Alpha-Ketoglutarate (AKG) is a molecule found in every living cell, contributing to many processes that are essential for healthy cellular function. Since it is not naturally present in the diet, AKG must be produced by our body or consumed as a supplement. Due to its potential health benefits, AKG supplementation has recently gained popularity in the antiaging community.
This article explores what is AKG, how it functions, the potential benefits of AKG supplements, the most common doses in clinical trials, and any associated safety concerns.
What is AKG?
AKG is a molecule naturally produced by our body that plays a critical role in energy production. It is also involved in nitrogen metabolism and protein synthesis because it is used to synthesize amino acids glutamine and glutathione.
Additionally, AKG functions as an antioxidant and help detoxify metabolic waste products such as ammonia.
AKG and Longevity
Unfortunately, AKG levels decline significantly with age, decreasing up to 10-fold between the ages of 40 to 80, according to unpublished data (1). A study in mice reported that blood AKG is already lower in middle-age compared to young animals. However, AKG levels were replenished with supplementation, and metabolic health improved (2).
In fruit flies (Drosophila), AKG supplementation extended lifespan. This effect was likely due to an upregulation of AMPK and a reduction in the mTOR pathway (3). If you are interested in learning more about these molecular pathways and their connection to longevity, check out our previous articles here.
Furthermore, AKG supplementation also enhanced autophagy, a cellular recycle process that breaks down and clears out old and damaged parts of the cell.
Another study in mice reported that AKG supplementation, compared to a control diet, reduced frailty in middle-aged mice, and extended lifespan only in female mice. These benefits were associated with a reduction in chronic inflammation (4). It is worth noting that some authors of this study are affiliated with companies involved in aging-related drug development, patent applications, and AKG supplement sales.
The multiple functions and potential health benefits of AKG make it an appealing supplement for health enthusiasts. AKG is usually formulated with other compounds, most commonly calcium (CaAKG). However, some studies have used AKG combined with the amino acid ornithine.
Human evidence
In this section we review the available evidence on AKG supplementation in humans, highlighting the benefits observed in clinical studies, the dosages used, and potential safety concerns.
Initial clinical studies on AKG were conducted in in patients with specific health conditions, such as encephalopathy, stroke, chronic renal failure, or in bedridden individuals. However, research on AKG supplementation in healthy population remains limited.
1. Bone health
A clinical trial in 61 postmenopausal women reported a reduction in bone degradation after consuming CaAKG for 6 months compared to the placebo group (receiving calcium alone). However, there were no differences in bone formation or bone mineral density (5).
2. Muscle mass
Studies that combine AKG with arginine are not considered in this section because arginine independently influences amino acid metabolism and exercise performance through vasodilation and nitric oxide production.
The use of AKG by the fitness community and the believe that its supplementation increase muscle mass likely stems from animal studies showing that mice supplemented with AKG increase muscle size (6), or from studies conducted in hospital settings, where tube or intravenous feeding was used in postoperative care (7) or in severe burn patients (8), showing that AKG supplementation reduced muscle degradation. Despite these indications, evidence supporting AKG's effect on muscle mass in healthy humans remains scarce.
3. Aging
A clinical trial in 185 elderly participants investigated the effects of high-dose ornithine AKG (10 g/day) for 2 months. Compared to the placebo group, participants taking AKG reported an increase in appetite, body weight, independence and quality of life, suggesting a reduction in malnutrition risk (9).
Interest in CaAKG supplementation for anti-aging purposes has grown in recent years, especially following the publication of an observational study. In a group of 42 subjects with a mean chronological age of ~63, CaAKG supplementation for 7 months (with vitamin A for males or vitamin D for females) was associated with a reduction in biological age, as assessed by DNA methylation tests, suggesting cellular rejuvenation (10).
However, several limitations should be noted. The study was not placebo controlled, no functional outcomes were evaluated, the DNA methylation test is not fully validated, and some authors have conflict of interests with the supplement manufacturer and the company selling the DNA test.
Another clinical trial in middle-aged adults is currently underway to investigate the effect of CaAKG supplementation on biological age (11).
AKG - Dosage
Although the typical marketed dose of CaAKG is 1 g/day, clinical trials have not established a clear optimal dose associated with benefits. For instance, the study on bone health in postmenopausal women used 6 g/day for 6 months, while the study reporting a reduction in biological age used 1 g/day for 7 months.
AKG - Safety
AKG supplementation at doses used in clinical trials is generally considered safe. The only study reporting adverse events found a similar rate between the placebo and the treatment group, with participants consuming 6 g/day of CaAKG for 6 months. The most common adverse event was mild gastrointestinal symptoms, which resolved within a few days. Based on the limited available data, CaAKG supplementation at low doses appears to be safe.
Conclusion
Given its importance in the human body and its role in molecular mechanisms related to aging, AKG supplementation shows promising. CaAKG has gained attention in the longevity field, largely due to a single study reporting a significant decrease in biological age.
However, this study had several limitations, and the overall evidence in humans remains limited. Until more robust clinical data are available, the potential benefits of CaAKG should be interpreted with caution.
References
1. Harrison AP, Pierzynowski SG. Biological effects of 2-oxoglutarate with particular emphasis on the regulation of protein, mineral and lipid absorption/metabolism, muscle performance, kidney function, bone formation and cancerogenesis, all viewed from a healthy ageing perspective state of the art--review article. J Physiol Pharmacol. 2008 Aug;59 Suppl 1:91–106.
2. Tian Q, Zhao J, Yang Q, Wang B, Deavila JM, Zhu MJ, et al. Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Aging Cell. 2020 Jan;19(1):e13059.
3. Su Y, Wang T, Wu N, Li D, Fan X, Xu Z, et al. Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging (Albany NY). 2019 Jun 26;11(12):4183–97.
4. Asadi Shahmirzadi A, Edgar D, Liao CY, Hsu YM, Lucanic M, Asadi Shahmirzadi A, et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. 2020 Sep 1;32(3):447-456.e6.
5. Filip RS, Pierzynowski SG, Lindegard B, Wernerman J, Haratym-Maj A, Podgurniak M. Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: six-month study. Int J Vitam Nutr Res. 2007 Mar;77(2):89–97.
6. Yuan Y, Xu P, Jiang Q, Cai X, Wang T, Peng W, et al. Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation. EMBO J. 2020 Apr 1;39(7):e103304.
7. Wernerman J, Hammarqvist F, Vinnars E. Alpha-ketoglutarate and postoperative muscle catabolism. Lancet. 1990 Mar 24;335(8691):701–3.
8. Coudray-Lucas C, Le Bever H, Cynober L, De Bandt JP, Carsin H. Ornithine alpha-ketoglutarate improves wound healing in severe burn patients: a prospective randomized double-blind trial versus isonitrogenous controls. Crit Care Med. 2000 Jun;28(6):1772–6.
9. Brocker P, Vellas B, Albarede JL, Poynard T. A two-centre, randomized, double-blind trial of ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects. Age Ageing. 1994 Jul;23(4):303–6.
10. Demidenko O, Barardo D, Budovskii V, Finnemore R, Palmer FR, Kennedy BK, et al. 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 (Albany NY). 2021 Nov 30;13(22):24485–99.
11. Sandalova E, Goh J, Lim ZX, Lim ZM, Barardo D, Dorajoo R, et al. Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)-intervention study protocol. Geroscience. 2023 Oct;45(5):2897–907.
