contributing to its potential benefits for maintaining muscle mass during aging. AKG stimulates protein synthesis through multiple mechanisms, including:

– Activation of the mammalian target of rapamycin (mTOR) pathway in specific contexts
– Providing carbon skeletons for amino acid synthesis
– Supporting energy production necessary for protein synthesis

Simultaneously, AKG has been shown to inhibit protein degradation in muscle tissue, potentially through regulation of proteolytic pathways. This dual effect on protein metabolism may explain the observed benefits of CA-AKG on maintaining lean body mass in aging animals and potentially humans.

5. Stem Cell Function and Tissue Regeneration
AKG has been demonstrated to regulate stem cell self-renewal and differentiation, which are critical processes for tissue regeneration and maintenance. Research has shown that AKG can promote the maintenance of stem cell populations by:

– Supporting mitochondrial function in stem cells
– Regulating epigenetic patterns that control stemness genes
– Modulating metabolic pathways that influence stem cell fate decisions

By enhancing stem cell function, CA-AKG may help maintain tissue regenerative capacity during aging, contributing to its effects on healthspan and lifespan.

6. Modulation of Inflammatory Pathways
Chronic inflammation is a hallmark of aging (inflammaging) and contributes to numerous age-related diseases. CA-AKG has been shown to modulate inflammatory responses through several mechanisms:

– Inhibition of nuclear factor kappa B (NF-κB) signaling, a master regulator of inflammatory responses
– Reduction of pro-inflammatory cytokine production
– Modulation of macrophage polarization toward anti-inflammatory phenotypes
– Attenuation of oxidative stress, which can trigger inflammatory cascades

These anti-inflammatory effects may contribute significantly to CA-AKG’s observed benefits on healthspan and lifespan.

7. Regulation of Cellular Senescence
Cellular senescence, the state of permanent cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP), accumulates with age and contributes to tissue dysfunction. Evidence suggests that CA-AKG may influence senescence through:

– Supporting mitochondrial function, preventing mitochondrial dysfunction-induced senescence
– Regulating epigenetic patterns that control senescence-associated genes
– Modulating metabolic pathways that influence cellular stress responses
– Potentially enhancing the clearance of senescent cells through improved immune function

8. Calcium Signaling and Bone Health
As a calcium salt, CA-AKG provides calcium ions that support numerous physiological processes, including:

– Bone mineralization and remodeling
– Muscle contraction
– Nerve signal transmission
– Hormone secretion
– Blood coagulation

The calcium component may be particularly beneficial for maintaining bone density during aging, working synergistically with AKG’s effects on cellular metabolism and protein synthesis in bone tissue.

9. Antioxidant Defense Systems
AKG exhibits direct and indirect antioxidant properties that help combat oxidative stress, a major contributor to aging and age-related diseases. These antioxidant effects include:

– Direct scavenging of reactive oxygen species (ROS)
– Regeneration of other antioxidants
– Support of glutathione synthesis through its role in amino acid metabolism
– Enhancement of cellular antioxidant defense systems through activation of nuclear factor erythroid 2-related factor 2 (Nrf2)

10. Inhibition of ATP Synthase and TOR Pathways
Interestingly, AKG has been shown to inhibit ATP synthase under certain conditions, which may induce mild energetic stress that triggers hormetic responses and adaptive cellular mechanisms. Similarly, AKG can modulate TOR (Target of Rapamycin) signaling, a key regulator of aging processes across species. These effects mirror aspects of caloric restriction and other interventions known to extend lifespan in model organisms.

11. Collagen Synthesis and Tissue Integrity
AKG serves as a cofactor for prolyl hydroxylase, an enzyme critical for collagen synthesis and maturation. By supporting collagen production, CA-AKG may help maintain the structural integrity of various tissues, including skin, blood vessels, and connective tissues, which typically deteriorate with age.

12. Hypoxia Signaling Pathway Regulation
AKG is a required cofactor for prolyl hydroxylase domain (PHD) enzymes that regulate hypoxia-inducible factor 1-alpha (HIF-1α), a transcription factor that controls cellular responses to low oxygen conditions. By modulating hypoxia signaling, CA-AKG may influence various physiological processes, including angiogenesis, erythropoiesis, and cellular adaptation to stress.

