Calcium Alpha-Ketoglutarate: Support Bone, Muscle, and Heart Health Over 40

Reviewed and Updated By: Emily Parsell, RDN

Our body’s metabolic function tends to decline with age, as we become less able to efficiently extract nutrients from food and turn them into the energy that fuels cellular activity. There are dozens of compounds involved in facilitating these food-to-fuel processes — including alpha-ketoglutarate (AKG). AKG is most known for its role in stimulating energy production, as it is a vital component of the Krebs cycle — a series of reactions that creates ATP (energy) from the foods we eat (1).

However, the compound also has wide-ranging purported biological functions, including its connection to supporting cardiovascular, bone, brain, and metabolic health. Additionally, AKG functions as an antioxidant and may help the body to fight free radical damage. Although AKG is created naturally in the body, its production tends to diminish with age, with levels reported to drop by 10-fold between the ages of 40 and 80 (2). 

In supplement form — the only available oral route, as the compound is not found in food — AKG can be attached to a calcium salt (Ca-AKG), which has been studied for its role in supporting metabolic function and longevity (1). Let’s take a closer look at how this compound may help support the aging process and a longer healthspan, or the years of life lived healthfully.

1. Ca-AKG’s Link to Longevity

Ca-AKG facilitates our internal recycling process known as autophagy, which removes dysfunctional cells, cell parts, and proteins from the body. Autophagy tends to decrease with age — and may play a role in accelerated aging when it diminishes — so Ca-AKG may be able to help support a healthier aging process (3).

Ca-AKG may also support longevity because the compound activates AMP-activated protein kinase (AMPK) — a pathway that senses and maintains cellular energy balance by supporting the function of our cells’ main energy hubs (the mitochondria) and healthy blood sugar control (3). 

A study published in Cell Metabolism found that mice who received supplemental Ca-AKG had improvements in their health and lifespan, which was extended by about 12%.  (1). 

There is also evidence that AKG supports longer lifespans in shorter-lived species, as seen by a 50% longevity boost in roundworms (C. elegans) and a 15% increase in maximum lifespan in fruit flies (D. melanogaster) (4, 5). However, although the data with animals is robust, we don’t yet know if the same results would apply to the human lifespan.

2. AKG’s Antioxidant Action on Aging

Oxidative stress — the buildup of inflammatory compounds (reactive oxygen species [ROS] and free radicals) that damage cells and DNA — is a known contributor to the aging process and impaired cellular functioning. 

AKG acts as an antioxidant by directly reacting with certain ROS, like ammonia and hydrogen peroxide, to neutralize the damaging compounds (6). Another pathway by which AKG helps to reduce oxidative stress is through its role as a precursor to the amino acid glutamate, which converts into glutathione — our body’s most potent antioxidant.

Ca-AKG has been shown to boost cellular antioxidant levels in aged mice, as supplementation with this compound significantly increased their total antioxidant status and lowered levels of oxidative damage (7).

3. Supports Bone and Muscle Health Over 40

AKG stimulates protein synthesis because the compound is a precursor to several essential amino acids — the building blocks of proteins. Notably, over 25% of dietary AKG is converted into the amino acids proline and glutamine, which are substrates for the synthesis of collagen — the fibrous protein that makes up one-third of all protein in the human body, helping to support bone, skin, and muscle health (3). 

As muscle and bone strength tend to decline with age, Ca-AKG may be able to help support their function in adults over 40 by inhibiting protein degradation in muscle, enhancing bone tissue formation, and reducing protein breakdown (3).

A 2020 study published in Nature Communications found that supplementing aged mice with AKG led to increased bone mass and regeneration, with a reduction in age-related bone loss. Although we don’t know for sure if this study would translate to humans, the results in animals are promising for supporting healthy bone and muscle structure with age. Plus, the addition of calcium in Ca-AKG may support bone health even more than AKG alone, as it’s well-known that calcium builds and protects bones (8).

4. Supports Brain and Heart Health with Age

Lastly, Ca-AKG may help to support heart and brain health with age. This is partly due to its status as an antioxidant, as oxidative stress is a leading cause of damage and dysfunction to these organs. 

One study found that supplemental Ca-AKG supported aged mice’s blood vessel elasticity — a measure of good cardiovascular health (7). Similarly, a 2018 study looked at how AKG administration affected markers of heart and brain health in mice with cardiovascular damage. The researchers found that AKG helped fight oxidative stress and free radicals, which correlated with better biomarkers of heart structure and function and supported cognitive activity (9). 

Key Takeaways: 

• Ca-AKG is an essential intermediate compound for energy production, cellular metabolism, and protein synthesis. 
• Studies with Ca-AKG have found the compound to support longer lifespans and healthspans in animals, including the delay of age-related frailty. 
• AKG also acts as an antioxidant and may support bone, muscle, metabolic, and brain health with age. 
• Although the majority of studies with Ca-AKG have been done with animals, research with humans has found the compound to be safe for human consumption without producing noticeable adverse effects. 

References: 

1. Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab. 2020;32(3):447-456.e6. doi:10.1016/j.cmet.2020.08.004
2. 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;59 Suppl 1:91-106. doi:
3. Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D. Alpha-Ketoglutarate: Physiological Functions and Applications. Biomol Ther (Seoul). 2016;24(1):1-8. doi:10.4062/biomolther.2015.078
4. Chin R, Fu X, Pai M., et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510:397–40. https://doi.org/10.1038/nature13264
5. Su Y, Wang T, Wu N, et al. Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging (Albany NY). 2019;11(12):4183-4197. doi:10.18632/aging.102045
6. Liu S, He L, Yao K. The Antioxidative Function of Alpha-Ketoglutarate and Its Applications. Biomed Res Int. 2018;2018:3408467. Published 2018 Mar 21. doi:10.1155/2018/3408467
7. Niemiec T, Sikorska J, Harrison A, et al. Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice. J Physiol Pharmacol. 2011;62(1):37-43.
8. Wang Y, Deng P, Liu Y, et al. Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations. Nat Commun. 2020;11(1):5596. Published 2020 Nov 5. doi:10.1038/s41467-020-19360-1
9. Tkachenko V, Kovalchuk Y, Bondarenko N, Bondarenko О, Ushakova G, Shevtsova A. The Cardio- and Neuroprotective Effects of Corvitin and 2-Oxoglutarate in Rats with Pituitrin-Isoproterenol-Induced Myocardial Damage. Biochem Res Int. 2018;2018:9302414. Published 2018 Sep 3. doi:10.1155/2018/9302414