A multi-species screening platform for lifespan extending drugs

Progress update, preliminary data and promising candidates

The first thing we set out to do at EPITERNA is to make a survey of all the drugs that have been shown to extend lifespan in any animal model. There is a great resource for that, called DrugAge, developed by João Pedro de Magalhães. We wanted to add an additional level of selection, so we developed our own EPITERNA lifespan drug database. In our database, one interesting thing which we saw right away is that almost the same number of drugs (~120) have been tested in flies than in mice. This was very surprising to us, knowing the time it takes to test a drug for lifespan in mice, the high cost and the logistics compared to flies. More understandably, almost twice as many drugs have been tested in worms (~230). The proportion of positive drugs is largely over-represented in these results (90% in flies, 60% in worms and mice), often referred to as “publication bias”.

After having set up our testing platform the next natural thing to do was to try to first validate results from the literature. We were expecting that some of the published lifespan extending drugs would work, but not all would be reproducible (“reproducibility crisis”). We initially tested the 3 most popular anti-aging drugs in the literature: metformin, rapamycin and resveratrol. For metformin the results were quite convincing, and it is still one of the best drugs we’ve seen so far. Being able to extend lifespan in yeast, worms, and flies, consistently and with a significant magnitude. In fish in our first trial it didn’t work, but we are repeating it at a different dose. Rapamycin was also able to extend lifespan in multiple models, but generally with a lower magnitude. We’ve heard claims that rapamycin may not be very stable in agar or media, which might explain some of the results we are seeing. Lastly, resveratrol, one of the most controversial molecules, surprisingly showed great performance in our platform. Although negative in yeast, it worked extremely well in worms, less so in flies (although significant), and more importantly we were able to reproduce the result from Dario Valenzano in killifish. If we look from a wider angle, of the top 20 drugs ever published to extend lifespan in worms we were able to reproduce 12 (60%), and in flies 11 out of 20 (55%), a fairly good percentage overall.

After that and for most of last year we have been scaling up our testing platform, allowing us to now have the largest platform to test lifespan extending drugs in the world. We can now test 2880 drugs in yeast, 3072 in worms, 584 in flies, 40 in killifish, 20 in mice per year. We estimate that our testing capacity is now comparable to Ora Biomedical for worms, and the ITP for mice. For flies and fish, we are not aware of anyone having a similar capacity. This platform is also completely ready to be scaled up even more, 2x, 3x or even 10x.

After a bit more than a year, we have now tested 227 drugs in yeast, 142 in worms and 78 in flies. This means that we have tested close to 60% as many drugs as have ever been tested in the literature for lifespan in each animal model! Our percentage of positive drugs for worms and flies is around 30%, this is probably still inflated because we chose to first test drugs with positive effect in the literature.

Among the 315 drugs that we have tested so far, 91 (29%) show a positive effect in at least one model organism. Of these 91, 45 are “absolutely novel”, meaning they were not known to extend lifespan in any animal before, 25 are “relatively novel”, meaning they were known to extend lifespan in one organism, and we showed that it also extends in others. Lastly, 27 are not novel, meaning the lifespan extension we observed was already known.

Finally, we’d like to show results for some of the best lifespan extending drugs we have identified in the platform conserved across multiple models.

We still have a lot of work ahead of us. After getting our first positive results in killifish, we are now waiting for our first results in mice. With more than 20 drugs currently being tested for lifespan extension in mice, we hope to get our first positive results at the beginning of next year! Stay tuned.