Rankings / Longevity — Supplements
Alpha-ketoglutarate (Ca-AKG)
Longevity · TCA cycle intermediate
Tier B+
Bottom line
Read Off Label grades Alpha-ketoglutarate (Ca-AKG) as B+ (7.1/10) based on moderate evidence, med benefit magnitude, and a low-risk safety profile.
Shahmirzadi 2020 Cell Metab: ~12% lifespan extension in mice started at 18 mo.
Studied, labeled, or reported-use context: 1-2 g/day sustained-release Ca-AKG — OTC; not individualized guidance.
Frontier potential — editorial judgment, not evidence
This is a separate axis from the grade above. It asks a different question: if this worked in humans, how much would it matter? It is our judgment, it is not part of the composite score, and it cannot raise a grade. A high number here is a statement about the idea, not about whether it works or whether anyone should take it.
What the ceiling rests on
Extended median lifespan and, more notably, compressed morbidity in mice — the animals spent a smaller fraction of life in poor health, which is closer to what healthspan advocates actually want than lifespan alone. AKG sits at a real metabolic junction as a TCA intermediate and epigenetic cofactor.
Why it may not get there
The mouse lifespan effect was modest and, in the key study, driven substantially by female animals. Human data are limited to biomarker and epigenetic-clock changes from a small industry-associated study. Endogenous AKG is abundant, so it is unclear whether oral supplementation meaningfully changes tissue concentrations.
What would change this An independent human trial with a functional endpoint.
What the evidence says
Shahmirzadi 2020 Cell Metab: ~12% lifespan extension in mice started at 18 mo. Retrospective TruAge study: ~8-year reduction in epigenetic age after ~7 months of Rejuvant. ABLE RCT ongoing. Better human data than most experimental compounds. Pabis 2026 (Aging Cell, Kennedy lab, n=4,260 health-enthusiast cohort, 9-CpG saliva clock): delayed-release Ca-AKG ("Rejuvant") associated with ~1.8-year lower Age Residual after adjustment for age, sex, smoking, health status, and covariates; regular non-dAKG much smaller and non-significant. CoQ10 + dAKG longitudinal subset trended favourable but did not survive multivariate correction. More conservative than the 2022 single-arm TruAge ~8-year estimate above — adjusted real-world data, but cross-sectional with healthy-user bias; ABLE RCT remains the gold-standard pending data point.
Mechanism
Krebs cycle metabolite; epigenetic regulator via TET/JHDM demethylases; substrate for collagen synthesis; nitrogen metabolism; declines ~10x from age 40-80
Studied, labeled, or reported dose & route
1-2 g/day sustained-release Ca-AKG
This records doses and routes described in studies, approved labeling, clinical practice, or documented use. It is not individualized guidance and does not establish safety; context changes with indication, formulation, health history, monitoring, and other medicines.
Citations
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Common questions
- What does the evidence show about Alpha-ketoglutarate (Ca-AKG)'s effects?
- Read Off Label rates the evidence for Alpha-ketoglutarate (Ca-AKG) as Moderate and the benefit magnitude as med, producing an overall grade of B+ (7.1/10). Shahmirzadi 2020 Cell Metab: ~12% lifespan extension in mice started at 18 mo.
- What safety findings are reported for Alpha-ketoglutarate (Ca-AKG)?
- Alpha-ketoglutarate (Ca-AKG) has a low risk profile in the database. Low Legal status: OTC (Rejuvant).
- What doses or routes are reported for Alpha-ketoglutarate (Ca-AKG)?
- 1-2 g/day sustained-release Ca-AKG This is context from studies, approved labeling, clinical practice, or documented use; it is not individualized guidance and does not establish safety.
- How does Alpha-ketoglutarate (Ca-AKG) work?
- Krebs cycle metabolite; epigenetic regulator via TET/JHDM demethylases; substrate for collagen synthesis; nitrogen metabolism; declines ~10x from age 40-80
This is an independent synthesis of published research by a non-clinician. Scores are opinions supported by citations, not prescriptions. See the full disclaimer and methodology for how this score was produced and what it does and doesn't mean.