A new 30% mouse lifespan extension paper just dropped!
Another example of rapamycin + something increasing mouse lifespan more than rapamycin or something alone. In this case, the something is trametinib, an anti-cancer drug.
Rapamycin makes cells think the animal is eating less food, causing recycling of old and broken cellular components. But rapa only hits one of the cells’ nutrient sensors, so the idea is to stop compensatory ‘huh, there is food really!’ signals getting through by another route.
Previous top-performing rapamycin + something combos were diabetes drugs acarbose and metformin, which diabetes drugs (as are SGLT-2 inhibitors, another top-performing class of anti-ageing drug in mice), so they work by a different mechanism again to rapamycin and trametinib. Could a combination of all three make mice live even longer? It’s an interesting question, but a challenging one to answer: with three drugs, trying a few different doses of each in combination results in very big experiments, very fast. eg trying three different doses of each in combination would be 27 separate experiments!
Hopefully as we understand more about ageing there will be other ways to hone in on the optimal combination of doses than dozens of lifespan experiments—and/or maybe we should do those dozens of experiments in a simpler, shorter-lived organism like worms to train AI to help.
Either way, interesting to see another way to get a fairly substantial increase in lifespan in mice!
Extra detail for the nerds! The study does have a few caveats:
1. The control mice (ie those who didn’t get the drug) are short-lived. Does that mean that the drugs were just correcting for sub-optimal living conditions?
Obviously ultimately we can’t be sure, and this effect does have mechanistic plausibility so maybe it’s interesting? But it’s a reason for caution. The good news is that the super-rigorous Interventions Testing Program is taking this cocktail forward, so we should know more soon.
Matt Kaeberlein is on the sceptical side of this, and discussed the study on the Optispan Podcast.
2. Most lab mice die of cancer. Isn’t it a bit unsurprising that a cancer drug makes them live longer?
Maybe, maybe not—‘it just reduces cancer’ is a pretty common comeback for mouse lifespan experiments (and perhaps often correct, I don’t think we know!), but trametinib also works in fruit flies which barely get any cancer because almost all their cells no longer divide in adulthood. And, even if it is just a cancer reduction effect, humans do get our fair share of cancers too… Also, the reason trametinib was chosen for this study was only semi-related to its anti-cancer effect. The scientists planned to hit ageing—and of course maybe they didn’t and it only hit cancer, biology is hard, but it’s at least plausible it’s not just cancer!
3. Doesn’t trametinib have really bad side-effects?
One comeback to this is that the drugs often extend lifespan at doses far lower than used clinically, so side-effects should be less. Rapamycin is the classic—organ transplant patients take very high doses and have bad side-effects, but much lower doses are used for longevity.
But bad news: the dose used in this study was way higher than the normal human dose. (1.44 mg/kg in mice is roughly equivalent to a human dose of 5–20 mg/day, but human cancer patients take 2 mg/day.) Could lower or intermittent dosing work in people? Maybe, but we don’t know yet, of course.
The other comeback then is that this experiment won’t turn directly into a human treatment, but helps us understand the pathway here which, given that it worked, could encourage us to develop a cleaner drug that targets it with fewer side-effects.
Given a limited number of shots on goal in mice, should we choose drugs with a better chance of being directly translatable to humans? I’m not actually sure! The pro of doing this would obviously be more potential to directly and rapidly translate results into people, but, on the cons side, it seems quite unlikely that any of the drugs in our existing medicine cabinet that weren’t developed for longevity are going to be the best drugs for keeping us healthy for longer. So perhaps we’re better off exploring the basic science (using existing drugs for convenience) and, once we’ve worked out a bit more about ageing, coming up with really safe, effective molecules (or other treatments like gene therapies) to maximally exploit the findings.
This is an interesting strategic question for the field!
Sources
- Check out the study I’m discussing here.
- For all your mouse lifespan experiment needs, check out the excellent LEVF RAID database.
- Thank to commenters on my Twitter thread who made some great observations which made it into this piece!
- Mouse image at the top CC-BY-SA George Shuklin. Thanks!
