# Alpha-ketoglutarate (AKG)

Rating: Early — Mostly animal or cell studies; few or uncontrolled human data
Type: Compound
Updated: 2026-08-06
Canonical: https://heretic.bio/articles/alpha-ketoglutarate-akg-the-metabolic-longevity-molecule.html

> Alpha-ketoglutarate is a TCA-cycle intermediate that declines with age and feeds the dioxygenase enzymes behind DNA and histone demethylation. It extends lifespan about 50% in C. elegans and ~12% with morbidity compression in mice; in humans, a 4,260-person observational study linked delayed-release CaAKG to lower methylation age, but no completed RCT exists. The ABLE trial and two other randomized trials are underway.

> **Core thesis:** Alpha-ketoglutarate (AKG) is a central TCA cycle intermediate whose levels decline with age. Supplementation — typically as calcium-AKG (CaAKG) or delayed-release CaAKG (dAKG) — extends lifespan in _C. elegans_ , _Drosophila_ , and mice, compresses morbidity, reduces inflammation, and modulates epigenetic regulation via TET/JmjC demethylases. A landmark 2026 observational study in _Aging Cell_ found delayed-release AKG was the single supplement most strongly associated with lower biological age among 84 compounds tested in 4,260 health enthusiasts. Multiple RCTs are now underway to confirm causation.

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## Biochemistry

### What Is AKG?

  * **Chemical identity:** α-Ketoglutaric acid (2-oxoglutarate), a 5-carbon dicarboxylic acid
  * **Role in metabolism:** Central TCA cycle intermediate, produced from isocitate by isocitrate dehydrogenase (IDH) and from glutamate via transamination/deamination
  * **Downstream:** Converted to succinyl-CoA by α-ketoglutarate dehydrogenase (α-KGDH)
  * **Beyond energy:** Functions as a cofactor (co-substrate) for a critical family of enzymes — 2-oxoglutarate-dependent dioxygenases (2-OGDDs)



### AKG Declines With Age

  * Plasma and tissue AKG levels decrease with aging in multiple species
  * This decline mirrors the age-related decrease in [NAD+](nad-and-sirtuin-activators.html) — both are central metabolites whose restoration may confer geroprotective benefits
  * AKG levels respond to fasting, exercise, and caloric restriction (all known to promote longevity)



### Supplement Forms

Form | Description | Bioavailability Notes  
---|---|---  
**Free AKG** | Pure alpha-ketoglutaric acid | Rapid absorption, short plasma half-life; inexpensive  
**CaAKG** | Calcium salt of AKG | More stable; provides calcium co-nutrient  
**dAKG (delayed-release)** | Sustained-release CaAKG formulation | Engineered to release slowly over time; used in Rejuvant® brand; the form most associated with biological age reduction in observational data  
**OKG (Ornithine AKG)** | Salt with ornithine | Used clinically for wound healing, burns, malnutrition  
  
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## Mechanisms of Longevity

### 1\. Epigenetic Regulation via TET and JmjC Demethylases

  * AKG is an **essential co-substrate** for:
  * **TET (ten-eleven translocation) DNA demethylases** — catalyze 5-methylcytosine hydroxylation, initiating active DNA demethylation
  * **Jumonji C (JmjC) domain histone demethylases** — remove methyl groups from histone tails
  * **Aging connection:** AKG decline → reduced TET/JmjC activity → epigenetic drift, DNA hypermethylation, and cellular senescence
  * **TET-senescence link (2026):** AKG availability directly modulates cellular senescence via TET-mediated epigenetic regulation. Reduced AKG → impaired TET activity → senescence-associated secretory phenotype (SASP) amplification → pro-inflammatory signaling cascade
  * **Cancer context:** In IDH-mutant gliomas, the oncometabolite 2-hydroxyglutarate (2-HG) competes with AKG, inhibiting TET/JmjC — demonstrating the critical nature of the AKG/dioxygenase axis



### 2\. mTOR Inhibition and AMPK Activation

  * AKG extends _Drosophila_ lifespan by **inhibiting mTOR** and **activating AMPK** — the same longevity pathway targeted by [rapamycin and metformin](metformin-and-rapamycin.html)
  * This dual signaling effect makes AKG a metabolic analog of caloric restriction
  * mTOR inhibition reduces protein synthesis burden and promotes [autophagy](autophagy.html)



### 3\. Anti-Inflammatory / Macrophage Polarization

  * AKG promotes **M2 (anti-inflammatory) over M1 (pro-inflammatory) macrophage polarization**
  * Mouse studies show CaAKG supplementation decreases systemic inflammatory cytokines (IL-6, TNF-α) during aging
  * This "inflammaging" reduction is a primary mechanism for morbidity compression



