Ora Biomedical and the Rapamycin Longevity Lab have launched a project to screen more than 600 mTOR inhibitors in the hope of finding some that are superior to geroscience’s poster child, rapamycin.
Better than chance
Rapamycin, one of the most potent compounds for prolonging lifespan in numerous animal models, was discovered serendipitously in one of the most remote locations on earth: Easter Island. The island’s name in its natives’ language is Rapa Nui, which is where “rapa” comes from. Rapamycin is produced by a certain type of soil bacteria to compete with fungi. For decades, rapamycin has been used mostly as an immunosuppressant in transplant and cancer patients before it was found that it can extend lifespan in animals.
The point is a compound discovered by chance might not be the best one for the job. Rapamycin works by inhibiting mTOR, a protein kinase that is a central regulator of nutrient sensing. However, it has its quirks and limitations. What if there are other, better mTOR inhibitors out there?
Enter Ora Biomedical, a young company focused on high-throughput screening of chemical compounds in the tiny nematode worm C. elegans. Ora uses a proprietary robotic system called WormBot. Ora’s Million Molecule Challenge is one of the most interesting crowdfunding initiatives in the longevity field. It allows anyone to buy an actual experiment for as little as 100 dollars and compete with other users while also contributing to science.
Ora’s philosophy is that the net we are currently casting to look for life-extending compounds is not nearly wide enough. Using short-lived worms and robotic systems allows us to extend the search space by orders of magnitude. The results might not necessarily be translatable to more complex animals, including humans, but the sheer volume might be able to compensate for that.
One found, 600 to go
The newest Ora’s project is a collaboration with the Rapamycin Longevity Lab led by Krister Kauppi. It entails screening more than 600 mTOR inhibitors to find the ones that work best.
“Currently, rapamycin is considered the gold standard longevity intervention – it works across many animal and even non-animal fungal models,” said Ora CEO Mitchell Lee. “The mechanism of mTOR inhibition has seen extensive development in cancer therapeutics. There’s a broad toolkit of mTOR inhibitors with different patterns of inhibition between mTOR complex 1, mTOR complex 2, and impacts on other kinases. Nobody has comprehensively looked to see if any are better than rapamycin.”
The current project began as a smaller partnership within the Million Molecule Challenge when, in an experiment funded by Kauppi and the Rapamycin Longevity Lab, Ora discovered an mTOR inhibitor that was superior to rapamycin in worms at the same dose. This molecule, called omepalisib, has already been approved by the FDA for treating certain types of cancer, so its way to the clinic as a geroprotector (anti-aging drug) might be relatively short.
The discovery of robust life extension by omepalisib gives Lee the hope that many even more promising molecules are out there. “There are at least 600 different mTOR inhibitors we could test with the WormBot platform,” he said. “We can screen through these in months, not the decades or years needed for mammalian studies, to identify what works best for extending lifespan in this system.”
Ora was spun out of Matt Kaeberlein’s laboratory at the University of Washington School of Medicine, Seattle. Kaeberlein, one of the world’s most prominent geroscientists, is a big believer in rapamycin and is currently running a rapamycin trial in dogs.
“Rapamycin is the best drug we know of to slow aging, increase lifespan, and improve healthspan,” Kaeberlein said. “There are undoubtedly other mTOR inhibitors out there that can have a similar impact, and I’m certain some of them will do even better than rapamycin. Ora’s technology affords the opportunity to find these hidden gems and develop them into the next generation of gerotherapeutics.”
Let’s go fishing!
According to the Rapamycin Longevity Lab’s white paper on the project, “There is a big gap in the literature around how good Rapamycin is compared to other mTOR inhibitors. While many mTOR inhibitors have been developed, no systematic effort exists to find the most effective mTOR inhibitors for improving healthy lifespan. This is something we need an answer to, and this project is an important first step in that direction. The end goal is improved human longevity.”
“One key reason why I founded the Rapamycin Longevity Lab was to accelerate the research around mTOR inhibition because it’s one of the most promising longevity pathways that we currently have,” Kauppi explained. “In this ambitious screening project, we aim to deliver a large volume of unique data to the longevity community with the potential to uncover new mTOR inhibitors that are even better than rapamycin. No one has done anything close to this before, and thanks to Ora Biomedical’s innovative WormBot technology, projects like this can be done in a highly efficient and cost-effective way.”
The mTOR inhibitors project is fueled by donations, and you can do your part. “Anyone can contribute through our website,” Lee said. “We hope to close the first half of financing by year-end. While it’s non-commercial initially, we’ll examine IP opportunities for the most promising compounds. Our development strategies often involve medicinal chemistry to create derivatives from lifespan-extending compounds – optimizing them for better chemical availability.”
According to Lee, the system of incentives that the longevity field is built around is the one responsible for some research directions being overlooked. “It’s striking that we’ve come this far testing only rapamycin for longevity,” he said. “It shows a misalignment between academic research and commercial/translational interests. If you proposed finding better mTOR inhibitors to the NIA (National Institute on Aging), they’d reject it for not finding new mechanisms. They’d call it a fishing expedition. Since most research relies on federal funding, important questions like identifying the best compound for this gold-standard target stagnate. That’s why Ora focuses on making these ‘fishing expeditions’ feasible – because we need to catch these fish.”
