"Alpha-ketoglutarate (AKG) has emerged as a promising candidate in the longevity field, showing potential to extend healthspan and compress morbidity in animal models."

Dr. Brian Kennedy, Professor at the Buck Institute for Research on Aging and Director of the Centre for Healthy Longevity at the National University of Singapore

The Comprehensive Longevity and Health Benefits of Alpha-Ketoglutarate (AKG)

Alpha-ketoglutarate (AKG) is rapidly gaining recognition as one of the most promising compounds in longevity research. A naturally occurring molecule in the body, AKG is a critical intermediate in the Krebs cycle, the process that generates cellular energy. While traditionally associated with athletic performance and bodybuilding, the compound’s potential in promoting healthspan and combating aging is now coming to light. Let’s explore the science-backed mechanisms and health benefits of AKG, focusing on its potential to revolutionize the field of longevity.

What is Alpha-Ketoglutarate?

AKG is an endogenous molecule integral to energy production and metabolic function. It is central to the Krebs cycle, helping convert nutrients into usable energy. Beyond its metabolic role, AKG is involved in amino acid synthesis, nitrogen metabolism, and even cellular signaling. However, AKG levels naturally decline with age, correlating with reduced energy levels, impaired cellular function, and other markers of aging.

How Alpha-Ketoglutarate Supports Longevity

Scientific studies on AKG and its calcium salt form (Ca-AKG) have uncovered several mechanisms by which the compound influences longevity:

Mimics Caloric Restriction for Lifespan Extension: A hallmark study demonstrated that AKG supplementation extended lifespan in Caenorhabditis elegans by 50%, primarily by inhibiting ATP synthase and TOR signaling, two key pathways associated with aging. This mimics the effects of caloric restriction, a well-documented intervention for increasing lifespan in various organisms (Chin et al., 2014).

Epigenetic Regulation and DNA Repair: AKG serves as a cofactor for enzymes that regulate DNA and histone methylation. These processes help maintain a youthful epigenome, reducing gene dysregulation, a key driver of aging. By supporting the ten-eleven translocation (TET) enzymes responsible for DNA demethylation, AKG may preserve cellular health and genomic stability (Guo et al., 2022).

Reduction in Systemic Inflammation: Chronic inflammation is a major contributor to age-related decline. Studies in aging mice show that Ca-AKG reduces inflammatory markers and increases IL-10, an anti-inflammatory cytokine, which collectively help delay the onset of frailty and disease (Shahmirzadi et al., 2020).

Enhancement of Mitochondrial Function: AKG fuels mitochondria, the powerhouses of cells. As mitochondrial function declines with age, supplementation with AKG can restore energy production and improve cellular vitality. Enhanced mitochondrial health is also linked to increased resistance to oxidative stress, another hallmark of aging (Niemiec et al., 2011).

Autophagy Activation: AKG promotes autophagy, the body’s natural process of clearing out damaged cells and proteins. By doing so, it helps rejuvenate cellular function and reduce the accumulation of age-related cellular debris (Chin et al., 2014).

Health Benefits Beyond Longevity

While AKG’s anti-aging potential is compelling, the molecule also supports various aspects of health:

Improved Muscle Health and Recovery: AKG stimulates protein synthesis and prevents protein degradation, making it particularly beneficial for maintaining muscle mass as we age. It has also been shown to support recovery following surgery or trauma by reducing nitrogen loss and enhancing tissue repair (Chen et al., 2019).

Enhanced Joint and Bone Health: Studies suggest that AKG reduces inflammation in joints and supports bone density by promoting osteogenesis. This dual action may protect against conditions like osteoarthritis and osteoporosis in aging populations (Ye et al., 2024).

Gut and Immune Health: AKG strengthens the intestinal barrier and reduces gut inflammation, improving overall digestive health. It also modulates immune responses, supporting the body’s defenses against age-related immune decline (Tian et al., 2021).

Energy and Performance Boost: Athletes have long valued AKG for its ability to enhance energy levels and reduce fatigue. By improving mitochondrial function and cellular energy metabolism, AKG may increase stamina and physical performance even in older individuals (Marconi et al., 2004).

Skin Health and Collagen Support: AKG plays a role in collagen synthesis and reduces fibrosis, contributing to firmer, more youthful skin. These properties may delay the visible signs of aging while improving overall skin health (Son et al., 2007).

