Caffeic acid phenethyl ester

Caffeic acid phenethyl ester is one of the active constituents of propolis, the resin honeybees use to seal their hives. It is studied in cell culture as an inhibitor of the transcription factor NF-kappa B, and in rodents as an anti-inflammatory and antioxidant in models of ischaemia, arthritis and chemical injury. It is sold as a purified research chemical and is present in variable amounts in propolis supplements.

Nobody has run a clinical trial of CAPE. A PubMed search restricted to clinical trials of caffeic acid phenethyl ester in humans returns nothing. Propolis extracts have been trialled in people for various conditions, but their CAPE content varies with the bees' plant sources and is rarely measured, so those trials cannot be read as trials of CAPE. There is no human pharmacokinetic study of the purified compound.

In mice, the NIA Interventions Testing Program fed CAPE at 30 and 300 ppm from 4 months of age and reported it as a null: neither dose extended lifespan in either sex by the protocol log-rank test. The 2024 Gehan reanalysis found that at 300 ppm, female median lifespan was 5 percent higher than controls (147 treated against 289 controls), with a log-rank p of 0.0665 and a Gehan p of 0.0481. Males showed nothing at either dose, and the proportional hazards assumption was not violated, so the log-rank test was a valid test here and simply did not reach significance.

CAPE is not an approved drug anywhere. It is sold as a supplement ingredient, most often inside propolis products.

The NIA Interventions Testing Program runs each compound in parallel at three sites (The Jackson Laboratory, the University of Michigan and UT Health San Antonio) in genetically heterogeneous UM-HET3 mice, tests both sexes, analyses them separately, pools the sites in a site-stratified log-rank test, and publishes every result whether or not the compound worked. It is publicly funded by the National Institute on Aging with no pharmaceutical sponsorship. CAPE was tested at 30 and 300 ppm from 4 months and reported as a null in both sexes.

"Gehan-only" needs explaining because it is a weaker and more specific claim than "extended lifespan". The ITP's protocol test is the log-rank test, which weights every death equally and is most sensitive when a treatment lowers mortality by a constant proportion across the whole lifespan. In 2024 a group at UT Health San Antonio reanalysed all ITP survival data from 2004 to 2022, 132 compound by sex comparisons, with the Gehan test, which weights deaths by how many animals are still alive and so gives more weight to early and midlife deaths. Five compounds that had failed the log-rank test passed the Gehan test: metformin, enalapril and 17-DMAG in males, CAPE and green tea extract in females. The authors are explicit that this pattern is what you would expect from a compound that lowers mortality before midlife and then stops helping, that these effects are "limited to midlife and may not be effective at older ages", and no correction for the number of comparisons is reported. A Gehan-only result therefore means: fewer mice died young, the survival curves converged later, and the effect on maximum lifespan was nil.

For CAPE the story is thinner than for the other Gehan positives. The proportional hazards assumption was not violated, so the log-rank test was appropriate and gave p = 0.0665; the Gehan test gave p = 0.0481. Those two numbers sit either side of the conventional threshold and a reader should treat them as the same finding, a borderline 5 percent female median effect, rather than as one negative and one positive. The absence of human research reflects that CAPE is a natural product with no patent protection, and that the propolis industry sells the whole resin rather than the purified molecule. No sponsor, no trial, no answer in either direction.