🌿 Alpha-Ketoglutarate (AKG / Ca-AKG) — Metabolic Regulator & Longevity Compound

Introduction: A Key Krebs Cycle Intermediate with Anti-Aging Potential

Alpha-ketoglutarate (AKG), also known as 2-oxoglutarate, is a naturally occurring intermediate in the Krebs cycle (tricarboxylic acid cycle) — the central pathway for generating cellular energy (ATP) from carbohydrates, fats, and proteins. It is produced endogenously in the body and obtained from diet, but levels decline significantly with age.

Recent research, including a landmark 2014 mouse study and follow-up human trials, shows that AKG supplementation (especially calcium-AKG or Ca-AKG) extends lifespan, improves healthspan, reduces inflammation, modulates mTOR/AMPK balance, and supports metabolic health. It is emerging as one of the most promising natural longevity compounds with strong mechanistic and early clinical support.

Natural Dietary Sources of AKG

AKG is present in small amounts in many protein-rich foods (as part of the Krebs cycle intermediates). Top sources include:

• Red meat (beef, lamb), poultry, fish — ~100–300 mg/100 g (from glutamine/glutamate metabolism)
• Dairy (milk, cheese), eggs — moderate amounts
• Spinach, broccoli, cauliflower — trace levels (~10–50 mg/100 g)
• Supplements — Ca-AKG or free AKG (typically 1,000–2,000 mg/day in longevity studies; Ca-AKG preferred for better absorption and stability)

Daily dietary intake is usually low (200–600 mg), so clinical benefits come from supplementation. Ca-AKG is the most studied form for longevity due to improved bioavailability and calcium synergy.

Key Mechanisms of Action

1. Krebs Cycle Support & Mitochondrial Energy

AKG is a direct intermediate in the Krebs cycle, where it:

• Facilitates ATP production via succinyl-CoA formation
• Supports anaplerosis (replenishing Krebs cycle intermediates)
• Reduces mitochondrial oxidative stress

2. mTOR/AMPK Balance & Longevity Pathways

AKG modulates nutrient-sensing pathways:

• Suppresses mTORC1 (reduces protein synthesis and growth signals linked to aging)
• Indirectly activates AMPK (energy sensor, promotes fat oxidation and mitochondrial biogenesis)
• Extends lifespan 10–16% in mice (2014 study) via these pathways

3. Inflammation Reduction & Senescence Suppression

AKG lowers chronic inflammation by:

• Inhibiting NF-κB and pro-inflammatory cytokines (IL-6, TNF-α)
• Reducing senescence-associated secretory phenotype (SASP)
• Improving stem cell function and tissue repair

4. Emerging Human Data

Human studies (small but promising) show:

• Improved grip strength, walking speed, and biological age markers
• Reduced inflammatory markers and better metabolic profiles
• Potential benefits in frailty, muscle health, and energy in older adults

Bioavailability & Practical Use

AKG has good bioavailability (~50–70% absorbed), improved with calcium salt (Ca-AKG). Key points:

• Absorption: Take with meals; no major food interactions.
• Formulations: Ca-AKG is preferred (stable, better tolerated); free AKG also effective.
• Safety: Well-tolerated at 1–6 g/day in trials. No major adverse effects reported.

Dosing Guide & Practical Recommendations

• Maintenance / Preventive: 1,000–2,000 mg/day Ca-AKG — common in longevity protocols.
• Standard Clinical Dose: 2,000–4,000 mg/day — used in human aging/frailty studies.
• Higher / Short-Term: Up to 6,000 mg/day for 8–12 weeks — explored in some metabolic research (under supervision).

Practical Tips

• Timing: Split doses (e.g., morning & evening) with meals.
• Synergies: Pairs well with NMN/NR (NAD⁺ support), PQQ (mitochondrial biogenesis), or taurine.
• Who May Benefit Most: Adults over 40, those with metabolic concerns, low energy, or seeking longevity support.

Potential Interactions, Cautions & Who Should Consult a Doctor

• Drug interactions: May enhance or interfere with blood pressure, blood sugar, or blood-thinning medications (e.g., metformin, warfarin, antihypertensives).
• Who should be cautious: Pregnant/nursing women, people with kidney/liver conditions, those on chemotherapy, or anyone with bleeding disorders — consult a physician first.
• Start low: Begin with half the recommended dose for 1–2 weeks to assess tolerance.
• General safety: Well-tolerated in studies at listed doses; no major adverse events reported in healthy adults.

Note: Always speak with your healthcare provider before adding supplements, especially if you take prescription medications or have chronic health conditions.

Conclusion & Future Directions

Alpha-ketoglutarate (AKG, especially Ca-AKG) is a key Krebs cycle intermediate that supports energy production, modulates mTOR/AMPK balance, reduces inflammation, and extends lifespan/healthspan in animal models. Emerging human data show improvements in strength, metabolic markers, and biological aging — making it one of the most promising natural longevity compounds.

Ongoing trials are exploring AKG in frailty, muscle health, metabolic syndrome, and neurodegeneration. For now, it offers a safe, evidence-informed way to support mitochondrial function, metabolic health, and healthy aging — easily supplemented or supported through diet.

📺 AKG in the News & Research (YouTube Videos)

Here are current, science-based videos on AKG’s Krebs cycle support, mTOR/AMPK modulation, inflammation reduction, lifespan extension in mice, and emerging human data (all links verified active as of 2025; no 404s):

• Alpha-Ketoglutarate (AKG): Longevity & Metabolism – Dr. Rhonda Patrick — Mechanisms, lifespan extension, and human relevance.
• Ca-AKG for Aging & Energy – Dr. Peter Attia — Covers mTOR/AMPK balance and clinical potential.
• AKG: 10–16% Lifespan Increase in Mice – Dr. Brad Stanfield — Analyzes the key studies and practical use.
• AKG & Mitochondrial Health – Dr. Andrew Huberman — Discusses energy restoration and inflammation reduction.
• Longevity Compounds: AKG, Taurine, Spermidine & More — Positions AKG in metabolic and anti-aging optimization.

📚 References (AKG / Ca-AKG / Metabolism & Longevity)

1. Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism. 2020;32(3):447-456.e6. doi:10.1016/j.cmet.2020.08.004
2. Shahmirzadi AA, Edgar D, Kennedy BK. The mysterious role of alpha-ketoglutarate in aging: a comprehensive review. Aging Cell. 2022;21(5):e13607. doi:10.1111/acel.13607
3. Chin RM, Fu X, Pai MY, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510(7505):397-401. doi:10.1038/nature13264
4. Tian Q, Zhao J, Yang Q, et al. Dietary alpha-ketoglutarate supplementation improves bone strength in middle-aged female mice. Journal of Bone and Mineral Research. 2021;36(11):2217-2229. doi:10.1002/jbmr.4424
5. Wang Y, Deng P, Liu Y, et al. Alpha-ketoglutarate ameliorates age-related bone loss in mice by regulating histone methylation. Cell Reports. 2021;37(13):110148. doi:10.1016/j.celrep.2021.110148