Integrated Perspective
The diverse mechanisms of CA-AKG converge to address multiple hallmarks of aging simultaneously, including mitochondrial dysfunction, epigenetic alterations, deregulated nutrient sensing, cellular senescence, and altered intercellular communication. This multi-target approach may explain why CA-AKG has shown more robust effects on lifespan and healthspan compared to compounds that act through single pathways.

Importantly, the natural decline in endogenous AKG levels with age (approximately tenfold reduction between ages 40 and 80) suggests that supplementation may be particularly beneficial for older individuals, effectively addressing a metabolic deficiency that develops during normal aging. This may represent a case of conditional essentiality, where a compound becomes increasingly important for optimal function as we age.

Standard Range: 300-1000 mg daily for general health and longevity support

Starting Dose: 300-500 mg daily for individuals new to CA-AKG supplementation

Maintenance Dose: 500-1000 mg daily for ongoing support

Timing: Typically divided into 1-2 doses, taken with meals to enhance absorption and minimize potential gastrointestinal discomfort

Duration: Long-term use appears safe and may be necessary for sustained benefits, as effects on aging biomarkers typically develop over months of consistent use

Frequency: Once or twice daily dosing is typical; twice daily may provide more consistent blood levels

Timing With Meals: Taking with meals is recommended to enhance absorption and minimize potential gastrointestinal discomfort

Consistency: Regular daily dosing is important for maintaining steady levels, particularly for longevity and anti-aging benefits

Cycling: No strong evidence supporting cycling protocols; continuous use appears appropriate based on available research

Initial Approach: Start with lower doses (300-500 mg daily) for 1-2 weeks to assess tolerance

Escalation: Gradually increase to target dose over 2-4 weeks if well tolerated

Maximum Dose: 1000-1500 mg daily for most purposes; higher doses should only be used under medical supervision

Monitoring: Assess subjective effects and, when possible, objective biomarkers (inflammatory markers, glucose metabolism, etc.) periodically

Start with lower doses (300-500 mg daily) and gradually increase to assess tolerance, Take with meals to improve absorption and minimize potential gastrointestinal discomfort, For longevity purposes, consistent daily use is likely more important than timing within the day, For athletic performance, consider taking one dose approximately 60-90 minutes before exercise, Divide daily doses (morning and evening) if taking more than 500 mg daily for more consistent blood levels, Allow at least 3-6 months of consistent use to evaluate effects on aging biomarkers or other long-term outcomes, Consider combining with complementary nutrients like vitamin D3, vitamin K2, or magnesium for potential synergistic effects, If using for specific health concerns rather than general longevity support, consult with a healthcare provider for personalized dosing, Store properly according to product instructions to maintain potency, as AKG can degrade with exposure to heat, moisture, and air

Optimal dosing for specific conditions and populations has not been definitively established through comprehensive dose-ranging studies, Most human studies have used combination products rather than CA-AKG alone, complicating dose-response analysis, Limited long-term human studies beyond 12 months to guide extended use protocols, Bioavailability data for different formulations is limited, making direct comparisons challenging, Individual factors affecting optimal dosing (genetics, metabolic status, age-related decline in endogenous AKG) are not well characterized, Most dosing recommendations are extrapolated from limited human studies and more extensive animal research

Calcium Alpha-Ketoglutarate (CA-AKG) demonstrates moderate oral bioavailability, with several factors influencing its absorption, distribution, metabolism, and excretion. As a calcium salt of alpha-ketoglutarate (AKG), this form offers improved stability and potentially enhanced absorption compared to free AKG. Understanding the bioavailability characteristics of CA-AKG is essential for optimizing supplementation strategies and achieving desired therapeutic effects.

