alpha-ketoglutarate for longevity and healthspan

Alpha-ketoglutarate for longevity

Alpha-ketoglutarate is a key molecule produced in your cells. Recently, research studies have shown that it may play a key role in healthy aging, including increasing healthspan and lifespan.

What is alpha-ketoglutarate?

Alpha-ketoglutarate (αKG) is a molecule that cells produce. It has several important functions in the body:[ref]

  • It is involved in the Krebs cycle for energy production
  • αKG is important in epigenetic regulation of the production of other molecules in the cells
  • It is involved in stem cell proliferation and formation of bone cells
  • αKG is important in regulating inflammation

All of these come together as essential in preventing the diseases of aging.

The key, before we get further into the science, is that αKG (alpha-ketoglutarate) levels are decreased in aging. In fact, there is a 10-fold decrease in αKG between ages 40 and 80.[ref]

ΑKG in Energy Production via the Krebs Cycle:

The Krebs cycle is part of the process for creating cellular energy in the mitochondria.

Quick background: Mitochondria are organelles within cells that can create ATP from either sugar or fats. Each cell can have hundreds to thousands of mitochondria, depending on the need for cellular energy. ATP (adenosine triphosphate) is the molecule that is produced in cells to store energy. The ATP bonds can easily be broken to release energy whenever and wherever it is needed inside the cells. No ATP, no energy = no life

Important here is that the alpha-ketoglutarate produced in the Krebs cycle can be used for ATP, or it can cross out of the mitochondria and be used elsewhere. Alpha-ketoglutarate can also be used by the cells to make glutamine, which can be used as a neurotransmitter.[ref]

Epigenetics: alpha-ketoglutarate and DNA methylation

TET proteins and αKG are important in methylation

Centenarians, people living to 100+, have differences in their DNA methylation. Essentially, methylation is one way that cells can turn off or on different processes.

The processes needed to be kept switched on in aging include the sirtuins, DNA repair enzymes, insulin signaling pathways, FOXO genes, telomere extension, and cellular antioxidants that decrease oxidative damage.

Alpha-ketoglutarate levels impact the transcription of the FOXO genes. This is the same pathway that calorie restriction impacts for extending lifespan. αKG is also a cofactor for DNA and histone demethylation enzymes.[ref]

Research studies on alpha-ketoglutarate

OK, so αKG is important for cellular energy production – and – it is necessary for DNA methylation regulation. Additionally, αKG decreases a bunch as we age.

What happens if we correct the decrease in αKG that naturally happens with aging?

Supplementing alpha-ketoglutarate increases lifespan in animals (mice, worms). This has been known for a decade or so. Researchers using C. elegans found that increasing αKG extended the lifespan of the animal.[ref]

A recent study in mice showed that alpha-ketoglutarate extended lifespan of about 10%. More importantly, though, it significantly improved healthspan.[ref]

Healthspan is the years that you remain healthy in aging. The last few years of life are often plagued with frailty, dementia, and severe chronic disease — healthspan is the time during aging when someone remains healthy.

The trial showed that the mice had less time where they were frail or had diseases of aging at the end of life.

How does alpha-ketoglutarate increase healthspan?

Supplementing with αKG, starting at mid-life and beyond, may increase energy production in the mitochondria and positively impact DNA methylation.

  • Animal research shows αKG supplementation prevented the increase in cytokine levels that are normally associated with aging in female mice.[ref]
  • αKG reduces the senescent cell inflammatory signaling, which is the problem with cellular senescence in aging.
  • Supplemental αKG induces the browning of fat in mice.
  • A positive effect on macrophages and shifting towards anti-inflammatory type was noted with αKG.
  • Giving female animals αKG during their reproductive years preserves ovarian function.

Suppressing inflammation: One of the causes of aging is an increase in chronic inflammation. The research on αKG in mice showed that female T-cells cells produce higher IL-10 (an anti-inflammatory molecule) with supplementation. The researchers theorize this is one of the main ways that frailty was reduced in the animals.[ref]

Reducing senescence phenotype: While αKG doesn’t clear out senescent cells, it does reduce the negative aspect of cellular senescence: constantly increased inflammation.[ref]

Brown fat: One reason, among many for increased inflammation in aging, is the alterations to adipocytes (fat tissue). As we age, fat cell turnover decreases, and existing fat cells become more dysfunctional and give off inflammatory cytokines.[ref]

A positive aspect of αKG is that it may cause white adipose tissue (fat) to become beige or brown fat. Brown fat is the good fat. It contains lots of mitochondria, causing it to look ‘brown’ under a microscope. These mitochondria are producing heat, burning off excess fat.