Mechanisms Underlying Its Benefits

The health benefits of AKG can be attributed to several interconnected mechanisms:

  • Metabolic Flexibility: Helps cells switch efficiently between carbohydrate and amino acid metabolism, ensuring consistent energy production.
  • Redox Balance: Maintains cellular antioxidant capacity, reducing oxidative damage to tissues.
  • Stem Cell Preservation: Supports stem cell health and activity, essential for tissue repair and regeneration.
  • Anti-Inflammatory Action: Modulates pathways like NF-κB, mitigating inflammation and its systemic effects.

The Future of AKG in Longevity

Ongoing research continues to uncover the multifaceted role of AKG in promoting healthy aging. From improving mitochondrial efficiency to preserving epigenetic integrity, this compound holds immense promise as a cornerstone of future longevity interventions. Clinical trials in humans, such as those showing reduced biological age with AKG supplementation, are a testament to its potential as a life-enhancing molecule (Demidenko et al., 2021).

How Calcium Alpha-Ketoglutarate (CA-AKG) Impacts Aging:

Specific Hallmarks:

  • Extends Lifespan by Mimicking Caloric Restriction: AKG may extend lifespan by inhibiting ATP synthase and TOR signaling, promoting autophagy and delaying aging-related cellular damage (Chin et al., 2014).
  • Reduces Systemic Inflammation: Ca-AKG reduces pro-inflammatory cytokines and increases anti-inflammatory markers like IL-10, helping combat chronic inflammation and promoting healthy aging (Shahmirzadi et al., 2020).
  • Supports Epigenetic Maintenance: As a cofactor for DNA and histone demethylases, AKG regulates gene expression, preserves a youthful epigenetic profile, and maintains genomic stability (Guo et al., 2022).
  • Enhances Mitochondrial Function: AKG supports energy production and reduces oxidative stress in mitochondria, key contributors to cellular aging (Niemiec et al., 2011).

Activates Autophagy for Cellular Renewal: By promoting autophagy, AKG clears out damaged proteins and cellular debris, rejuvenating cells and reducing age-related decline (Chin et al., 2014).

Mechanism of Action

  • Improves Muscle Health and Recovery: AKG enhances protein synthesis and reduces muscle protein degradation, aiding in recovery and preserving muscle mass in aging individuals (Chen et al., 2019).
  • Supports Bone and Joint Health: By promoting collagen synthesis and reducing inflammation, AKG helps protect cartilage and improve bone density, potentially reducing the risk of osteoarthritis and osteoporosis (Ye et al., 2024).
  • Boosts Energy Metabolism: AKG optimizes cellular energy production through the Krebs cycle, improving energy levels and physical performance (Marconi et al., 2004).
  • Enhances Gut Health: AKG strengthens intestinal barrier function, reduces inflammation in the gut, and supports overall digestive health (Tian et al., 2021).
  • Promotes Skin Health and Collagen Production: AKG stimulates procollagen synthesis and enhances skin elasticity, potentially reducing visible signs of aging (Son et al., 2007).

Hallmarks of Aging Impacted by CA-AKG

  • Mitochondrial Dysfunction: AKG enhances mitochondrial energy production and reduces oxidative stress, protecting cells from age-related declines in mitochondrial function (Niemiec et al., 2011).
  • Epigenetic Alterations: AKG serves as a cofactor for histone and DNA demethylases, preserving youthful gene expression patterns and genomic stability (Guo et al., 2022).
  • Inflammaging: AKG reduces pro-inflammatory cytokines and induces anti-inflammatory IL-10, mitigating age-related chronic inflammation (Shahmirzadi et al., 2020).
  • Loss of Proteostasis: By promoting autophagy, AKG clears damaged proteins and cellular debris, reducing the accumulation of dysfunctional cellular components (Chin et al., 2014).
  • Stem Cell Exhaustion: AKG rejuvenates stem cells by reducing senescence markers and supporting stem cell differentiation, aiding tissue repair and regeneration (Wang et al., 2020).

Functional Benefits of CA-AKG

  • Improved Energy Levels: AKG supports cellular energy production through its role in the Krebs cycle, combating fatigue and promoting overall vitality (Wu et al., 2016).
  • Enhanced Joint Health: AKG reduces inflammation and supports cartilage health, protecting against conditions like osteoarthritis (Ye et al., 2024).
  • Stronger Bones: AKG promotes osteogenesis and prevents age-related bone density loss by enhancing mesenchymal stem cell function (Wang et al., 2020).
  • Gut Health Support: AKG strengthens intestinal barriers and reduces gut inflammation, improving digestive health (Tian et al., 2021).

Collagen Production: AKG stimulates collagen synthesis, promoting skin elasticity and potentially reducing visible signs of aging (Son et al., 2007).

