Alpha-ketoglutarate in human trials against diseases and aging

Highlights

‍

• AKG is a versatile endogenous compound that serves multiple functions in the human body
• Decline in AKG levels is strongly associated with aging, with up to 10-fold decrease between 40 and 80 years of age
• Supplementation of AKG supports healthy longevity due to its beneficial effects on cardiac, bone and muscle health. It was also shown to reduce frailty and may have an anti-aging effect
• Though the number of recent clinical studies is somehow limited, there are multiple pieces of evidence pointing toward the pleiotropic effects of AKG
• AKG clinical trials, with a preliminary study showing 8 years reduction in biological age

‍

Introduction

‍

Alpha-ketoglutarate (AKG) is a crucial metabolite that impacts multiple pathways in mammals. AKG is most known for its role in the Krebs cycle, which serves as an energy-generating mechanism for cells. Other known mechanisms include cellular utilization of carbon and nitrogen compounds, being a glutamine precursor, immune regulation, and gene expression. AKG is also involved in growth- and aging pathways, such as mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) pathways. These various functions have sparked long-lasting interest in the potential health benefits of AKG and its potential anti-aging applications. This article will discuss existing clinical trials addressing AKG’s applications for health and longevity benefits.

‍

‍

Effects of AKG on human health

‍

AKG can be easily synthesized and used in clinical practice to assist in cardiovascular diseases, wound healing, and kidney dysfunction (1). It can be administered in pure form, calcium or sodium salt, or combined with arginine or ornithine. Ornithine is generally more prevalent in clinical studies, but no studies demonstrated the difference in the effects between pure AKG or its combined forms (2).

As a supplement, it was extensively studied during the 80s and 90s (3,4), but the topic received little attention until recently. The interest in AKG was reheated with the increased understanding of its omnipresent role in metabolism, but even more by the hypothesis that it can impact aging and prolong lifespan. By now, the known list of organs and tissues that benefit from healthy AKG levels include:

‍

• Heart and blood vessels,
• muscles and bones,
• brain,
• liver and kidneys,
• and the gastrointestinal system.

‍

AKG in cardiovascular and metabolic conditions

‍

Employing AKG for cardiovascular conditions (especially during and after heart surgery) is one of its most ubiquitous applications. Already in the 90s, it was shown (5) that during critical cardiac conditions, AKG concentrations can become critically low, leading to a low energy state in the cells and potential myocardial injury. This led to the practice of using exogenous AKG as an accompanying preventative intervention during heart surgery.

In early clinical trials (5), researchers showed that using AKG decreases the levels of ischemic biomarkers, such as creatine kinase and troponin (regulatory proteins, involved in mitochondrial metabolism and muscle contraction). In another study by the

same authors (6), it was demonstrated that adding AKG enables better oxygen extraction and reduces lactate production, thus protecting the heart during surgery. Simultaneously, the decreased risk of cardiac injury was accompanied by improved renal function.

Though there are almost no recent clinical studies focused on the application of pure AKG as a cardioprotective agent, a body of research is dedicated to the application of AKG combined with histidine and tryptophane (HTK, histidine-tryptophane-ketoglutarate solution). A systematic review by Aldabrani (7) discusses 12 randomized clinical trials of HTK in various cardiac surgeries. All the studies show that HTK provides prolonged cardiac protection and shortens the recovery period. Though it might also be linked to the synergetic interaction of components, it shows the beneficial role of AKG for cardiac health and recovery.

As for metabolic disorders, it was shown that the use of AKG reduces plasma low-density lipoprotein and cholesterol levels in humans (8). This implies that this metabolite can downregulate hyperlipidemia (a condition that increases fatty deposits in arteries and is commonly associated with diabetes). Though there are promising animal model results for the application of AKG in diabetes (9), no studies have been yet conducted in humans. Similarly of interest is the observation that AKG is able to inhibit the development of non-alcoholic fatty liver disease in animal models (10). Still, there is no confirmation of this mechanism in humans.

‍

AKG for muscle and bone health

‍

In older adults, sarcopenia is a well-known and widespread condition characterized by a decrease in muscle mass, strength, and function. It islinked to multiple adverse outcomes, such as falls and fractures. As a sports supplement, AKG was used across multiple athletic fields (11,12) and was shown to increase muscle mass and strength. AKG is thought to prevent muscle protein breakdown through a mechanism involving prolyl hydroxylase (an enzyme regulating multiple cellular survival mechanisms, including apoptosis) (13). These muscle-preserving effects point towards the necessity of further clinical studies of AKG effects in older adults with sarcopenia.

