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.
Summary drafted from this entry’s sources; editorial review pending.
01Key questions
Has AKG been tested in humans?
Only observationally so far. A 2026 study of 4,260 supplement users found delayed-release CaAKG most strongly associated with lower biological age, and an earlier retrospective analysis claimed about 8 years lower methylation age. No completed randomized trial exists.
Does AKG slow aging?
In animals, consistently: ~50% lifespan extension in C. elegans, extension in Drosophila via mTOR inhibition and AMPK activation, and ~12% lifespan with morbidity compression in mice. Human translation is what the ongoing ABLE and NCT07114536 trials are testing.4
Is AKG safe?
AKG has FDA GRAS status. Studies up to 6 g/day for six months and 4.5 g/day for three years in hemodialysis patients reported no significant adverse events beyond mild GI symptoms.
What would change this rating?
Completed randomized trials. The ABLE study (120 adults, DNA methylation age as primary endpoint) and NCT07114536 (PhenoAge endpoint) are running; a positive result would establish the causation observational data cannot.4
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.
02Biochemistry
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+ — 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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03Mechanisms 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
- This dual signaling effect makes AKG a metabolic analog of caloric restriction
- mTOR inhibition reduces protein synthesis burden and promotes autophagy
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
04Evidence 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): 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; 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
05Human 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; PMCID: 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 (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 |
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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.
06Doses in studies
General Longevity / Healthspan
| Parameter | Recommendation | Source |
|---|---|---|
| Form | CaAKG (delayed-release preferred) | Observational data favors dAKG |
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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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07Comparison 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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08Research Gaps and Open Questions
- RCT confirmation: No completed RCT demonstrates causal biological age reduction — the ABLE study (2026-2027 expected) is the key trial to watch
- Dose optimization: Is 1g/day optimal? Animal studies suggest dose-response may be non-linear
- Form matters: Is delayed-release truly superior, or is this an artifact of the single brand (Rejuvant) used in observational data?
- Sex differences: Animal studies show some sex-specific effects; human data insufficient
- Combination therapy: AKG + rapamycin? AKG + NAD+ boosters? No combination data exists
- Age of initiation: Does AKG work best as prevention (starting early) or intervention (starting late)?
- Cancer risk: Theoretical concern (TET activation could affect cancer epigenetics) — no evidence of harm, but long-term data is lacking
09Connections
10Sources
- Su Y et al. (2019). "Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK." Aging . 11(12):4183-4197. PMID 31242135PubMed 31242135
- 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 studyDOI 10.1016/j.cmet.2020.08.044 · PMC8508957
- 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 studyPubMed 42166733 · PMC13239866
- NCT07114536NCT07114536
- ABLE Trial Protocol. (2023). "Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults." PMC10643463 . — Ongoing RCT designPMC10643463
- PMC13113529 . (2025). "Alpha-Ketoglutarate: A Metabolic Regulator of Cellular Homeostasis and Pathophysiology." — Comprehensive mechanism reviewPMC13113529
11Entry history
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Heretic informs and never prescribes. Where amounts appear, they describe what published studies used. Talk to a qualified clinician before acting on anything here.