Scientific studies

  • Alpha-ketoglutarate extends lifespan and compresses morbidity in aging mice.

    Researchers administered calcium alpha-ketoglutarate (Ca-AKG) to 18-month-old mice and observed a significant increase in lifespan, alongside improved healthspan. The mice exhibited lower levels of systemic inflammatory markers, such as pro-inflammatory cytokines, and higher levels of anti-inflammatory IL-10. These changes reduced frailty and compressed morbidity, demonstrating AKG's dual role in extending life and improving its quality. Published in Cell Metabolism (2020), titled “Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice.

  • Alpha-ketoglutarate delays aging by mimicking caloric restriction.

    This study explored the anti-aging effects of AKG in C. elegans, revealing that it extended lifespan by approximately 50%. AKG inhibited ATP synthase and TOR signaling, crucial pathways linked to aging, while increasing autophagy and reducing cellular ATP levels. These findings demonstrate AKG’s ability to mimic caloric restriction, a proven longevity intervention. Published in Nature (2014), titled “The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.”

  • AKG stimulates collagen synthesis and skin health.

    Researchers demonstrated that AKG boosted collagen production in fibroblasts by 25.6% and improved skin elasticity in UV-damaged mice. This points to AKG’s potential in reducing signs of aging and supporting connective tissue health. Published in Biological & Pharmaceutical Bulletin (2007), titled “Alpha-ketoglutarate stimulates procollagen production in cultured human dermal fibroblasts.”

  • AKG promotes stem cell activity and tissue regeneration.

    Research demonstrated that AKG rejuvenated stem cells by reducing senescence markers and supporting differentiation, essential for tissue repair. These findings suggest its role in maintaining regenerative capacity during aging. Published in Nature Communications (2022), titled “Disrupted alpha-ketoglutarate homeostasis induces skeletal stem cell aging.” Read more here.

  • Reference link

    AKG enhances oxygen saturation and performance during exercise.

    Summary Paragraph: In a controlled trial with trained individuals, supplementation with AKG and 5-hydroxymethylfurfural increased oxygen saturation (SpO₂) during prolonged exercise under hypoxic conditions. Although performance metrics like time trial completion were unaffected, the enhanced oxygen delivery suggests AKG’s role in optimizing aerobic efficiency under stress. Published in International Journal for Vitamin and Nutrition Research (2019), titled “5-Hydroxymethylfurfural and α-ketoglutaric acid supplementation increases oxygen saturation during prolonged exercise in normobaric hypoxia.

  • AKG improves training tolerance and stress recovery

    In a double-blind study with untrained young adults, AKG supplementation improved training outcomes, including increased maximum power output and peak muscle torque. Participants reported better stress recovery and reduced emotional exhaustion compared to controls, highlighting AKG’s benefits for exercise adaptation and recovery. Published in Journal of the International Society of Sports Nutrition (2012), titled “Improved training tolerance by supplementation with α-keto acids in untrained young adults: a randomized, double-blind, placebo-controlled trial.”

Recommended Dosage

1000-2000 mg

per day

Estimated Amount Needed

~40

glasses of red wine

You would have to consume approximately 40 glasses of red wine to obtain the same amount of resveratrol in one daily dose of Longevity Foundation.

Source and origin

Calcium Alpha-Ketoglutarate (CA-AKG) is not naturally found in significant amounts in food sources but is synthesized within the human body as part of the Krebs (citric acid) cycle. While AKG itself isn't directly available in foods, its precursor amino acids, like glutamine and glutamate, are found in protein-rich foods such as meat, dairy products, and certain vegetables like spinach and broccoli. For supplementation, CA-AKG is typically produced synthetically to ensure stable, bioavailable forms suitable for therapeutic use.

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CA-AKG found in

Calcium Alpha-Ketoglutarate (CA-AKG) is a key component in our Longevity Foundation due to its powerful benefits in supporting cellular energy, reducing cellular senescence, and promoting autophagy—all essential for healthy aging. Formulated at clinically recommended doses, CA-AKG in the Longevity Foundation works synergistically with other targeted compounds to help you maintain mitochondrial health and metabolic balance, making it a comprehensive foundational supplement protocol for longevity.

People Also Ask

  • What is the best time of day to take CA-AKG?

    CA-AKG is typically taken in the morning with food, as it aligns with natural energy metabolism cycles, supporting cellular functions throughout the day. We’ve formulated it as part of our AM dose of our Longevity Foundation protocol.

  • Is CA-AKG safe for long-term use?

