In May, a review article titled "Mitochondria at the Crossroads of Health and Disease" was published in the journal Cell by researchers from Finland and the USA. This article systematically discussed the critical role of mitochondria in human health and disease. Following this, in June, an article on cellular senescence markers in Nature Reviews Molecular and Cell Biology highlighted mitochondrial dysfunction as a key feature of cellular aging.
Mitochondria play a crucial role in energy conversion, providing power for various cellular activities. Today’s spotlight is on an essential player in the mitochondrial energy conversion process – Alpha-Ketoglutarate (AKG).
nature
What is AKG?
AKG, or Alpha-Ketoglutarate, is a critical intermediate in the tricarboxylic acid (TCA) cycle, vital for cellular energy metabolism. It plays a key role in various metabolic pathways. In the TCA cycle, AKG is decarboxylated by AKG dehydrogenase to form succinyl-CoA and CO2, serving as a rate-limiting intermediate. Additionally, AKG is produced from isocitrate by isocitrate dehydrogenase (IDH) and can be generated from glutamate via oxidative deamination by glutamate dehydrogenase.
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As we age, AKG levels decline, making dietary supplementation necessary. Studies show that AKG absorption is optimal in the upper part of the small intestine. Its absorption is enhanced by low pH, Fe2+, and SO4 2- ions. AKG is quickly metabolized in the liver and cells, with over 60% of intestinal AKG crossing the gut in various forms, not completely oxidized to glutamine and glutamate. In intestinal cells, AKG is converted into proline, leucine, and other amino acids.
AKG for Athletic Support
As a precursor to glutamine and glutamate, AKG is a central metabolic fuel for gastrointestinal cells. Research indicates that glutamine and arginine can indirectly convert to AKG, regulating gut innate immunity through multiple signaling pathways and gut microbiota modulation in mouse models. AKG can also reduce protein catabolism and increase protein synthesis, promoting skeletal muscle and bone tissue formation, making it useful in clinical applications. For instance, Arginine Alpha-Ketoglutarate (AAKg) increases nitric oxide production, leading to vasodilation and enhanced muscle formation during resistance training. Studies also show that AKG therapy can help maintain bone mass and reduce bone turnover in postmenopausal women.
The Anti-Aging Potential of AKG
The journey of AKG as an anti-aging substance began in 2014 when a Nature study revealed that AKG could extend the lifespan of adult Caenorhabditis elegans by approximately 50%. This study opened the door to extensive research on AKG's anti-aging properties.
In 2019, a study published in Aging found that AKG could extend the lifespan of fruit flies by inhibiting mTOR and activating AMPK. In 2020, two articles in Cell Metabolism demonstrated that supplementing middle-aged mice with calcium alpha-ketoglutarate (CaAKG) improved their survival rate, reduced disease incidence, and decreased frailty. Additionally, it inhibited chronic inflammation in female mice and induced T cells to secrete IL-10, which negatively correlates with age.
In 2021, Aging published a retrospective analysis on AKG supplementation (primarily CaAKG), analyzing DNA methylation age in 42 individuals (28 men and 14 women, average age of 63) who took AKG supplements for an average of 7 months. The results showed an average biological age reduction of 8 years.
Regulatory Status of AKG
In the USA, AKG is FDA-approved for use as a dietary supplement. In China, AKG is listed as an allowed food additive in the GB 2760-2024 standard, making it a unique anti-aging supplement ingredient that is permitted for use.
While human clinical trials on AKG's anti-aging effects are still limited, its potential as an emerging star in anti-aging continues to grow, promising exciting developments in the future.
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Reference:
[1] Hee Chan Yoo, Ya Chun Yu, Yulseung Sung, Jung Min Han. (2020). Glutamine reliance in cell metabolism. Experimental & Molecular Medicine. 52:1496–1516.
[2] Dulaney, M. D., Jr, Brumley, M., Willis, J. T., & Hume, A. S. (1991). Protection against cyanide toxicity by oral alpha-ketoglutaric acid. Veterinary and human toxicology, 33(6), 571–575.
[3] Timothy W. Rhoads,Rozalyn M. Anderson.(2020). Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice. Cell Metab. 32(3): 323–325.
[4] Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao. (2020). Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metabolism.32(3):447–456.
[5] Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, Diep S, Lomenick B, Meli VS, Monsalve GC.(2014). The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 510:397–401.
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Post time: Aug-05-2024
