Ca-AKG (calcium alpha-ketoglutarate)

What Ca-AKG is

Alpha-ketoglutarate is not an exotic peptide but an intermediate of the citric acid cycle — the cycle with which every cell generates energy. The body produces it constantly. It is also a cofactor for a class of enzymes that set and remove epigenetic marks on DNA.

That is the theoretical link to the biological clock. In addition, the level in the blood falls with age: endogenous, central to metabolism, epigenetically relevant, lower in old age — everything a good story needs.

The strong finding: less frailty

In 2020, a careful study from the Buck Institute appeared in Cell Metabolism. C57BL/6 mice, start at 18 months — that is, late, roughly at human retirement age — with 2 percent calcium alpha-ketoglutarate in the feed. Median lifespan rose in both cohorts, although in the males the survival curve was not statistically significant.

The real finding sits alongside it, and the authors name it themselves: the decline in frailty was more dramatic than the gain in lifespan. They put the compression of the morbidity phase at 52 percent in females and 40 percent in males — grip strength, gait, coat condition, all better. So the animals did not mainly live longer; they were ill for a shorter time.

The replication nobody mentions

The Interventions Testing Program tests substances at 3 independent sites with genetically mixed mice, according to a fixed protocol, with publication regardless of the outcome. With a start at 18 months of age, exactly as in the Cell Metabolism study: no effect. A second run with a start at 7 months of age: again no effect, in neither sex.

There is, however, a good objection. The testing program aimed for 20,000 ppm in the feed, that is, the 2 percent of the original study. Only 3,262 ppm were measured — about one sixth, because alpha-ketoglutarate is not stable enough in the feed. That is a hard objection to the replication.

Where the 8 years come from

In 2021, the journal Aging published an analysis of a product with 1 gram of calcium alpha-ketoglutarate per tablet, 2 tablets a day. Participants: 42 people, 14 women and 28 men, average age around 63 years, self-reported healthy, mean duration of intake 7 months, range 4 to 10 months. Result: on average 8 years less biological age in the DNA methylation test, with a p-value of 6.5 times 10 to the power of minus 12.

This tiny p-value is the most instructive moment of the story. A p-value says how unlikely a measurement result would be if there were no effect — assuming that the design is sound. It says nothing about the design itself. A tiny p-value from a poor study is a precise measurement of the wrong thing.

The authors list the limitations themselves: open-label, no blinding, no placebo group, retrospective, small, a single biomarker, no data on stopping. Then there is self-selection: anyone who buys a longevity product and voluntarily takes an epigenetic test is often in the middle of changing their life, and all of that moves epigenetic clocks without having anything to do with the molecule. Then there is regression to the mean: anyone who scored poorly at the first measurement will, on average, score better the second time.

Why an epigenetic clock is not a year of life

An epigenetic clock measures methylation patterns on DNA and calculates an age from them. Nobody has shown that a person whose clock jumps back by 8 years lives even one day longer. The clock is calibrated against mortality — it is not mortality. 8 years in 7 months would also be the largest rejuvenation effect humanity has ever measured, achieved without a control group in 42 people. When a result is too large for its study size, the study is usually the problem.

What the studies show

Mouse study, Cell Metabolism 2020, Buck Institute

C57BL/6 mice, start at 18 months, 2 percent calcium alpha-ketoglutarate in the feed. Median lifespan of females plus 16.6 and plus 10.5 percent in two cohorts, of males plus 9.6 and 12.8 percent with a non-significant survival curve. Compression of the morbidity phase by 52 percent in females and 40 percent in males.

Interventions Testing Program, two runs

3 independent sites, genetically mixed mice, fixed protocol. Start at 18 months: no effect. Start at 7 months: males 841 versus 813 days, p equal to 0.429; females 889 versus 903 days, p equal to 0.228. Targeted 20,000 ppm in the feed, measured 3,262 ppm.

Retrospective user analysis, Aging 2021

42 users of a commercial product with 1 gram of calcium alpha-ketoglutarate per tablet, 2 tablets daily: 14 women, 28 men, average age around 63 years. On average 8 years less biological age in the DNA methylation test. Open-label, without placebo, retrospective, small, a single biomarker. The company behind the methylation test has a service contract with the manufacturer, and one of the authors is an adviser and board member there.

Where the number comes from — and where it does not

The 8 years are not a study in the sense in which the word is otherwise used. 42 people, no placebo, a surrogate endpoint, a disclosed conflict of interest: anyone who cites this as evidence is citing a customer survey with a lab test. That the conflict is openly stated in the paper speaks for the authors; it does not make the result wrong, but it changes its value.

The life extension is not established either, and even in mice it is unresolved: one positive finding from one group, 2 null findings from the independent replication program, one of which has a plausible technical explanation. That is not a refutation, but it is far from what the shelf claims. The strong source says: less frail. The package says: 8 years younger. At least the protocol of a randomized trial on alpha-ketoglutarate and biological age has been published, and further trials are registered.

Status, approval and legal

In Germany, Ca-AKG is a freely available food supplement and not a medicine. No approval exists for any longevity purpose, and the advertising claim about biological age rests on a retrospective analysis of 42 users of a commercial product. Controlled studies in humans are underway.

Safety

There is little reason for concern about tolerability: an endogenous metabolite in moderate amounts. One practical point: the calcium form also supplies calcium. Anyone who takes a gram dose and already supplements calcium should factor that in. Individual health questions belong in a conversation with a physician.

Sources

• Asadi Shahmirzadi et al., Cell Metab 2020 (alpha-ketoglutarate, lifespan and frailty in mice)
• Korstanje et al., GeroScience 2026 (Interventions Testing Program on alpha-ketoglutarate)
• Demidenko et al., Aging (Albany NY) 2021 (retrospective analysis of Ca-AKG and epigenetic age)
• Sandalova et al., GeroScience 2023 (protocol of the randomized ABLE trial on alpha-ketoglutarate)
• Epigenetic clocks as an endpoint