Similarly, AKG demonstrated an ability to preserve bone health. Cell studies showed that it could upregulate transcription factors responsible for the regeneration of bone cells and promote bone structural stability. In the six-month study of post-menopausal women with osteoporosis, a daily AKG supplementation for six months significantly increased bone density by 2%. Also, patients on AKG had visibly lower levels of bone reabsorption markers. 

‍

Brain health and AKG

‍

A decrease in cognitive function is one of the most prominent signs of aging, further amplified by an increased risk of neurodegenerative disorders. AKG, a precursor to the excitatory neurotransmitter glutamate (14), might be essential in facilitating memory and neurotransmission improvement in older adults. Moreover, AKG is able to reduce oxidative stress, which has been associated with multiple neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases (15).

This points toward potential applications of AKG supplementations in older adults to promote brain health and reduce the risk of cognitive impairment. Though specialized clinical trials have not been conducted till now , early studies in patients with stroke might serve as indirect evidence of the viability of such an approach (16,17). It was shown that administration of ornithine form of AKG within 96 hours after stroke leads to a significant improvement in consciousness and lesser neurological impairment compared to placebo. Further studies are required to evaluate the neuroprotective potential of AKG.

‍

Other potential applications of AKG

‍

Despite a limited number of studies, there are indications of the role of AKG in alleviating kidney diseases in humans. As mentioned earlier, positive renal effects of AKG can be observed in patients after coronary operations (18). Similarly to other clinically applicable properties, AKG’s ability to improve renal function was primarily studied in the 80-90s; now the interest in a deeper understanding of the mechanisms is revived (19). 

Emerging evidence suggests that AKG can positively influence gut integrity, nutritional status, and maintain a healthy appetite. This is of particular importance in older adults, who frequently have malnutrition problems due to various reasons. Previously, it was shown that elderly patients receiving AKG demonstrate significant improvement in appetite and body weight compared to those without AKG (1).

AKG also has been linked to signaling pathways related to oncogenesis (20), which makes it a promising candidate for potential cancer-accompanying therapy. However, no human studies were conducted.

‍

‍

Anti-aging effect of AKG

‍

The most exciting prospect of AKG is its putative ability to slow down aging. Its ability to promote longevity was initially reported by Chin et al. (21) and has been attributed to its ability to improve protein metabolism and synthesis and its effects on the mTOR pathway. Combined with its known effects in age-related diseases, implying its use as a longevity enhancer.

Currently, only a single retrospective study of the anti-aging effects of AKG was exists (22). A total of 42 healthy adults aged 45 to 65 were taking AKG in the form of Rejuvant®. Rejuvant® is a commercial formulation of AKG, which includes vitamin A for women and vitamin D for men. This product provides sustained release of the AKG during a prolonged time. The participants were taking Rejuvant® for seven months, after which period their biological age was measured using the TruAge DNA methylation test. 

The randomized clinical trial, which is a logical continuation of the previous study, is currently in progress at the University of Singapore (23) and is being conducted by Professor Brian Kennedy and his group. This randomized clinical trial includes 300 individuals and placebo control. As well as biological age, multiple biomarkers are going to be measured to robustly estimate the effects of AKG supplementation on aging. 

‍

Conclusions

‍

AKG is a uniquely multi-functional molecule, which was extensively researched and abandoned for over a decade. Hopefully, the revived interest will spark more clinical studies, which are urgently needed for its many applications. The most promising and intriguing effect is AKG’s ability to sustain health and prolong the lifespan, which makes it one of the central molecules in the current longevity research.