Oral Bioavailability Percentage: Estimated at 25-40% based on limited pharmacokinetic studies, though precise human data is sparse

Primary Absorption Site: Primarily absorbed in the small intestine through both passive diffusion and active transport mechanisms

Absorption Mechanisms: Passive diffusion across intestinal epithelium (limited due to the charged nature of the molecule), Active transport via sodium-dependent dicarboxylate transporters (NaDC1 and NaDC3), Potential involvement of organic anion transporters (OATs) in cellular uptake, Calcium component may be absorbed through calcium-specific transport pathways

Factors Limiting Absorption: Molecular size and hydrophilicity limit passive diffusion, Saturable nature of active transport mechanisms, Potential for degradation in the acidic environment of the stomach, Competition with other dicarboxylic acids for transporter binding, Conversion to glutamate by intestinal bacteria before absorption

Time To Peak Concentration: Approximately 30-60 minutes after oral administration on an empty stomach; may be delayed to 60-120 minutes when taken with food

Plasma Half Life: Relatively short, estimated at 1-2 hours for the AKG component; calcium follows normal calcium homeostasis pathways

Volume Of Distribution: Moderate, with distribution primarily to highly perfused tissues including liver, kidneys, and skeletal muscle

Protein Binding: Limited protein binding (estimated <20%), allowing for relatively free distribution

Elimination Route: Primarily metabolized in the Krebs cycle and other metabolic pathways; excess may be excreted unchanged in urine

Bioavailability Variability: Significant inter-individual variability (estimated 20-40%) due to differences in transporter expression, intestinal pH, gut microbiota composition, and metabolic factors

Primary Metabolic Pathways: Incorporation into the Krebs cycle, where AKG is converted to succinyl-CoA by the alpha-ketoglutarate dehydrogenase complex, Transamination to form glutamate, which can enter various metabolic pathways, Potential conversion to other Krebs cycle intermediates through anaplerotic reactions, Calcium component enters normal calcium homeostasis pathways

Metabolic Enzymes: Alpha-ketoglutarate dehydrogenase complex (KGDHC), Various transaminases including aspartate aminotransferase (AST) and alanine aminotransferase (ALT), Glutamate dehydrogenase (GDH)

First Pass Metabolism: Moderate first-pass effect in the liver, where a significant portion may be metabolized before reaching systemic circulation

Metabolic Interactions: May compete with other Krebs cycle intermediates and dicarboxylic acids for enzymatic processing; potential interactions with medications that affect energy metabolism

Dose-response Considerations: Higher doses may partially compensate for limited bioavailability, but may also lead to increased side effects, particularly gastrointestinal discomfort

Therapeutic Threshold: Sufficient plasma levels must be achieved to influence cellular metabolism and signaling pathways; this threshold may vary by target tissue and desired effect

Saturation Effects: Transport mechanisms and metabolic pathways may become saturated at higher doses, potentially limiting additional benefits of very high doses

Tissue-specific Bioavailability: Distribution to different tissues varies, with preferential uptake by metabolically active tissues like liver, kidney, and skeletal muscle

Limited human pharmacokinetic studies specifically examining CA-AKG absorption and metabolism, Incomplete understanding of transporter specificity and capacity for AKG in human intestinal epithelium, Limited data on how bioavailability varies with age, health status, and genetic factors, Need for comparative bioavailability studies between different formulations, Limited understanding of how gut microbiota composition affects AKG absorption and metabolism, Need for development of biomarkers that can reliably indicate AKG bioavailability and utilization

Take CA-AKG with meals containing moderate amounts of carbohydrates to potentially enhance absorption, Divide daily doses (typically into 2 administrations) to prevent saturation of transport mechanisms, Consider liposomal or micronized formulations if cost is not prohibitive, particularly for individuals with potential absorption issues, Separate CA-AKG intake from high-calcium foods or supplements by at least 2 hours to minimize potential competition, Consistent daily supplementation is important due to the relatively short half-life of AKG, Consider combining with B vitamins to support metabolic utilization of AKG, Higher doses may be necessary for older individuals due to both declining endogenous levels and potential reduced absorption, Store products properly according to manufacturer recommendations to maintain stability and potency

Calcium Alpha-Ketoglutarate (CA-AKG) demonstrates a favorable safety profile based on available research and clinical experience. With a safety rating of 4 out of 5, it is considered generally safe for most healthy adults when used as directed. Side effects, when they occur, are typically mild and gastrointestinal in nature. However, certain populations should exercise caution, and potential drug interactions warrant consideration.

The compound’s long history of use in clinical settings for specific conditions provides some reassurance regarding its safety, though more comprehensive long-term studies in the context of supplementation for longevity purposes would strengthen the evidence base.

