Oxaloacetate

Oxaloacetate is a four-carbon intermediate of the citric acid cycle, sold as a stabilised anhydrous salt because the free acid degrades quickly. The longevity interest came from worm work, where supplementation extended Caenorhabditis elegans lifespan, apparently through AMP-activated protein kinase and the FOXO transcription factor, and from the idea that raising the cytosolic NAD to NADH ratio mimics some of calorie restriction's signalling.

The Interventions Testing Program tested it in the cohort that also carried resveratrol, green tea extract, curcumin and medium-chain triglyceride oil, with treatment beginning at 4 months of age. None of the five agents had a statistically significant effect on lifespan in either sex by log-rank test, with a secondary analysis hinting that green tea extract might reduce midlife deaths in females only.

The human record is genuinely thin, and what exists is not about ageing. A three-month randomised controlled trial in 82 people with myalgic encephalomyelitis or chronic fatigue syndrome found that 2,000 mg daily reduced fatigue by more than 25 percent from baseline against roughly 10 percent in controls. A one-month dose-finding study in 30 Alzheimer's patients found 1,000 mg twice daily was safe and increased brain glucose uptake on FDG PET and parietal glutathione on spectroscopy, while cognitive scores did not improve and blood levels did not track dose consistently.

That is the entire human evidence base: about 112 people, none of them studied for longer than three months, none of them measured on an ageing endpoint.

A lifespan null from this programme is a real, expensive, well-powered finding, and it is narrower than it sounds. What was tested was one concentration in the diet, started at one age, in one mouse strain, with death as the endpoint. A null tells you that this dose, in these animals, did not move that endpoint. It does not tell you the compound is inert, that a different dose would also fail, that the mechanism is wrong, or that the reason people actually take it has been refuted. Those are separate questions and most of them were never asked. The failure mode this site is trying to avoid runs in both directions: treating a mouse lifespan positive as proof that a supplement works, and treating a mouse lifespan null as proof that it does nothing.

Oxaloacetate is where that paragraph has to be applied carefully in the other direction. The mouse result is a clean null, and it would be easy to write the compound off. But almost nothing has been established about oxaloacetate in either direction: roughly 112 people have taken it in a published trial, for at most three months, on endpoints that have nothing to do with ageing.

The honest position is that the specific claim tested, that dietary oxaloacetate from 4 months of age extends mouse lifespan, failed. The claim most buyers are responding to, which usually involves calorie-restriction mimicry or brain energetics, has never been properly tested in people at all. A small randomised fatigue trial and a one-month brain imaging study are a starting point, not an answer.

The worm lifespan result that generated the interest is also worth putting in proportion. Caenorhabditis elegans lifespan is extended by a very large number of compounds, most of which do nothing in mice. The ITP test is what happens when one of them is checked.

The Interventions Testing Program is funded by the National Institute on Aging and run in parallel at three independent laboratories, in Bar Harbor, Ann Arbor and San Antonio. It uses UM-HET3 mice, a four-way genetic cross, so no result can be an artefact of a single inbred background. Both sexes are studied, cohorts are sized to detect roughly a 10 percent shift in lifespan, compounds are fed in the diet from a stated starting age, and the programme commits in advance to publishing negative results alongside positive ones. That last commitment is why this batch can exist at all: almost no other part of ageing research reliably tells you what did not work.