‍

References 

‍

1. Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Goh J, et al. Alpha-Ketoglutarate dietary supplementation to improve health in humans. Trends Endocrinol Metab. 2022 Feb;33(2):136–46.
2. Xiao D, Zeng L, Yao K, Kong X, Wu G, Yin Y. The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications. Amino Acids. 2016 Sep;48(9):2067–80.
3. Donati L, Ziegler F, Pongelli G, Signorini M. Nutritional and clinical efficacy of ornithine alphaketog-ketoglutaratein severe burn patients. Clin Nutr. 1999 Oct;18(5):307–11.
4. Cynober LA. The use of α-ketoglutarate salts in clinical nutrition and metabolic care: Curr Opin Clin Nutr Metab Care. 1999 Jan;2(1):33–7.
5. Kjellman U, Björk K, Ekroth R, Karlsson H, Nilsson F, Svensson G, et al. α-ketoglutarate for myocardial protection in heart surgery. The Lancet. 1995 Mar;345(8949):552–3.
6. Kjellman UW, Björk K, Ekroth R, Karlsson H, Jagenburg R, Nilsson FN, et al. Addition of α-Ketoglutarate to Blood Cardioplegia Improves Cardioprotection. Ann Thorac Surg. 1997 Jun;63(6):1625–33.
7. Albadrani M. Histidine–tryptophan–ketoglutarate solution versus multidose cardioplegia for myocardial protection in cardiac surgeries: a systematic review and meta-analysis. J Cardiothorac Surg. 2022 Dec;17(1):133.
8. 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 Off J Pol Physiol Soc. 2008 Aug;59 Suppl 1:91–106.
9. Yuan Y, Zhu C, Wang Y, Sun J, Feng J, Ma Z, et al. α-Ketoglutaric acid ameliorates hyperglycemia in diabetes by inhibiting hepatic gluconeogenesis via serpina1e signaling. Sci Adv. 2022 May 6;8(18):eabn2879.
10. Nagaoka K, Mulla J, Cao K, Cheng Z, Liu D, William Mueller, et al. The metabolite, alpha-ketoglutarate inhibits non-alcoholic fatty liver disease progression by targeting lipid metabolism. Liver Res. 2020 Jun;4(2):94–100.
11. Gatterer H, Böcksteiner T, Müller A, Simi H, Krasser C, Djukic R, et al. 5-Hydroxymethylfurfural and Alpha-Ketoglutaric Acid as an Ergogenic Aid During Intensified Soccer Training: A Placebo Controlled Randomized Study. J Diet Suppl. 2020 Mar 3;17(2):161–72.
12. Kaczka P, Kubicka K, Batra A, Maciejczyk M, Kopera E, Bira J, et al. Effects of Co-Ingestion of β-Hydroxy-β-Methylbutyrate and L-Arginine α-Ketoglutarate on Jump Performance in Young Track and Field Athletes. Nutrients. 2021 Mar 25;13(4):1064.
13. Cai X, Yuan Y, Liao Z, Xing K, Zhu C, Xu Y, et al. α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway. FASEB J. 2018 Jan;32(1):488–99.
14. Tapiero H, Mathé G, Couvreur P, Tew KD. II. Glutamine and glutamate. Biomed Pharmacother Biomedecine Pharmacother. 2002 Nov;56(9):446–57.
15. Liu S, He L, Yao K. The Antioxidative Function of Alpha-Ketoglutarate and Its Applications. BioMed Res Int. 2018;2018:3408467.
16. Woollard ML, Pearson RM, Dorf G, Griffith D, James IM. Controlled trial of ornithine alpha ketoglutarate (OAKG) in patients with stroke. Stroke. 1978 May;9(3):218–22.
17. Geeganage C, Bath PM. Vasoactive drugs for acute stroke. Cochrane Stroke Group, editor. Cochrane Database Syst Rev [Internet]. 2010 Jul 7 [cited 2022 Oct 21]; Available from: https://doi.wiley.com/10.1002/14651858.CD002839.pub2
18. Jeppsson A, Ekroth R, Friberg P, Kirnö K, Milocco I, N. Nilsson F, et al. Renal Effects of α-Ketoglutarate Early After Coronary Operations. Ann Thorac Surg. 1998 Mar;65(3):684–90.
19. Guo L, Chen S, Ou L, Li S, Ye ZN, Liu HF. Disrupted Alpha-Ketoglutarate Homeostasis: Understanding Kidney Diseases from the View of Metabolism and Beyond. Diabetes Metab Syndr Obes Targets Ther. 2022 Jun;Volume 15:1961–74.
20. Raimundo N, Baysal BE, Shadel GS. Revisiting the TCA cycle: signaling to tumor formation. Trends Mol Med. 2011 Nov;17(11):641–9.
21. Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014 Jun;510(7505):397–401.
22. 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. 2021 Nov 30;13(22):24485–99.
23. Centre for Healthy Longevity [Internet]. Available from: https://coe.nuhs.edu.sg/Centre-for-Healthy-Longevity/Pages/What%20We%20Do.aspx

‍