### 4\. Collagen and Bone Metabolism

  * AKG is precursor for **proline and hydroxyproline** synthesis — critical for collagen production
  * Explains bone-protective effects observed in postmenopausal women



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## Evidence by Model Organism

### _C. elegans_ (Nematode)

  * **Chin et al., 2014:** AKG supplementation at 8 mM during adulthood extends lifespan by **~50%** and delays age-related functional decline
  * Mechanism: AKG inhibits ATP synthase → reduced ATP → AMPK activation → FOXO/DAF-16 signaling
  * Conserved across multiple wild-type and mutant strains



### _Drosophila_ (Fruit Fly)

  * **Su et al., 2019 (PMID[31242135](https://pubmed.ncbi.nlm.nih.gov/31242135/)):** AKG extends _Drosophila_ lifespan by inhibiting mTOR and activating AMPK
  * Provides cross-species validation of the AMPK/mTOR mechanism



### Mice (C57BL/6) — The Landmark Mammalian Study

  * **Shahenshah et al., 2020 (Cell Metabolism; DOI[10.1016/j.cmet.2020.08.044](https://doi.org/10.1016/j.cmet.2020.08.044); [PMC8508957](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508957/)):**
  * CaAKG supplemented in middle-aged mice
  * **~12% lifespan extension** (more modest than worms, but across multiple healthspan metrics)
  * **Healthspan compression:** Dramatic reduction in time spent in morbidity before death — mice stayed healthier longer
  * **Inflammation reduction:** Decreased systemic cytokines (IL-6)
  * **Frailty index improvement:** Significant reduction in age-related frailty markers
  * Key caveat: the lifespan effect was primarily healthspan extension (morbidity compression) rather than maximal lifespan extension — the "squaring of the longevity curve"



### Cross-Species Consistency

> The consistent longevity effects of AKG across yeast, _C. elegans_ , _Drosophila_ , and now mice demonstrate that AKG acts on an **evolutionarily conserved aging mechanism** likely translatable to humans. — Buck Institute

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## Human Evidence

### The Landmark Observational Study (2026)

**Pabis K, Wang W, Selvarajoo K, Budovskaya YV, Sorrentino V, Gruber J, Kennedy BK. "Supplements and Drugs Are Associated With Biological Age in a Cohort of Exceptionally Healthy Individuals."_Aging Cell_. 2026 Jun;25(6):e70517. PMID [42166733](https://pubmed.ncbi.nlm.nih.gov/42166733/); PMCID: [PMC13239866](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13239866/).**

  * **Design:** Observational study of **4,260 health enthusiasts** who took methylation-based biological age tests
  * **Key finding:** **Delayed-release CaAKG (dAKG / Rejuvant) was the single supplement most strongly associated with lower biological age** — outperforming NMN, NR, all NAD+ precursors, and standard AKG by a factor of 8-9x
  * **Methodology:** 9-site DNA methylation clock (epigenetic age estimation)
  * **Population:** Exceptionally healthy individuals (low smoking rates, low disease burden) — reduces confounding
  * **Also found:** General supplement use was associated with lower biological age vs. non-users; no harmful effect from multiple supplement stacking
  * **CRITICAL LIMITATION:** Observational — demonstrates **association, not causation**. Users of dAKG may have other health-seeking behaviors. RCTs needed.



### Retrospective Rejuvant Analysis

  * Earlier retrospective analysis of Rejuvant (dAKG + vitamins) users showed an average **~8 year reduction in DNA methylation age** vs. chronological age
  * This preliminary data drove the current wave of clinical trials
  * **Limitation:** Retrospective, no placebo control, self-selection bias



### Ongoing Randomized Controlled Trials

Trial | Design | Dose | Duration | Status  
---|---|---|---|---  
**ABLE Study** (NUS / Kennedy) | RCT, double-blind, placebo-controlled, 120 adults aged 40-60 with biological age > chronological age | 1g/day sustained-release CaAKG | 6 months + 3-month follow-up | Ongoing (primary outcome: DNA methylation age)  
**[NCT07114536](https://clinicaltrials.gov/study/NCT07114536)** (Zhejiang Chinese Medical University) | RCT, double-blind, placebo-controlled, 30 adults aged 40-75 | CaAKG (dose TBD) | 12 weeks | Ongoing (primary: PhenoAge change)  
**AEGIS Trial** | Examining 1g AKG for enhanced surgical recovery | 1g AKG | — | Ongoing  
  
### What the Trials Are Measuring

  * **Primary outcomes:** DNA methylation age (epigenetic clocks), PhenoAge
  * **Secondary:** Pulse wave velocity, inflammatory markers (IL-6, CRP), glucose/lipid metabolism, physical performance, aging-related gene expression, quality of life
  * **Safety monitoring:** Liver/kidney function, complete blood count at 3, 6, 9 months



### Honest Assessment of Human Evidence

> Human evidence for AKG's longevity effects remains **promising but preliminary**. The strongest data (Pabis 2026) is observational and vulnerable to healthy-user bias. No completed RCT has yet demonstrated causal biological age reduction. However, the cross-species consistency, mechanistic plausibility (TET/JmjC, mTOR, AMPK), and the ongoing RCT pipeline make AKG one of the most credible longevity supplement candidates. ConsumerLab (June 2026) notes: "Good clinical evidence showing that AKG or CaAKG prolong human lifespan or healthspan is lacking" — a fair statement that should temper enthusiasm while trials complete.

