Longevity Briefs: Have We Overlooked Some Lifespan-Extending Drugs?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The current gold standard for testing whether a drug extends lifespan in mice is the Interventions Testing Program, or ITP. You can read all about the ITP and why it is considered so reputable here. The majority of drugs tested by the ITP have so far failed to significantly extend mouse lifespan, including some drugs that were considered quite promising. However, the main statistical tests used by the ITP are designed to detect consistent effects on mortality throughout life. In other words, they work better if the drug reduces the risk of death at any age, but might not detect a reduced risk of death that only applies within a certain age range, which would still be beneficial for health and longevity. In this study, researchers took ITP data and re-analysed it using a different statistical test (the Gehan test) that is more sensitive to age-specific benefits, particularly at younger ages, to see if any beneficial effects might have been missed by initial analyses.

The discovery:

The researchers identified six additional compounds for which the effects on lifespan were significant when using the Gehan test, but had not been significant in previous tests. Five of these were sex-specific effects, meaning that lifespan only significantly improved in one or the other sex. This isn’t particularly surprising, as many of the lifespan-extending drugs identified by the ITP so far have also been sex-specific or have worked significantly better for one sex than for the other. 

The antidiabetic drug metformin, the antihypertensive drug enalapril, and the antibiotic-derived compound 17-DMAG were found to be effective in male mice only. The anti-inflammatory and anticancer plant compound CAPE and green tea extract were only effective in female mice. Researchers also found that the blood sugar-lowering compound 1,3-butanediol, which had previously been found to significantly extend lifespan only in females, was also effective in males according to the Gehan test.

The implications:

This research highlights one reason why the study of ageing and its treatment can be so tricky. There are many different mechanisms involved in the ageing process. These processes may carry different levels of importance at different stages of life, and hence a drug that slows ageing by targeting a certain mechanism might not work uniformly throughout one’s lifespan. Based on this study, it seems like there may be a risk of such drugs (in this case those that work best at younger ages) slipping through the net depending on how data is analysed. The authors do note that reanalysing data comes with an increased risk of false positives (detecting an effect where there is none), but argue that this is preferable to the alternative of false negatives (missing out on an effective drug).

That said, a drug that slows ageing only at a young age is arguably less valuable than one that slows ageing throughout life or in old age only. If we’re going to develop a lifespan-extending drug for humans, we would want it to benefit the entire population, not just those who are fortunate enough to get it while they’re still young. Yet the ITP is ultimately there to identify drugs that should be investigated further in animals and eventually humans, so we would not want to miss out on any candidates at this stage.