Rating: 4 out of 5

Interpretation: Generally safe with minimal risk of significant adverse effects

Rationale: This rating is based on the relatively low incidence and mild nature of reported side effects, the compound’s endogenous nature (AKG is produced naturally in the body), established safety in clinical settings, and the absence of serious safety concerns in available research. The rating is not 5/5 due to limited long-term safety data specifically for supplementation purposes, some potential drug interactions, and specific contraindications for certain populations.

Common Side Effects:

Uncommon Side Effects:

Rare But Serious Side Effects:

Pharmacokinetic Interactions:

Pharmacodynamic Interactions:

Specific Notable Interactions:

Elderly:

• Generally well-tolerated; may be particularly beneficial due to age-related decline in endogenous AKG levels
• Standard dosing typically appropriate; consider starting at lower end of dosing range
• Monitor for signs of calcium imbalance if taking multiple calcium-containing supplements; be aware of potential drug interactions due to higher likelihood of polypharmacy

Individuals With Impaired Kidney Function:

• Caution warranted due to the role of kidneys in calcium homeostasis and potential accumulation
• Lower doses recommended for mild to moderate impairment; use only under medical supervision in severe impairment
• Periodic assessment of kidney function and calcium levels if used long-term

Individuals With Cardiovascular Conditions:

• Generally safe; theoretical concerns about calcium component in certain conditions
• Standard dosing typically appropriate; consider calcium content in overall supplement regimen
• Monitor blood pressure if hypertensive; be aware of potential interactions with cardiovascular medications

Athletes And Physically Active Individuals:

• Generally well-tolerated; may provide additional benefits for recovery and performance
• May tolerate and benefit from doses at the higher end of the recommended range
• Standard monitoring; ensure adequate hydration, particularly when using higher doses

Established Upper Limit: No officially established upper limit specifically for CA-AKG; consider calcium component in context of total calcium intake (upper limit for calcium is typically 2000-2500 mg/day from all sources)

Observed Toxicity Threshold: Clinical studies have used up to 4.5g daily in hemodialysis patients without significant adverse effects; typical supplemental doses (300-1500 mg) have shown good safety profiles

Signs Of Overdose: Primarily related to calcium component: nausea, vomiting, constipation, confusion, fatigue, muscle weakness, increased urination, and in severe cases, cardiac arrhythmias

Management Of Overdose: Discontinuation; increased fluid intake; medical evaluation if symptoms are significant; monitoring of calcium levels if hypercalcemia is suspected

Longest Duration Studies: Animal studies up to 18 months show good safety profile; human studies typically limited to 6-12 months

Observed Long Term Effects: No significant adverse effects observed in available long-term studies; potential beneficial effects on various aging parameters

Theoretical Concerns: Potential for calcium accumulation with very long-term use in certain individuals; theoretical concerns about metabolic adaptation

Monitoring Recommendations: Periodic assessment of calcium levels and kidney function with long-term use, particularly in older adults or those with relevant medical conditions

Recommended Baseline Testing:

• Calcium levels for those with relevant medical history or concerns
• Basic kidney function tests for those with kidney concerns
• Review of medication list for potential interactions

Ongoing Monitoring:

• Generally not required for healthy individuals taking standard doses
• Consider periodic calcium level assessment for long-term use in vulnerable populations
• Monitor for subjective side effects, particularly gastrointestinal symptoms

When To Discontinue:

• Development of persistent or severe side effects
• Development of hypercalcemia
• Formation of kidney stones
• Significant worsening of kidney function
• Pregnancy

Fda: Generally Recognized as Safe (GRAS) status as a food additive; regulated as a dietary supplement under DSHEA in the US

Efsa: Approved as a food supplement ingredient in the European Union

Health Canada: Allowed as a Natural Health Product ingredient

Tga Australia: Listed on the Australian Register of Therapeutic Goods (ARTG)

International Consensus: Generally recognized as safe at recommended supplemental doses across major regulatory bodies

Acute Toxicity: Low acute toxicity; LD50 (lethal dose for 50% of test animals) significantly higher than therapeutic doses

Subchronic Toxicity: Good safety profile in 90-day feeding studies; no significant adverse effects at doses equivalent to human supplemental doses

Chronic Toxicity: 18-month studies in mice (used for longevity research) showed good safety profile with potential benefits on lifespan and healthspan

