Alpha Ketoglutarate
Also known as: Alpha-ketoglutarate, 2-oxoglutarate, Alpha-ketoglutaric acid, AKG, CaAKG, Calcium alpha-ketoglutarate
Overview
Alpha-ketoglutarate (AKG), also known as 2-oxoglutarate, is a crucial endogenous metabolite naturally produced in the mitochondria as a key intermediate in the tricarboxylic acid (TCA) cycle, central to cellular respiration. Found in all aerobic organisms, AKG plays a vital role in energy metabolism, nitrogen balance, and various cellular processes. As a dietary supplement, it is often administered as calcium alpha-ketoglutarate (CaAKG). Supplementation with AKG is primarily explored for its potential to support energy metabolism, reduce systemic inflammation, enhance muscle recovery, improve reproductive capacity, and, most notably, extend lifespan and healthspan. Beyond its metabolic functions, AKG is involved in epigenetic regulation, immune modulation, and acts as an antioxidant. While preclinical evidence, particularly from animal models, is robust and suggests significant benefits, human data are currently limited and mostly preliminary, with a scarcity of large-scale, controlled clinical trials.
Benefits
Alpha-ketoglutarate (AKG) offers several potential benefits, primarily supported by strong preclinical evidence and emerging human data: * **Lifespan and Healthspan Extension:** In animal models, particularly C57BL/6 mice, CaAKG supplementation has been shown to extend the lifespan in females and improve healthspan in both sexes. This effect is attributed to a reduction in frailty and systemic inflammation, notably through the induction of IL-10, and a compression of morbidity. While statistically significant in animals, the translation to humans requires further research. * **Epigenetic Age Reduction:** Preliminary human data from a small cohort (n=42) indicated that CaAKG supplementation over approximately seven months significantly decreased biological (methylation) age by an average of about eight years relative to chronological age. This finding is promising but comes from a small, uncontrolled study, necessitating larger, placebo-controlled trials for confirmation. * **Reproductive Health:** Animal studies suggest that AKG modulates reproductive potential by improving oocyte quality, delaying reproductive aging, and supporting stem cell pluripotency. This area is primarily supported by animal research, with human implications still under investigation. * **Immune Modulation:** AKG has demonstrated the ability to reduce chronic inflammation and enhance the secretion of the anti-inflammatory cytokine IL-10 in T cells, as observed in mouse models. This suggests a role in regulating the immune response. * **Intestinal Health:** In fish models, AKG supplementation improved intestinal barrier integrity and immune response, particularly under low protein diets, indicating potential benefits for gut health.
How it works
Alpha-ketoglutarate (AKG) exerts its effects through several key biological pathways. As a central intermediate in the tricarboxylic acid (TCA) cycle, it directly influences cellular energy metabolism and ATP production. AKG plays a critical role in nitrogen and ammonia balance by participating in transamination reactions, helping to detoxify ammonia. It also functions as an antioxidant, scavenging reactive oxygen species. Furthermore, AKG is a crucial co-factor for various dioxygenase enzymes, including those involved in epigenetic regulation, such as histone and DNA demethylation. This epigenetic modulation can influence gene expression and cellular aging processes. In the immune system, AKG has been shown to induce the secretion of anti-inflammatory cytokines like IL-10, thereby reducing systemic inflammation. Oral supplementation, particularly as calcium alpha-ketoglutarate (CaAKG), is bioavailable, allowing it to enter the bloodstream and influence these systemic and cellular mechanisms.
Side effects
Alpha-ketoglutarate (AKG) is generally regarded as safe based on available animal studies and limited human use, with no major adverse events reported in the reviewed literature. However, the comprehensive safety profile, especially for long-term use and in diverse populations, is not yet fully established due to the limited number of large-scale human clinical trials. * **Common Side Effects:** No significant or common side effects have been consistently reported in the studies reviewed. Data on frequency and severity are insufficient. * **Uncommon/Rare Side Effects:** Information regarding uncommon or rare side effects is currently insufficient to draw definitive conclusions. * **Drug Interactions:** There are no well-documented drug interactions for AKG. However, given its central role in metabolism, caution is advised, especially for individuals on medications that significantly impact metabolic pathways. Consultation with a healthcare professional is recommended. * **Contraindications:** Specific contraindications for AKG supplementation have not been established. However, individuals with pre-existing metabolic disorders should exercise caution and consult a physician before use, as its metabolic effects are still being fully elucidated. * **Special Populations:** The effects and safety of AKG supplementation in pregnant or lactating women, children, and individuals with chronic diseases have not been well studied. Therefore, its use in these populations is not recommended without medical supervision. Overall, while promising, more extensive human research is needed to fully characterize the safety profile of AKG.
