Great expectations: rapamycin longevity
The drug rapamycin is used to prevent rejection of transplanted organs. But it also has the effect of extending lifespan although we don't know exactly how at this stage. We also don't know whether this longevity boosting effect occurs equally in males and females, at higher or lower doses, whether a short course of a drug is as good as lifelong use or if the age at which treatment begins makes a difference. Matt Kaeberlein from the University of Washington recruited a cohort, a middle-aged mice to investigate, as he explained to Chris Smith...
Matt - So rapamycin is a compound that was isolated on Easter Island or Rapa Nui. That's where it gets its name rapamycin. It's isolated from a bacterium called Streptomyces hygroscopicus and it is a specific inhibitor of this protein called TOR which stands for Target of Rapamycin. You can think of it as a molecule in the cell that involves sensing the nutrients that are available in the environment and then helping the cell decide how to respond appropriately to how much nutrient is around. When there's lots of nutrients around, lots of food around, that's a good time to grow, divide if you're a cell, reproduce if you're an organism, and that turns TOR activity up. The opposite of that is when there's not a lot of food around, that's a good time to stop growing, become stress resistant, and it turns out, live longer. And so, rapamycin is a drug that kind of mimics that low food or low nutrient condition.
Chris - What does it do in the bacterium living on Easter Island that makes it?
Matt - So that's a good question. I think people don't really know the answer to that. It's been speculated that as a way to help that bacteria actually compete against fungi that are also in the soil. So, it doesn't slow down the division of bacterial cells because bacterial cells don't have this TOR in their cells. It's a molecule that is only present in the cells of eukaryotic organisms. So, cells like fungi, rapamycin might slowdown those cells' ability to divide and allow the bacteria to compete better.
Chris - We know that if you restrict calories for an individual, they do appear to live longer. Lifespan can be extended. Are you arguing that rapamycin in some apes or mimics that process?
Matt - So certainly, I think everybody would agree that to some extent rapamycin does mimic caloric restriction. We know that caloric restriction turns down TOR activity and we also know that rapamycin does that. My sort of view is that caloric restriction and rapamycin have overlapping but also distinct mechanisms of action.
Chris - So, what did you do in the present study to see what it would do in mice?
Matt - We obtained middle-aged mice. We aged them to 20 months of age and then we split them into two groups. One group got a control treatment and the other group got rapamycin for 3 months. We stopped the treatment and we just kind of watched to see what would happen. Our prediction was that the short term treatment with rapamycin would increase lifespan and improve at least some measures of health. And that's exactly what we saw. So, we tested a couple of different doses but the take home message is, that in both experiments, we saw increase in lifespan and we also saw improvements in some measures of muscle function. So it looks like short term treatment with rapamycin in middle-aged mice is enough to give long term benefits.
Chris - When you said there was a longevity effect, it prolonged the life of these animals, what are we talking here, a matter of weeks, months, or even years?
Matt - It depended a little bit on the dose and the cohort, but the biggest effect that we saw was in the male mice at the highest dose. So they got the drug for 3 months and their absolute lifespan was increased by about 140 days. So, that works out to about 15 per cent increase in total lifespan or 60 per cent increase in life expectancy where we're defining life expectancy as the length of life after the treatment was stopped.
Chris - Do you anticipate that had you wound back the clock further and started with younger mice that the gain would've been even more profound or do you think it would be about the same?
Matt - That's a really good question. So, my guess is, it would be about the same. It might be a little bit bigger but I don't think it would be a lot bigger. In fact again, this magnitude of effect that we saw from this short term treatment is pretty close to what has been published for lifelong treatment starting at 9 months of age with this drug.
Chris - So having managed to defer death in these animals, what did they die of?
Matt - So we don't completely know the answer to that question. What we do know in this case is that particularly in the female mice, they showed very striking changes in the kinds of cancer that they died with. The female mice getting the high dose of rapamycin had many more hematopoietic cancers or cancers of the immune system than the control treated mice. So, we believe that that contributed to their death and cause them not to have a life span extension from rapamycin. So that's interesting. The other thing that was really unexpected and interesting though was that they were completely protected against non-hematopoietic cancers. Only one of the female mice in the entire cohort that had gotten rapamycin had a non-hematopoietic tumour. And so, that suggested to us that what rapamycin did in those animals is that it shifted the cancer spectrum so that there was an increase in these immune cancers and a dramatic decrease in other kinds of cancers.