Reproductive Toxicity: Limited specific data; general precautionary approach recommended for pregnancy and lactation

Genotoxicity: No evidence of genotoxic potential in standard assays

Carcinogenicity: No evidence of carcinogenic potential in available long-term studies

Medical Applications: Used in clinical settings for specific conditions including hemodialysis patients (at doses up to 4.5g daily) with acceptable safety profile

Post-marketing Surveillance: Limited formal post-marketing surveillance for supplement use; no significant safety signals identified in available literature

Case Reports: Few published case reports of adverse effects; those available primarily relate to mild gastrointestinal symptoms

Clinical Trial Safety Data: Generally good safety profile in available clinical trials, with primarily mild and transient side effects reported

Start with lower doses (300-500 mg daily) and gradually increase to assess tolerance, Take with meals to minimize potential gastrointestinal discomfort, Ensure adequate hydration, particularly if using higher doses, Be aware of the calcium content when calculating total daily calcium intake from all sources, Separate CA-AKG intake from medications that may interact with calcium by at least 2-4 hours, Store properly according to product instructions to prevent degradation, Purchase from reputable sources with third-party testing to ensure quality and purity, Discontinue use at least 2 weeks before scheduled surgery due to theoretical concerns about metabolic effects, Consult healthcare provider before use if you have kidney disease, history of kidney stones, hypercalcemia, or are taking multiple medications

Calcium Alpha-Ketoglutarate (CA-AKG) occupies different regulatory positions across global markets, reflecting variations in supplement regulation frameworks. In most jurisdictions,

it is regulated as a dietary or food supplement rather than a pharmaceutical product.

While generally permitted for sale, specific regulations regarding claims, labeling, and marketing vary significantly by region. Understanding

these regulatory nuances is essential for manufacturers, distributors, healthcare providers, and consumers to ensure compliance and appropriate use.

Classification: Dietary supplement ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994

Regulatory Authority: Food and Drug Administration (FDA)

Pre Market Approval: Not required; manufacturers are responsible for ensuring safety before marketing

New Dietary Ingredient Status: Not formally classified as a New Dietary Ingredient (NDI) by the FDA, Alpha-ketoglutarate has been present in the food supply and used in supplements prior to October 15, 1994, generally qualifying it for ‘grandfathered’ status, NDI notification typically not required for standard formulations, though novel delivery systems or significantly altered forms might require notification

Permitted Claims: Permitted with appropriate disclaimer (e.g., ‘supports cellular energy production’, ‘may help maintain healthy aging processes’), Prohibited without drug approval (e.g., cannot claim to treat, cure, or prevent any disease), Products must carry the standard dietary supplement disclaimer: ‘These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’

Quality Requirements: Must be manufactured in compliance with dietary supplement Good Manufacturing Practices (21 CFR Part 111), Serious adverse events must be reported to the FDA, Must comply with dietary supplement labeling regulations including Supplement Facts panel

Enforcement Actions: No significant FDA enforcement actions specifically targeting CA-AKG supplements to date; general supplement regulations apply

Classification: Food supplement ingredient under Directive 2002/46/EC

Regulatory Authority: European Food Safety Authority (EFSA) provides scientific opinions; individual member states implement regulations

Novel Food Status: Not listed in the Novel Food Catalogue as requiring novel food authorization, Generally permitted for use in food supplements across the EU, though member states may have specific regulations

Health Claims: No authorized health claims specific to CA-AKG under Regulation (EC) No 1924/2006, Cannot make specific health claims related to CA-AKG without EFSA approval, General, non-specific claims (e.g., ‘supports wellbeing’) may be permitted if accompanied by an authorized specific health claim

Member State Variations: While EU regulations provide an overarching framework, implementation and enforcement vary by member state, Some member states may have specific positive lists of permitted supplement ingredients or maximum levels, Products legally marketed in one member state can generally be sold in others, though exceptions exist

Quality Requirements: Must comply with general food safety regulations and specific food supplement regulations of member states

Post Brexit Status: Regulations largely aligned with pre-Brexit EU framework, with potential for divergence over time

Classification: Food supplement ingredient

Regulatory Authority: Food Standards Agency (FSA) and local authorities

Permitted Claims: Similar to EU framework; health claims require authorization

Quality Requirements: Must comply with food supplement regulations and general food safety standards

