Alpha-ketoglutarate (Calcium AKG)

(This article is for educational purposes only and does not constitute medical advice. Lithium can interact with medications and is not appropriate for everyone. Do not start, stop, or change any treatment without talking to your healthcare professional.)

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Following the publication of my new book Nutritional Epigenetics, several people have asked me about alpha-ketoglutarate (AKG), a molecule to which I devote a section within the chapter on molecules and nutrients that activate tumor-suppressor genes.

I’ve been surprised that this molecule has sparked more interest than other supplements. It’s true that in the book I analyze its epigenetic role—how it boosts the activity of genes that protect against cancer, stabilizes the genome, keeps cells healthy, and prevents the uncontrolled proliferation typical of tumors. However, I also examine other compounds with similar functions.

I think the curiosity AKG inspires comes from its unusual name and the fact that it isn’t as well known as other nutrients I also discuss in the book, such as curcumin, vitamin D, omega-3 fatty acids, selenium, green tea catechins, or the butyrate produced by our microbiota.

I’ll use this space on the blog to delve deeper into it—a compound with great potential that deserves more attention. Its impact on health and epigenetics isn’t limited to cancer protection, since recent studies in humans suggest it may also reduce biological age, improving a wide range of health markers that we’ll examine later.

Let’s start at the beginning.

What is alpha-ketoglutarate?

AKG is a natural compound produced by our bodies that plays a key role in energy production.

I’ll try to explain it simply.

Our cells need the calories in food (”fuel”: potential energy) to turn them into ATP (usable energy) so they can function—just as a traditional combustion-engine car needs gasoline to “burn” it, transform it into energy, and move.

In cells, this transformation takes place inside the mitochondria through a series of steps known as the Krebs cycle. In this process, different molecules work together, turning into one another like parts of a complex machine. AKG is one of those key parts.

For example, in this cycle, a molecule called isocitrate is converted into AKG, and AKG, in turn, becomes succinyl-CoA. In both steps, NADH is generated—an essential molecule that acts like a “delivery truck.”

NADH carries chemical energy (electrons) from the molecules in food to the final stage of the process, where ATP is generated. Without NADH, ATP production in the mitochondria would be impossible. In other words, without AKG there would be no NADH, and the process would grind to a halt, leaving our cells without the energy they need to perform their functions.

In short:

Calories are the raw material—the “fuel.” Just as burning gasoline generates mechanical energy to move a vehicle, the calories in food, through metabolic processes like the Krebs cycle (where AKG is indispensable), produce ATP. ATP is the form of energy our cells use to sustain essential activities such as breathing, moving, and thinking.

Benefits of AKG for human health and aging

Beyond its fundamental role in cellular energy production—which is essential for life—and in improving mitochondrial function, AKG performs other important functions with a significant impact on health and aging. Let’s look at them.

Epigenetic function: activation of tumor-suppressor genes and enhanced cellular self-renewal

AKG influences gene expression by serving as a substrate for TET dioxygenases. These enzymes require AKG to remove chemical marks from DNA and histones, a process that helps reactivate key genes, such as tumor-suppressor genes.

As a consequence of this process, AKG also helps stem cells maintain their ability to become different cell types—that is, it allows them to retain a more primitive, flexible state, increasing their “versatility.” This effect is particularly important in:

Tissue regeneration and cellular repair, speeding recovery after injuries and during wound healing.
Cellular rejuvenation, by restoring functions in aged cells and helping them regain a younger, more functional profile.

Antioxidant protection and reduction of oxidative stress

AKG acts as an antioxidant by neutralizing reactive oxygen species (ROS, also known as “free radicals”), reducing the damage these molecules can cause to cells and tissues. This effect is especially relevant in organs and systems with high metabolic demand, such as the mitochondria, and is key to delaying cellular degeneration.

In addition, AKG stimulates the production of glutathione, one of the body’s most powerful antioxidants, helping protect cells from oxidative damage and promoting longevity.

Reduction of inflammation

AKG can attenuate excessive inflammatory responses in the body by regulating the activity of certain molecules associated with inflammation. This effect is particularly useful in conditions such as chronic diseases or situations of cellular stress.

Anti-aging effect and reduction of biological age

AKG influences biological processes related to aging, helping to extend both lifespan and quality of life in studies conducted in mice and humans. This effect stems from the mechanisms already mentioned: improved mitochondrial function, reduced systemic inflammation and oxidative stress, and lower cellular senescence—all key aspects of the aging process.

