Research suggests that alpha-ketoglutarate supplementation may have anti-aging properties by influencing several cellular processes. Some studies indicate that it can modulate mitochondrial function, increase the activity of enzymes involved in DNA repair, and regulate the activity of certain signalling pathways associated with longevity.
One study published in the journal Cell Metabolism in 2014 demonstrated that dietary supplementation with alpha-ketoglutarate extended the lifespan of C. elegans, a commonly used model organism in aging research. This effect was attributed to its ability to mimic caloric restriction, a well-known intervention that extends lifespan in various species.
Moreover, alpha-ketoglutarate has been shown to enhance the function of stem cells, which play crucial roles in tissue regeneration and repair. By promoting the maintenance of healthy stem cell populations, alpha-ketoglutarate may contribute to the preservation of tissue integrity and function during aging.
However, while these findings are promising, further research is needed to fully understand the mechanisms underlying the potential anti-aging effects of alpha-ketoglutarate and to determine its safety and efficacy in humans. Clinical trials are ongoing to investigate its therapeutic potential in age-related conditions and diseases.
In summary, alpha-ketoglutarate shows promise as a potential anti-aging intervention due to its effects on cellular metabolism, DNA repair, stem cell function, and lifespan extension in model organisms. However, more research is required to validate these findings and translate them into clinical applications for human healthspan extension.
Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives
Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications (Naeini et al., 2023).
Free article: https://www.sciencedirect.com/science/article/pii/S053155652300075X
- Alpha-ketoglutarate extends lifespan and healthspan in various organisms.
- Alpha-Ketoglutarate controls stem pluripotency and self-renewal.
- Alpha-Ketoglutarate supports fertility in animal models.
- Alpha-Ketoglutarate is a key metabolite in regulating cancer cell behaviours.
- AKG plays important roles in cell metabolism and physiology.
- Intermediate of the Krebs cycle in the mitochondria
- AKG is essential for the oxidation of fatty acids, amino acids, and glucose.
- DNA repair
- Epigenetic regulator
- Tested for role in reducing cancer and infertility
- Extended the lifespan of C. elegans (worms)
- mimics caloric restriction
- enhance the function of stem cells
Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice
Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.(Asadi Shahmirzadi et al., 2020)
Alpha-Ketoglutarate: Physiological Functions and Applications
Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications (Wu et al., 2016).
https://www.ncbi.nlm.nih.gov/pubmed/26759695
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703346/pdf/bt-24-001.pdf
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
BACKGROUND: Arginine-alpha-ketoglutarate (AAKG) supplements are alleged to increase nitric oxide production, thereby resulting in vasodilation during resistance exercise. This study sought to determine the effects of AAKG supplementation on hemodynamics and brachial-artery blood flow and the circulating levels of L-arginine, nitric oxide metabolites (NOx; nitrate/nitrite), asymmetric dimethyl arginine (ADMA), and L-arginine:ADMA ratio after resistance exercise. METHODS: Twenty-four physically active men underwent 7 days of AAKG supplementation with 12 g/day of either NO(2) Platinum or placebo (PLC). Before and after supplementation, a resistance-exercise session involving the elbow flexors was performed involving 3 sets of 15 repetitions with 70-75% of 1-repetition maximum. Data were collected immediately before, immediately after (PST), and 30 min after (30PST) each exercise session. Data were analyzed with factorial ANOVA (p < .05). RESULTS: Heart rate, blood pressure, and blood flow were increased in both groups at PST (p = .001) but not different between groups. Plasma L-arginine was increased in the NO(2) group (p = .001). NOx was shown to increase in both groups at PST (p = .001) and at 30PST (p = .001) but was not different between groups. ADMA was not affected between tests (p = .26) or time points (p = .31); however, the L-arginine:ADMA ratio was increased in the NO(2) group (p = .03). CONCLUSION: NO(2) Platinum increased plasma L-arginine levels; however, the effects observed in hemodynamics, brachial-artery blood flow, and NOx can only be attributed to the resistance exercise (Willoughby et al., 2011).
https://www.ncbi.nlm.nih.gov/pubmed/21813912
https://journals.humankinetics.com/abstract/journals/ijsnem/21/4/article-p291.xml
Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice
The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from nonvertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements. Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms , can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.
Calcium versus arginine alpha-ketoglutarate
The calcium form of alpha-ketoglutarate extended lifespan by 12 percent in mice and increased health span by 41 percent (Naeini et al., 2023).
There is no suggestion the effect of AKG is due to the calcium. Arginine-AKG will work just as well.
Arginine-AKG is available in bulk from www.bulknutrients.com.au
References
Asadi Shahmirzadi, A., Edgar, D., Liao, C. Y., Hsu, Y. M., Lucanic, M., Asadi Shahmirzadi, A., Wiley, C. D., Gan, G., Kim, D. E., Kasler, H. G., Kuehnemann, C., Kaplowitz, B., Bhaumik, D., Riley, R. R., Kennedy, B. K., & Lithgow, G. J. (2020). Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metab, 32(3), 447-456 e446. https://doi.org/10.1016/j.cmet.2020.08.004
Naeini, S. H., Mavaddatiyan, L., Kalkhoran, Z. R., Taherkhani, S., & Talkhabi, M. (2023). Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives. Experimental Gerontology, 175, 112154. https://doi.org/https://doi.org/10.1016/j.exger.2023.112154
Willoughby, D. S., Boucher, T., Reid, J., Skelton, G., & Clark, M. (2011). 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. Int J Sport Nutr Exerc Metab, 21(4), 291-299. https://doi.org/10.1123/ijsnem.21.4.291
Wu, N., Yang, M., Gaur, U., Xu, H., Yao, Y., & Li, D. (2016). Alpha-Ketoglutarate: Physiological Functions and Applications. Biomol Ther (Seoul), 24(1), 1-8. https://doi.org/10.4062/biomolther.2015.078