Dosage
The optimal and minimum effective dosages for Alpha-ketoglutarate (AKG) in humans are not yet well-established due to limited standardized clinical trials. Animal studies have used doses scaled to body weight, but direct translation to humans is challenging. Human studies investigating epigenetic age reduction have utilized calcium alpha-ketoglutarate (CaAKG) over several months, suggesting that chronic supplementation is necessary for observed effects. However, specific dosage ranges from these preliminary human studies are not standardized across research. * **Optimal Dosage Ranges:** There is no universally agreed-upon optimal dosage for humans. Research is ongoing to determine effective and safe ranges for various applications. * **Maximum Safe Dose:** The maximum safe dose for AKG in humans is currently unknown. No toxicity has been reported at the doses studied in animal models, but human data on upper limits are lacking. * **Timing:** Effects, such as epigenetic age reduction and lifespan benefits, appear to require chronic supplementation over months to years rather than acute dosing. * **Form-Specific:** The calcium salt form (CaAKG) is commonly used in supplementation due to its bioavailability. Other forms may have different absorption characteristics. * **Absorption Factors:** Oral CaAKG appears to be adequately bioavailable, but the exact pharmacokinetics and any cofactor requirements for optimal absorption and utilization in humans are not yet fully defined.
FAQs
Is AKG safe for long-term use?
Animal studies suggest AKG is generally safe, but long-term human safety data are currently limited. More research is needed to confirm its safety profile over extended periods in humans.
Does AKG improve muscle recovery?
Older human studies hinted at potential benefits for muscle recovery, but recent high-quality randomized controlled trials specifically on this aspect are lacking. Further research is required.
Can AKG reverse aging?
Preliminary human data show a reduction in biological (methylation) age, which is a marker of aging. However, this does not equate to 'reversing' aging, and more rigorous, large-scale trials are needed to confirm these anti-aging effects.
How fast do benefits appear?
Lifespan benefits observed in animal models require months to years of supplementation. Epigenetic age changes in humans were noted after approximately seven months of consistent use.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8508957/ – This randomized controlled trial in mice demonstrated that calcium alpha-ketoglutarate (CaAKG) extended the lifespan of female mice and improved healthspan in both sexes by reducing frailty and systemic inflammation, particularly through IL-10 induction. The study provides strong preclinical evidence for AKG's anti-aging potential, though its direct translation to humans is uncertain.
- https://www.aging-us.com/article/203736/text – This preliminary observational study on a small human cohort (n=42) found that CaAKG supplementation over approximately seven months significantly decreased biological (methylation) age by an average of eight years. While promising, the study's small sample size and lack of a placebo control limit the generalizability and strength of its conclusions, necessitating further controlled research.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC11558802/ – This systematic scoping review synthesized findings from various animal studies, indicating that AKG modulates reproductive potential by improving oocyte quality, delaying reproductive aging, and supporting stem cell pluripotency. The review highlights AKG's role in reproductive health, primarily based on animal data, underscoring the need for human studies.
- https://research.vu.nl/files/160079366/AlphaKetoglutarate_dietary_supplementation_to_improve_health_in_humans.pdf – This systematic review summarizes AKG's diverse roles in metabolism, aging, muscle function, and wound healing, drawing from various studies. It emphasizes the promising preclinical evidence and calls for more rigorous human trials to confirm the efficacy and safety of AKG supplementation for human health improvement.
- https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.915657/full – This experimental study in common carp demonstrated that AKG supplementation improved intestinal immunity and barrier function, especially under low protein dietary conditions. The research suggests AKG's potential to enhance gut health and immune response in animal models, providing insights into its broader physiological effects.
