Highlights
- AKG is a natural compound made by our cells produced by the metabolic pathway that generates ATP from glucose, or more specifically Acetyl-CoA generated from nutrient breakdown.
- AKG supplement was shown to extend lifespan is experimental animals including worms, flies and mice.
- Studies show that AKG suppresses the mTOR nutrient signaling pathway, reduces inflammation, and helps prevent muscle loss.
- In a small human clinical trial, 7 months of 1000 mg/day AKG supplementation was shown to reverse biological age in the participants.
- It is tolerated in doses as high as 6 gm/day for 6 months
The Biology
Alpha-ketoglutarate (AKG) is a key metabolite of the cellular pathway that breaks down glucose to produce ATP, the fundamental energy carrier of life. AKG can be derived from the pathway called tricarboxylic acid (TCA) or Krebs cycle or from endogenous amino acid metabolism. AKG has been tested in clinical nutrition for muscle regeneration and for supporting kidney function. Recent interest in AKG stems from experiments in C. elegans, flies, and mice that showed lifespan and healthspan extension when was added to their diet. Mechanistically, AKG is a key intermediate in cellular energy metabolism. It also activates AMP kinase and inhibits the mTOR nutrient-sensing pathway, serves as a cofactor for enzymes including epigenetic and collagen-modifying enzymes. Interestingly AKG inhibits the enzyme ATP synthase which produces ATP, and the loss of ATP synthase also eliminates the life extending effect of AKG in animals. Interestingly, AKG levels are naturally increased by calorie restriction in animals, and under starvation conditions, AKG supplementation does not provide additional lifespan extension, suggesting that AKG supplementation increases lifespan by mimicking dietary restriction.
Clinical Evidence
In humans, there has been one clinical trial that suggests lifespan benefit of taking AKG supplement. In this clinical study, the supplement Rejuvant (Calcium-AKG plus added vitamins) was used in adults (n=42) reported an average reduction of around 7–8 years in DNA methylation–based biological age after about 7 months of use. Currently ongoing and planned randomized, placebo-controlled trials are testing sustained release Ca-AKG in biologically older middle-aged adults and in 45–75 year olds, with primary endpoints including DNA methylation age clocks (e.g., PhenoAge) and secondary outcomes such as inflammation, exercise performance, vascular and metabolic health. Beyond aging, prior clinical studies with AKG salts in specific diseases (e.g., renal disease, osteopenia etc.) suggest benefits for bone health, nitrogen balance, and prevention of muscle loss.
Safety
AKG supplementation, including Ca-AKG at 1000mg/day for 7 months, is generally well tolerated in adults, with most reported adverse effects being mild and transient gastrointestinal symptoms. One study in post-menopausal women using 6 gm per day of Ca-AKG for 6 months reported similar rates of adverse events in active and placebo arms, suggesting no major safety signal even at that high dose. However, because of insufficient safety data, conservative dosing and medical supervision are prudent in higher-risk groups.
Supplementation
In practice, commercial Ca-AKG supplements for healthy adults typically provide on the order of 300–1,000 mg per day, often taken once in the morning, with some products recommending 1,000–2,000 mg/day (e.g., 2–4 capsules of 500 mg) as an upper routine dose. Longevity-focused literature and company guidance sometimes cite experimental or “maximum safe” intakes up to about 6 g/day in adults, but such higher doses have far less long term safety and efficacy data in generally healthy populations. For athletic use, sarcopenia, or other clinical use, total daily AKG in the 2–4 g range has been used for several weeks to months to support muscle metabolism and recovery.
Hakimi Naeini, S., Mavaddatiyan, L., Rashid Kalkhoran, Z., Taherkhani, S., & Talkhabi, M. (2023, May). Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives. Experimental Gerontology. https://doi.org/10.1016/j.exger.2023.112154
Wu, N., Yang, M., Gaur, U., Xu, H., Yao, Y., & Li, D. (2016, January 1). Alpha-ketoglutarate: Physiological functions and applications. Biomolecules & Therapeutics. https://doi.org/10.4062/biomolther.2015.078
Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017). Alpha-ketoglutarate as a molecule with pleiotropic activity: Well-known and novel possibilities of therapeutic use. Archives of Immunology and Therapy. https://doi.org/10.1007/s00005-016-0406-x
Demidenko, O., Barardo, D., Budovskii, V., Finnemore, R., Palmer, F. R. III, Kennedy, B. K., & Budovskaya, Y. V. (2021, November 30). Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8-year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test. Aging. https://doi.org/10.18632/aging.203736
Filip, R. S., Pierzynowski, S. G., Lindegard, B., Wernerman, J., Haratym-Maj, A., & Podgurniak, M. (2007). Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: Six-month study. International Journal of Vitamin and Nutrition Research. https://doi.org/10.1024/0300-9831.77.2.89
What is Ca-AKG (Calcium Alpha-Ketoglutarate) and how does it work? Decode Age https://decodeage.com/blogs/supplements/what-is-ca-akg-calcium-alpha-ketoglutarate-and-how-does-it-work