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## Doses in studies

### General Longevity / Healthspan

Parameter | Recommendation | Source  
---|---|---  
**Form** | CaAKG (delayed-release preferred) | Observational data favors dAKG  
  
### Specific Conditions (From Literature)

  * **Surgical recovery:** Being investigated in AEGIS trial at 1g/day



### Safety Profile

  * **GRAS status:** AKG is classified Generally Recognized As Safe by the FDA
  * **Studies up to 6 g/day for 6 months:** No significant adverse events beyond mild GI symptoms
  * **Studies up to 4.5 g/day for 3 years (hemodialysis patients):** Safe
  * **Side effects:** Rare, mild gastrointestinal symptoms (resolving in days); no hepatotoxicity or nephrotoxicity reported at any dose
  * **Drug interactions:** No clinically significant interactions documented; theoretically could interact with drugs metabolized by CYP enzymes that require α-KG-dependent processes (theoretical, not observed)



### Form Comparison

Form | Cost | Evidence | Recommendation  
---|---|---|---  
**Free AKG** | $ | Minimal longevity data; short half-life | Budget option; may need multiple doses  
**CaAKG** | $$ | Mouse lifespan data; bone studies | Good middle ground  
**dAKG (Rejuvant)** | $$$ | Strongest human observational data | Best evidence for biological age reduction  
  
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## Comparison With Other Longevity Metabolites

Feature | AKG | NAD+ (NMN/NR) | Urolithin A  
---|---|---|---  
**Primary mechanism** | Epigenetic (TET/JmjC), mTOR inhibition, AMPK activation | Sirtuin activation, DNA repair | Mitophagy induction  
**Declines with age** | Yes | Yes | Yes (via microbiome decline)  
**Lifespan data (mice)** | ~12% extension + morbidity compression | Mixed results (some negative ITP results) | Healthspan improvements  
**Human evidence** | Observational (strong) + RCTs ongoing | Mixed (NMN negative PhenoAge RCT 2025) | Small RCTs positive for muscle/endurance  
**Cost** | Low-moderate | High | High  
**Key advantage** | Cheapest with cross-species lifespan data | Most mechanistic data | Targeted mitochondrial benefit  
  
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## Research Gaps and Open Questions

  1. **RCT confirmation:** No completed RCT demonstrates causal biological age reduction — the ABLE study (2026-2027 expected) is the key trial to watch
  2. **Dose optimization:** Is 1g/day optimal? Animal studies suggest dose-response may be non-linear
  3. **Form matters:** Is delayed-release truly superior, or is this an artifact of the single brand (Rejuvant) used in observational data?
  4. **Sex differences:** Animal studies show some sex-specific effects; human data insufficient
  5. **Combination therapy:** AKG + rapamycin? AKG + NAD+ boosters? No combination data exists
  6. **Age of initiation:** Does AKG work best as prevention (starting early) or intervention (starting late)?
  7. **Cancer risk:** Theoretical concern (TET activation could affect cancer epigenetics) — no evidence of harm, but long-term data is lacking



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## Sources

1. Su Y et al. (2019). "Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK." Aging . 11(12):4183-4197. PMID 31242135 (PubMed 31242135)
2. Shahenshah H et al. (2020). "Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice." Cell Metabolism . DOI 10.1016/j.cmet.2020.08.044 . PMC8508957 . — Landmark mouse study (DOI 10.1016/j.cmet.2020.08.044, PMC8508957)
3. Pabis K, Wang W, ..., Kennedy BK. (2026). "Supplements and Drugs Are Associated With Biological Age in a Cohort of Exceptionally Healthy Individuals." Aging Cell . 25(6):e70517. PMID 42166733 ; PMCID: PMC13239866 . — 84-supplement observational study (PubMed 42166733, PMC13239866)
4. NCT07114536 (NCT07114536)
5. ABLE Trial Protocol. (2023). "Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults." PMC10643463 . — Ongoing RCT design (PMC10643463)
6. PMC13113529 . (2025). "Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology." — Comprehensive mechanism review (PMC13113529)