Mouse studies show that increasing αKG through supplementation increases the “beige-ing” or browning of fat.[ref] In aging, DNA methylation is involved in the reduction of brown fat. Thus αKG may be impacting fat storage, energy production, and inflammation via the positive methylation changes.

Macrophages and inflammation: One component of the immune system is a cell type called macrophages. Dual purposed immune cells, macrophages can either become pro-inflammatory (M1) or anti-inflammatory (M2). Higher levels of inflammatory cytokines, such as TNF-alpha or interferon-gamma, cause macrophages to activate to an M1 (inflammatory) type. Higher levels of alpha-ketoglutarate, though, can promote the MT anti-inflammatory type of macrophage.[ref]

Reproductive years extended: Animal research shows that αKG extends the time that the animals are fertile. One reason for this was that αKG prevented the shortening of telomeres in the ovaries.[ref]

Why would this be important in aging? For women, many of the deleterious effects of aging occur with the decrease in estrogen after menopause.

Osteoporosis and alpha-ketoglutarate:

αKG promotes bone development in animal studies and in a study of postmenopausal women. One way that αKG impacts bone strength is through producing needed proteins for the type of collagen found in bones. Another way is via regulating histone methylation of genes involved in bone formation.[ref]

Human clinical trials on alpha-ketoglutarate

You’ll notice that the above trials are all in animals. While animal research is great for finding an effect on longevity in short-lived animals, it doesn’t always correlate to the same effect in humans.

And honestly, who cares about mice living longer…

Currently, there are no longevity trials in humans for αKG. So we really can’t know the effect of αKG on aging in humans. Instead, we can look at the trials that have been done — mostly on athletes to see if αKG could enhance performance.

Male athletes training with low oxygen (e.g. high altitude) were given alpha-ketoglutarate as a supplement. The supplement didn’t change athletic performance, but it did improve blood oxygen levels.[ref]

Male athletes (ages 30-50) were given arginine alpha-ketoglutarate supplement 3 times per day for a total of 12 g/day. The results showed some improvement in specific exercises, such as bench press. Importantly, it was well-tolerated and safe.[ref]

Another trial of male athletes found that 12g/day of arginine alpha-ketoglutarate had little effect on nitric oxide or blood flow.[ref]

To me, the trials on well-trained, fairly young male athletes weren’t all that impressive, but they likely already had sufficient alpha-ketoglutarate levels due to age and athletic training.

Supplementing with αKG

My first question on a supplement is always “Is it safe”.

The answer is going to be different for each individual, but the FDA considers alpha-ketoglutarate as “GRAS” or generally regarded as safe.

When it comes to supplements for longevity, I also always want to think about whether they can promote the growth of cancer. The answer here is that alpha-ketoglutarate has several anticancer properties including blocking the formation of new blood vessels for tumors.[ref]

αKG is not readily available in the diet, at least not at significant levels. Thus, the effects seen in clinical trials are at levels found in supplements.

Supplements of alpha-ketoglutaric acid are available in capsules. Ornithine alpha-ketoglutarate is also available. Shop around to find your favorite brand or reviews that you’re comfortable with.

A commonly used bodybuilding supplement, arginine plus alpha-ketoglutarate is available in powdered form, which is more economical for higher doses. Arginine boosts nitric oxide and theoretically improves workouts (studies aren’t great there). The flavor is mild and it easily mixes into a beverage or smoothie.

Ornithine alpha-ketoglutarate is also available as a powder. (I haven’t tried it, so I can’t comment on the flavor or ease of dissolving.)

Other ways of increasing αKG

There are a few diet and lifestyle hacks that can increase your endogenous production of alpha-ketoglutarate:

  • ketogenic diet[ref]
  • metformin, a commonly used diabetes drug, increases alpha-ketoglutarate in clinical trials[ref]

Side effects of αKG, supplement interactions

Supplements that contain arginine plus αKG may decrease your blood pressure. Be sure to check the interaction with blood pressure medications.

If you are using arginine plus αKG: check for interactions with blood thinners, erectile dysfunction, nitrates, anticoagulants, diabetes medications.