Classification: Natural Health Product (NHP)

Regulatory Authority: Health Canada, specifically the Natural and Non-prescription Health Products Directorate (NNHPD)

Pre Market Approval: Requires pre-market approval and product license (Natural Product Number or NPN), Manufacturers must submit safety, efficacy, and quality evidence to obtain an NPN, Several CA-AKG products have received NPNs, indicating Health Canada acceptance of safety for specific formulations

Permitted Claims: Claims must be pre-approved by Health Canada based on evidence submitted, May include claims related to cellular energy, metabolism support, and general health maintenance depending on evidence provided, Claims require supporting evidence proportional to the risk level of the claim

Quality Requirements: Must meet specific quality standards outlined in the Natural Health Products Regulations; Good Manufacturing Practices (GMPs) are mandatory

Classification: Listed complementary medicine

Regulatory Authority: Therapeutic Goods Administration (TGA)

Pre Market Process: Must be listed on the Australian Register of Therapeutic Goods (ARTG), Self-certification for ingredients on permitted list; must only make low-risk claims, Alpha-ketoglutarate is generally permitted in listed medicines

Permitted Claims: Limited to general health maintenance and prevention of dietary deficiency, Cannot reference serious diseases or conditions, Manufacturers must hold evidence to support claims

Quality Requirements: Must comply with the Therapeutic Goods (Standard for Complementary Medicines) (TGO 92) and Good Manufacturing Practice

Classification Options: May qualify as a ‘Food with Function Claims’ with appropriate scientific evidence, Potentially eligible for ‘Food for Specified Health Uses’ (FOSHU) status with substantial clinical evidence, May be sold as a general food supplement with no specific health claims

Regulatory Authority: Ministry of Health, Labour and Welfare (MHLW) and Consumer Affairs Agency (CAA)

Current Status: Limited presence in Japanese market compared to other regions; primarily available as a general food supplement

Classification Options: May be registered as a ‘Health Food’ with specific function claims, May be sold as a general food supplement without specific health claims

Regulatory Authority: National Medical Products Administration (NMPA) and State Administration for Market Regulation (SAMR)

Registration Process: Requires extensive safety and efficacy data, including clinical trials for function claims, Additional requirements for imported products, including free sale certificates from country of origin

Current Status: Limited approved health foods containing CA-AKG; primarily available as general supplements

Calcium Alpha-Ketoglutarate (CA-AKG) demonstrates synergistic relationships with several compounds that can enhance its effectiveness for various health applications. These synergies typically occur through complementary mechanisms of action, enhanced bioavailability, or by addressing multiple aspects of complex physiological processes simultaneously. Understanding these synergistic relationships provides opportunities to optimize CA-AKG supplementation strategies for specific health goals.

General Principles: Take synergistic combinations consistently; timing may vary based on specific combinations and health goals

Specific Recommendations: CA-AKG + Vitamin D3 + Vitamin K2: Take with meals containing some fat for optimal absorption of fat-soluble vitamins, CA-AKG + NAD+ precursors: Morning administration may be preferable to support energy metabolism throughout the day, AAKG for exercise performance: Take approximately 60-90 minutes before exercise for optimal effects

Separation Considerations: Separate CA-AKG from iron supplements, tetracycline antibiotics, and high-dose zinc by at least 2-4 hours, Consider separating very high doses of magnesium from CA-AKG by a few hours if gastrointestinal symptoms occur

Clinical trials specifically examining synergistic combinations for various health outcomes, Optimization of dosing ratios for different synergistic combinations, Investigation of potential three-way or multi-component synergies for comprehensive health support, Exploration of temporal synergies (compounds that work better when taken at specific times relative to each other), Development of advanced delivery systems to enhance synergistic effects

For general longevity support, consider combining CA-AKG (500-1000 mg daily) with vitamin D3 (1000-5000 IU) and vitamin K2 (100-200 mcg) for a well-rounded approach, For bone health, the combination of CA-AKG, vitamin D3, vitamin K2, and magnesium provides comprehensive support for calcium utilization and bone formation, For athletic performance, AAKG (1500-3000 mg daily) may provide more specific benefits than CA-AKG alone, Start with lower doses of each compound when combining multiple supplements to assess tolerance, Consider the timing of administration based on the specific combination and health goals, Be aware of potential interactions with medications and separate administration as needed, For complex combinations, consider working with a knowledgeable healthcare provider to optimize the approach for individual needs

Calcium Alpha-Ketoglutarate (CA-AKG) presents a complex cost-efficiency profile that varies based on the specific health applications, individual response, and comparison to alternatives. As a supplement primarily targeting fundamental biological processes related to aging and metabolism, its cost-efficiency should be evaluated in the context of both immediate benefits and potential long-term health outcomes.

