3HA: the tryptophan molecule that extends lifespan

Within tryptophan metabolism there is a molecule that has gone largely unnoticed by most longevity researchers: 3-hydroxyanthranilic acid, known as 3HA. In this conversation with a researcher in the field, the discussion covers 3HA's journey from its discovery in worms to early experiments in mice and the still distant prospects for human studies.

What 3HA is and how it was discovered

3HA is a metabolite of the kynurenine pathway, the metabolic route that converts tryptophan into NAD. During an experiment in Caenorhabditis elegans, the lab identified that knocking down the enzyme HAO (3HA dioxygenase), which degrades 3HA, produced a 25 to 30% lifespan extension. When they examined the long-lived worms, they found they had accumulated extremely high concentrations of this metabolite, reaching millimolar levels in organisms that normally contain it at subnanomolar concentrations.

The mechanism is not yet fully worked out, but the data point to several complementary pathways:

• Improved interaction with the gut microbiome and resistance to pathogenic bacteria.
• Activation of multiple stress response pathways, including NRF2 and the hypoxic response.
• Possible interaction with mitochondrial function.
• Storage in intestine-specific organelles called lysosome-related organelles.

Mouse data and the lifespan signal

Mouse experiments confirm the signal, though the effect is somewhat smaller than in worms, as is often the case when scaling between models:

• Genetic suppression of HAO produces a lifespan extension of approximately 15% in mice.
• Mice fed a 3HA-enriched diet also show lifespan extension.
• In 27-month-old mice (equivalent to very old individuals), dietary 3HA intervention produced a lifespan effect even when started late.

The team has completed three independent studies showing lifespan extension: two dietary and one genetic. Reproducibility across different methodological approaches is one of the most valued indicators when deciding whether an intervention deserves further investment.

Sex differences also appear: the lifespan effect seems larger in males in the dietary groups and larger in females in the genetic group. These differences are not yet explained.

The path to humans: real obstacles

3HA is not classified as GRAS (Generally Recognized As Safe) by the FDA. The historical problem stems from 1960s and 1970s rat studies where bolus doses of the molecule were administered directly into the bladder at very high concentrations, suggesting a possible link to bladder cancer. Subsequent studies did not reproduce that finding, and 3HA was removed from the carcinogen list just a few years ago.

Despite this, 3HA still lacks the classification needed to be tested in humans without first going through a regulatory process. The alternative route the lab is exploring is developing inhibitors of the HAO enzyme, which would yield a modified, potentially patentable molecule. However, HAO turns out to be a pharmacologically difficult target, and available inhibitors generate reactive oxygen species as a byproduct of the inhibition mechanism.

The structural problem of funding

3HA is an endogenous molecule and therefore not patentable in its current form. Without a patent, the private sector has no financial incentive to fund the expensive drug development process. Public funding, which would be the alternative, is subject to grant cycle timing and priorities.

The lab had a National Institute on Aging grant to support the mouse studies that was canceled before completion. Since then, the core aging and longevity work in mice has been on hold pending new funding. The researcher summarizes it plainly: good science does not always get funded, and that is precisely why advances in longevity take so long.

Current state of the research

Work on 3HA continues within an NIGMS grant focused on stress response pathway interactions, where 3HA is a strong candidate for study because it activates many of those pathways. But the direct aging and lifespan extension work in mammals is paused.

At this point, 3HA is not available as a supplement and there is no human evidence to justify considering it as an intervention. Taking it is not advisable in its current state.

Conclusion

3HA is a molecule with solid and reproducible preclinical evidence in two different animal models. A long road remains before knowing whether those effects translate to humans, and that road depends on funding that is currently not secured. The story of 3HA is also an example of how the scientific incentive system can slow the progress of promising molecules that cannot be protected through patents.