Support for gut health

AKG can help improve gut health by serving as an energy source for the cells lining the digestive tract. This strengthens the intestinal barrier, helping prevent problems such as inflammation and infections.

Stimulation of collagen synthesis and protection against degenerative joint diseases

AKG plays a crucial role in the formation of collagen, an essential protein for the skin, bones, and connective tissues. This helps maintain skin elasticity, bone strength, and cartilage integrity.

In the context of osteoarthritis, AKG helps restore the cartilage matrix, inhibiting collagen degradation and promoting the synthesis of new tissue. It also downregulates inflammatory pathways, which reduces inflammation and minimizes damage associated with senescence in cartilage cells.

Improved bone health

AKG contributes to bone health by regulating calcium levels within cells, showing benefits for bone density—especially in cases of age-related bone loss or conditions such as osteoporosis. In addition, this compound promotes the activity of the cells responsible for bone regeneration, helping maintain stronger, healthier bones.

Promotion of skin hydration and barrier function

AKG stimulates the proliferation of keratinocytes, the main cells of the epidermis. It also regulates key genes such as:

Filaggrin, an essential protein for forming the skin barrier and retaining water in the skin.
Serine palmitoyltransferase, involved in the synthesis of epidermal lipids that are fundamental for keeping the skin hydrated.
Involucrin, a protein that reinforces the structure of the epidermis.

These processes strengthen the skin barrier—making it more resistant to external aggressors—improve water retention, and help maintain skin that is hydrated, smooth, flexible, and firm.

In addition, clinical studies with AKG-containing creams have shown a reduction in wrinkles and improvements in skin texture and elasticity after continued use.

Improved oocyte quality and fertility

AKG helps reduce oxidative damage in aged oocytes by lowering reactive oxygen species (ROS). Over time, oocytes tend to lose the ability to divide correctly; in this regard, AKG also supports proper spindle assembly—the egg’s internal machinery that controls its cell division.

Both processes are fundamental to ensuring that oocytes and future eggs maintain high quality and viability. This benefit has been studied in aged mice, where an increase in ovarian reserve and an improvement in early embryonic development were observed. These properties suggest that AKG could be a promising tool to preserve fertility in older women or younger women with difficulties.

Other

Kidney: Regulates acid–base balance in the renal tubules and improves kidney function.
Liver: Reduces ammonia levels and maintains nitrogen and protein balance.
Heart and blood vessels: Prevents ischemic injury in the myocardium and reduces plasma levels of low-density lipoproteins and cholesterol.
Brain: Reduces oxidative neuronal damage and increases oxygen and glucose utilization in response to cerebral hypoxia.
Muscles: Reduces muscle protein breakdown, increases strength and endurance, reduces fatigue, improves skeletal muscle regeneration (especially after injuries), and mitigates atrophy.

Supplementation

The main source of AKG in our bodies is endogenous production within the mitochondria during the Krebs cycle, as we mentioned at the beginning.

To a lesser extent, it can also be obtained indirectly through the diet. Although foods don’t contain it in its pure form, it can be formed from precursors present in protein-rich foods, as well as in tomatoes, mushrooms, pumpkin seeds, spinach, and kale (curly kale). In addition, it can be synthesized from the amino acid glutamate.

However, alpha-ketoglutarate levels decline with age as cellular metabolism becomes less efficient. This reduction contributes to the energy and functional decline associated with aging. For this reason, AKG supplementation is a very interesting option to maintain its levels in the body and slow this age-related loss.

Type of supplement

The most widely used and studied supplement—and the molecule I’ve been discussing in this article—is calcium alpha-ketoglutarate (CaAKG).

Do NOT confuse it with:

– Arginine alpha-ketoglutarate (AAKG): a vasodilator, purportedly useful for athletic performance.
– Ornithine alpha-ketoglutarate (OKG): anticatabolic, used after surgeries and in burn patients to support wound healing, etc.

These three are different molecules with different purposes.

Daily dose

The recommended dose is 2 to 4 grams per day. It’s best to split the dose into 2–4 doses.

Precautions and side effects

The reviewed studies indicate that AKG is safe for consumption and does not show significant adverse effects at the doses investigated, both in animal models and in human trials. In healthy individuals, studies suggest a favorable safety profile even at high doses. However, as with any supplement, it is essential not to exceed the recommended doses.

Pregnancy and breastfeeding

Following the precautionary principle, it is recommended that pregnant or breastfeeding women avoid AKG supplementation until there is stronger scientific evidence supporting its safety in these groups.

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