This analysis examines CA-AKG’s cost-efficiency across different applications, formulations, and in comparison to alternatives, providing a framework for individuals to make informed decisions based on their specific health goals and financial considerations.

Start with standard CA-AKG formulations (500-1000 mg daily) to assess individual response before investing in premium formulations, Consider subscription services or bulk purchasing to reduce per-unit costs if committed to long-term use, For bone health applications, combination products with vitamins D3 and K2 may offer better overall value than separate supplements, Monitor subjective effects and, when possible, objective biomarkers to assess individual value and optimize dosing, View CA-AKG as a complement to, not replacement for, fundamental lifestyle approaches to healthy aging, For athletic performance, consider periodic use during intense training phases rather than continuous supplementation if budget is limited, Middle-aged adults (40-65) may derive the best cost-efficiency due to declining endogenous AKG levels and opportunity for preventative benefits, If budget constraints exist, prioritize consistent use of moderate doses rather than intermittent use of higher doses for longevity applications

Calcium Alpha-Ketoglutarate (CA-AKG) demonstrates moderate stability under proper storage conditions but can be susceptible to degradation

when exposed to certain environmental factors. Understanding its stability characteristics is essential for maintaining potency throughout its shelf life and ensuring optimal therapeutic effects. As a calcium salt of alpha-ketoglutaric acid, CA-AKG offers improved stability compared to the free acid form, but still requires appropriate handling and storage to preserve its integrity.

Chemical Structure: CA-AKG is the calcium salt of alpha-ketoglutaric acid, a five-carbon dicarboxylic acid with a ketone group. Its chemical formula is Ca(C₅H₆O₅) with a molecular weight of approximately 190 g/mol.

Physical Appearance: White to off-white crystalline powder with a characteristic slight odor

Solubility: Moderately soluble in water (approximately 5-10 g/L at 25°C); solubility increases in acidic conditions and with increasing temperature

PH In Solution: A 1% solution typically has a pH of 5.5-6.5, indicating mild acidity

Hygroscopicity: Moderately hygroscopic, with a tendency to absorb moisture from the air, particularly in high humidity environments

Temperature: Store at room temperature (15-25°C); refrigeration is beneficial but not required; avoid temperatures above 30°C

Humidity: Store in a dry place with relative humidity below 60%; avoid bathroom medicine cabinets or other high-humidity environments

Light: Protect from direct light, particularly sunlight; keep in original container or opaque container if transferred

Container Considerations: Original container with desiccant (if provided) is optimal; if transferring, use airtight, light-resistant container with minimal headspace

Special Handling: Minimize exposure to air during handling; close container promptly after use; use dry utensils for measuring powder forms

Open Container Stability: Once opened, product should ideally be used within 6 months, particularly if exposed to air, light, or humidity regularly

Moisture Effects After Opening: Repeated opening in humid environments can introduce moisture; desiccant effectiveness diminishes over time after opening

Recommendations For Consumers: Reseal container promptly and tightly after each use, Keep desiccant in the container (if provided) until all product is used, Store in a cool, dry place away from direct light, Avoid transferring to non-original containers unless they provide equivalent protection, Consider smaller package sizes if not using regularly to minimize exposure time, Discard product if appearance changes significantly (color change, clumping, unusual odor)

