KDC-MN-105 – Kodiac biolabs

Plain-language summaryIntrigue 65 / 100

Alpha-ketoglutarate (AKG) is a TCA cycle intermediate that has shown lifespan extension in mouse studies. Calcium AKG (Ca-AKG) is sold as a longevity supplement, popularized by Rejuvant. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished, active research

44/100

Old metabolite with a genuinely interesting epigenetic aging angle, but thin human evidence and COI-clouded pilot data keep it mid-tier

Look, AKG has been sitting in the TCA cycle since the first organisms figured out oxidative metabolism. Calling it novel is a stretch. But there’s a specific modern angle that deserves a serious look: AKG is a required co-substrate for the 2-oxoglutarate-dependent dioxygenase (2-OGDD) superfamily, which includes TET enzymes driving DNA demethylation, JmjC-domain histone demethylases, and prolyl hydroxylases feeding into HIF pathway regulation. When plasma and tissue AKG levels fall with age, which they do, you’re potentially starving a set of enzymes that maintain epigenetic fidelity. That’s a real mechanistic hypothesis, not just “it’s in the Krebs cycle so it must be good.”

The animal data is what put Ca-AKG on the map for longevity researchers. The 2020 work (Shahmirzadi et al., Cell Metabolism) showed Ca-AKG supplementation at 2 percent chow concentration extended healthspan and lifespan in mice, with reduced senescence markers and attenuated inflammaging signals. The C. elegans results are older and show up to 50 percent lifespan extension, though worm data translates poorly. The mouse work is from a real lab with real methodology, but it’s essentially one study from one group at this point.

The human pilot is where things get complicated. Tian et al. 2022 (Aging journal, n=42, open-label) reported roughly 8 years of epigenetic age reduction using Horvath-type methylation clocks after Rejuvant supplementation. What we like: it’s actual human data with a pre-specified methylation endpoint, which is rare in this space. What we dont like: the study is from the Rejuvant commercial team, its open-label with no placebo arm, and epigenetic clocks as primary endpoints remain contested even among clock developers. Replicated, blinded data from independent groups simply doesnt exist yet.

As a bench tool, AKG has real utility for investigators studying 2-OGDD biology or aging-related epigenetic drift. If you’re running a research program on TET enzyme activity, substrate availability experiments are straightforward and informative. The compound is easy to source, stable, and inexpensive. That’s worth something, even if it’s not a sophisticated probe.

We think the 2-OGDD epigenetic aging story is the most interesting thing going on with this compound, and it’s underexplored relative to the NAD+/sirtuin and mTOR spaces that absorb most longevity research attention. But the honest assessment is that the human evidence is one small, conflict-laden pilot, and the mouse mechanism is incompletely worked out. This is a compound worth watching, not one to prioritize. If independent groups replicate the methylation clock findings in a blinded design, the score goes up meaningfully.

Novelty: 38
Mechanism promise: 58
In-category differentiation: 45
Evidence quality: 37
Translational signal: 35
Research bench value: 45

Rationale AKG would normally sit under the foundational-metabolite cap, but the 2-oxoglutarate-dependent dioxygenase story for epigenetic aging qualifies as a novel indication with real (if preliminary) human signal, lifting the cap exemption. Scores land in the low-40s because the mechanism is compelling but the evidence base is thin and largely consortium-sourced.

TCA cycle intermediate / 2-oxoglutarate

A TCA cycle intermediate sold as calcium alpha-ketoglutarate (Ca-AKG) for longevity applications based on extension of lifespan in mice and worms.

Abstract

Alpha-Ketoglutarate (AKG, 2-oxoglutarate; CAS 328-50-7; molecular formula C5H6O5; molecular weight 146.10) is a tricarboxylic acid cycle intermediate that declines with age in plasma and tissues. The compound is a substrate for the 2-oxoglutarate-dependent dioxygenase family of enzymes (including DNA and histone demethylases, prolyl hydroxylases, and TET enzymes), placing it at a hub of cellular regulation. AKG supplementation extends lifespan in C. elegans (up to 50 percent) and in mice when given as the calcium salt at 2 percent in chow. The mechanism in mice is incompletely characterized but appears to involve reduced cellular senescence, improved metabolic flexibility, and reduced inflammaging markers. Sold as calcium alpha-ketoglutarate (Ca-AKG, Rejuvant) for supplemental use. Doses are typically 500 to 2000 mg per day.

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The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

Tag: KDC-MN-105

Alpha-Ketoglutarate (AKG)

Abstract

Read the full monograph