    Current studies suggest CA-AKG is generally safe for long-term use when taken at recommended doses; however, it's best to consult a healthcare provider for personalized guidance.

  • Can CA-AKG be combined with other longevity supplements?

    Yes, CA-AKG is often compatible with other longevity supplements, but it’s important to monitor total intake and interactions, especially with compounds affecting cellular energy and metabolism.

  • Are there any contraindications for taking CA-AKG?

    People with kidney or liver conditions, as well as those on specific medications, should consult a healthcare provider before using CA-AKG, as it may affect nitrogen and ammonia levels.

  • Can I take CA-AKG while fasting?

    CA-AKG is commonly used during fasting as it supports energy metabolism and mimics some benefits of caloric restriction, though individual responses may vary.

  • How does CA-AKG support energy levels?

    CA-AKG supports cellular energy production by participating in the Krebs cycle, which is essential for converting nutrients into usable cellular energy, or ATP.

  • Does CA-AKG have any side effects?

    CA-AKG is generally well-tolerated, but mild side effects like bloating or nausea may occur, especially at higher doses (1500-3000 mg). Reducing the dose can alleviate these symptoms.

  • Can CA-AKG impact sleep quality?

    While CA-AKG primarily supports daytime cellular functions, it may enhance overall metabolic balance, which could indirectly contribute to better sleep quality in some users.

  • How quickly can I expect to see results with CA-AKG?

    Effects may vary, but users generally report noticeable benefits in energy and vitality within a few weeks. Cellular-level effects, such as those related to aging, are long-term and may take months to manifest.

References

  • Reference link

    Bayliak, M., & Lushchak, V. (2020). Pleiotropic effects of alpha-ketoglutarate as a potential anti-aging agent. Frontiers in Aging Neuroscience, 12, 100-120.

  • Chen, J., Zhang, H., Gao, H., Kang, B., Chen, F., Li, Y., Fu, C., & Yao, K. (2019). Effects of dietary supplementation of alpha-ketoglutarate in a low-protein diet on fatty acid composition and lipid metabolism-related gene expression in muscles of growing pigs. Animals, 9(10), 838.

  • Chin, R. M., Fu, X., Pai, M. Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V. S., Monsalve, G. C., Hu, E., Whelan, S. A., Wang, J. X., Jung, G., Solis, G. M., Fazlollahi, F., Kaweeteerawat, C., Quon, A., Reddy, D., … Clarke, C. F. (2014). The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature, 510(7505), 397-401.

  • Demidenko, Z. N., Barardo, D., Bartlett, D. B., & Lithgow, G. J. (2021). Rejuvant®: A potential life-extending compound. Aging, 13(6), 7957-7973.

  • Doliba, M., Kurhaliuk, N., Muzyka, F., Shostakovska, I. V., & Kondrashova, M. (1993). Effect of alpha-ketoglutarate and acetylcholine synergism on energy metabolism in mitochondria. Fiziologicheskii Zhurnal, 39(5-6), 65-70.

  • Filip, R., Pierzynowski, S., Lindegård, B., Wernerman, J., Haratym-Maj, A., & Podgurniak, M. (2007). Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: Six-month study. International Journal for Vitamin and Nutrition Research, 77(2), 89-97.

  • Guo, C., Chen, F., Yang, H., et al. (2022). Disrupted alpha-ketoglutarate homeostasis induces skeletal stem cell aging. Nature Communications, 13(1), 1234.

  • Kaczka, P., Kubicka, K., Batra, A., Maciejczyk, M., Kopera, E., Bira, J., & Zając, T. (2021). Effects of co-ingestion of β-hydroxy-β-methylbutyrate and L-arginine alpha-ketoglutarate on jump performance in young track and field athletes. Nutrients, 13(4), 1064.

  • Li, Y., Zhang, S., Huang, C., & Lin, D. (2023). NMR-based metabolic profiling of the effects of alpha-ketoglutarate supplementation on C2C12 myotubes. Molecules, 28(9), 3840.

  • Marconi, C., Sassi, G., & Cerretelli, P. (2004). The effect of an alpha-ketoglutarate-pyridoxine complex on human maximal aerobic and anaerobic performance. European Journal of Applied Physiology and Occupational Physiology, 49(4), 307-317.

  • Niemiec, T., Sikorska, J., Harrison, A., Szmidt, M., Sawosz, E., Wirth-Dzieciołowska, E., Wilczak, J., & Pierzynowski, S. (2011). Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice. Journal of Physiology and Pharmacology, 62(1), 37-43.

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