Conclusion:

While the human trials for longevity are non-existent, the safety profile for alpha-ketoglutarate seems good. The questions remain, though, as to what levels of supplementation are needed to achieve increases in healthspan.


References:

Asadi Shahmirzadi, Azar, et al. “Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.” Cell Metabolism, vol. 32, no. 3, Sept. 2020, pp. 447-456.e6. PubMed, doi:10.1016/j.cmet.2020.08.004.
—. “Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.” Cell Metabolism, vol. 32, no. 3, Sept. 2020, pp. 447-456.e6. PubMed, doi:10.1016/j.cmet.2020.08.004.
Campbell, Bill, et al. “Pharmacokinetics, Safety, and Effects on Exercise Performance of L-Arginine Alpha-Ketoglutarate in Trained Adult Men.” Nutrition (Burbank, Los Angeles County, Calif.), vol. 22, no. 9, Sept. 2006, pp. 872–81. PubMed, doi:10.1016/j.nut.2006.06.003.
Chitalia, Vipul. “α-Ketoglutarate-A New Currency of Longevity.” Science Translational Medicine, vol. 6, no. 244, July 2014. PubMed Central, doi:10.1126/scitranslmed.3009803.
Cuyàs, Elisabet, et al. “Metformin Induces a Fasting- and Antifolate-Mimicking Modification of Systemic Host Metabolism in Breast Cancer Patients.” Aging, vol. 11, no. 9, May 2019, pp. 2874–88. PubMed, doi:10.18632/aging.101960.
Kössler, Florian, et al. “5-Hydroxymethylfurfural and α-Ketoglutaric Acid Supplementation Increases Oxygen Saturation during Prolonged Exercise in Normobaric Hypoxia.” International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- Und Ernahrungsforschung. Journal International De Vitaminologie Et De Nutrition, vol. 91, no. 1–2, Jan. 2021, pp. 63–68. PubMed, doi:10.1024/0300-9831/a000606.
Liu, Shaojuan, et al. “The Regulatory Role of α-Ketoglutarate Metabolism in Macrophages.” Mediators of Inflammation, vol. 2021, Mar. 2021. PubMed Central, doi:10.1155/2021/5577577.
Mancuso, Peter, and Benjamin Bouchard. “The Impact of Aging on Adipose Function and Adipokine Synthesis.” Frontiers in Endocrinology, vol. 10, Mar. 2019. PubMed Central, doi:10.3389/fendo.2019.00137.
Sharma, Rishi, and Arvind Ramanathan. “The Aging Metabolome—Biomarkers to Hub Metabolites.” Proteomics, vol. 20, no. 5–6, Mar. 2020. PubMed Central, doi:10.1002/pmic.201800407.
Tian, Qiyu, et al. “Dietary Alpha‐ketoglutarate Promotes Beige Adipogenesis and Prevents Obesity in Middle‐aged Mice.” Aging Cell, vol. 19, no. 1, Jan. 2020. PubMed Central, doi:10.1111/acel.13059.
Wells, Jana, et al. “Efficacy and Safety of a Ketogenic Diet in Children and Adolescents with Refractory Epilepsy—A Review.” Nutrients, vol. 12, no. 6, June 2020. PubMed Central, doi:10.3390/nu12061809.
Willoughby, Darryn S., et al. “Effects of 7 Days of Arginine-Alpha-Ketoglutarate Supplementation on Blood Flow, Plasma L-Arginine, Nitric Oxide Metabolites, and Asymmetric Dimethyl Arginine after Resistance Exercise.” International Journal of Sport Nutrition and Exercise Metabolism, vol. 21, no. 4, Aug. 2011, pp. 291–99. PubMed, doi:10.1123/ijsnem.21.4.291.
Zdzisińska, Barbara, et al. “Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use.” Archivum Immunologiae et Therapiae Experimentalis, vol. 65, no. 1, 2017, pp. 21–36. PubMed Central, doi:10.1007/s00005-016-0406-x.
—. “Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use.” Archivum Immunologiae et Therapiae Experimentalis, vol. 65, no. 1, 2017, pp. 21–36. PubMed Central, doi:10.1007/s00005-016-0406-x.
Zhang, Zhenzhen, et al. “Α‐ketoglutarate Delays Age‐related Fertility Decline in Mammals.” Aging Cell, vol. 20, no. 2, Feb. 2021. PubMed Central, doi:10.1111/acel.13291.