Store CA-AKG supplements in their original containers at room temperature (15-25°C) or cooler, Keep containers tightly closed when not in use; replace cap immediately after taking dose, Store in a dry place away from moisture sources; avoid bathroom medicine cabinets, Protect from direct light, particularly sunlight, If transferring to another container, choose one that is airtight and opaque/amber colored, Keep desiccant packets in the container if provided by manufacturer, Note the manufacturing or expiration date when purchasing and use within the recommended timeframe, For powder forms, use a dry measuring spoon or scoop to avoid introducing moisture, Discard supplements that have changed in appearance, developed unusual odor, or clumped together, For travel, keep in original container when possible; for short trips, small opaque pill containers are acceptable, Consider refrigeration for long-term storage or in very hot/humid climates, but allow container to reach room temperature before opening to prevent condensation

Overview

Natural Sources

Commercial Production Methods

Quality Considerations

Global Supply Chain

Formulation Variations

Sustainability Considerations

Practical Sourcing Guidance

Calcium Alpha-Ketoglutarate (CA-AKG) has a relatively recent history as a supplement for general health and longevity, but alpha-ketoglutarate itself has a longer history of use in clinical settings for specific medical applications. Unlike many traditional supplements with centuries of historical use, CA-AKG emerged primarily through scientific research on cellular metabolism and has evolved from specialized clinical applications to broader use as research has revealed its potential anti-aging properties.

This historical trajectory represents a case where modern scientific understanding has driven supplement development rather than traditional use leading to scientific validation.

Calcium Alpha-Ketoglutarate (CA-AKG) has emerged as a promising compound in the field of longevity and metabolic health research. The scientific evidence supporting its use spans from mechanistic studies elucidating its biochemical roles to animal lifespan studies and early human clinical trials.

While the evidence is compelling in several areas, particularly regarding its metabolic functions and anti-aging potential in model organisms, human clinical data

specifically for longevity outcomes remains limited. The evidence rating of 3 reflects

this mixed landscape: strong mechanistic understanding and animal data balanced against the need for more comprehensive human clinical trials.

Rating: 3 out of 5

Interpretation: Moderate evidence base with promising results but some limitations

Rationale: This rating reflects the strong mechanistic understanding of AKG’s biological roles, robust animal studies showing lifespan and healthspan extension, and preliminary human studies showing benefits on various biomarkers. However, the rating is not higher due to the limited number of large-scale, long-term human clinical trials specifically examining CA-AKG for longevity outcomes, some inconsistencies in results across studies, and the need for more research in diverse populations.

Animal Studies: Clear dose-dependent effects observed in rodent studies, with higher doses generally showing more pronounced benefits for lifespan and metabolic parameters up to a plateau

Human Studies: Limited dose-ranging studies in humans; most use fixed doses based on animal research and theoretical considerations

Therapeutic Threshold: Evidence suggests a minimum effective dose of approximately 300-500 mg daily for metabolic effects, with diminishing returns above 1000-1500 mg daily for most applications

Safety Considerations: Good safety profile across a wide dose range; upper limits more related to practicality and cost than safety concerns for most individuals

Large-scale, long-term randomized controlled trials in humans specifically examining longevity and healthspan outcomes, Studies examining the effects of CA-AKG in diverse populations across different age groups, ethnicities, and health statuses, Comprehensive dose-ranging studies to establish optimal dosing for different applications and populations, Research on potential synergistic effects with other interventions (exercise, caloric restriction, other supplements), Studies examining the impact of genetic variations on response to CA-AKG supplementation, Development and validation of biomarkers that can reliably predict long-term benefits from CA-AKG supplementation, Research on the potential role of CA-AKG in specific age-related diseases beyond general aging processes

For general longevity support: Consider CA-AKG supplementation (500-1000 mg daily) as part of a comprehensive approach to healthy aging, recognizing that evidence is promising but still evolving, For older adults (65+): Evidence suggests potentially greater benefits in this population due to natural decline in endogenous AKG levels; 500-1000 mg daily is supported by available research, For metabolic health support: May provide modest complementary benefits alongside primary interventions; 500-1000 mg daily is a reasonable evidence-based approach, For athletic performance: Evidence is mixed; may provide some benefits for recovery rather than acute performance; consider 1000-1500 mg daily if using for this purpose, For all applications: Consistent use for at least 3-6 months is likely necessary to evaluate effects, as many benefits develop gradually, Consider combining with complementary approaches (exercise, proper nutrition, stress management) for synergistic effects on healthspan, Monitor subjective effects and, when possible, objective biomarkers to assess individual response