Rapamycin and lifespan extension

by Charles Daney in Science and Reason

Will a pill containing the immunosuppressant drug rapamycin someday extend human lifespan a few years? In spite of the hopeful research announcements that appeared a few days ago, I wouldn't recommend getting one's hopes up just yet.This is a topic I've discussed before: Calorie restriction, TOR signaling, and aging. And for related stuff on mTOR: here.The executive summary is that inhibition of mTOR signaling has been shown to extend lifespan in yeast, roundworms, and fruit flies. Mice can now be added to this list, in experiments that included rapamycin in their diet.Here's the press release: Easter Island Compound Extends Lifespan Of Old Mice: 28 To 38 Percent Longer Life (7/8/09)On July 8, in the journal Nature, The University of Texas Health Science Center at San Antonio and two collaborating centers reported that the Easter Island compound – called "rapamycin" after the island's Polynesian name, Rapa Nui – extended the expected lifespan of middle-aged mice by 28 percent to 38 percent. In human terms, this would be greater than the predicted increase in extra years of life if cancer and heart disease were both cured and prevented.Although rapamycin and some related compounds have been investigated as anti-cancer therapies, the hypothesized lifespan-extending benefits are thought to be related to the by now well-documented benefits of calorie restricted diets. (For very recent news on that front, see here, for example.)Aging researchers currently acknowledge only two life-extending interventions in mammals: calorie restriction and genetic manipulation. Rapamycin appears to partially shut down the same molecular pathway as restricting food intake or reducing growth factors.It does so through a cellular protein called mTOR (mammalian target of rapamycin), which controls many processes in cell metabolism and responses to stress.A decade ago, Dr. [Dave] Sharp proposed to his colleagues that mTOR might be involved in calorie restriction. "It seemed like an off-the-wall idea at that time," Dr. Richardson said.Experiments were performed in parallel at three separate research centers and consisted of feeding hundreds of mice, starting at an age of 20 months, a diet containing a special formulation of rapamycin designed to evade breakdown in the digestive system. It was found that the age at which 90% of mice had died rose from 1,078 days to 1,179 days in male mice, compared to controls, and from 1,094 days to 1,245 days in females. The total lifespan extension, on average, was therefore 9.4% in males and 13.8% in females. Note that some accounts of the research claim lifespan extensions of 28% to 38%, but this is misleading, since those figures represent the extension of the "old age" period of mouse life beginning at 20 months. They do not mean that the mice lived up to almost 40% longer in total. (Some pretty shoddy reporting going on here....) And there was no particular evidence to indicate that extensions of such size would have occurred if the special diet began at an earlier age. However, in experiments still going on, there is evidence for some extension when addition of rapamycin to the diet begins for mice 270 days old.Of course, even an extension of human lifespan in the 10% range – 7 or 8 years – would be quite an accomplishment, provided quality of life in the final years remained about where it is today. (Which is a big if.)But there are various reasons to suspect that even a 10% extension in humans is rather optimistic. Some reasons:Rapamycin is an immunosuppressant, currently used therapeutically to prevent organ transplant rejection. The experimental mice were maintained under conditions that carefully protected them from infection – conditions that would not be realistic for humans.Although mice and humans are both mammals, their genetics are not all that similar. The complete sequence of the mouse genome was recently announced (see here), and it turns out that about 20% of mouse genes are different from human analogs, or not found in humans at all. (It's been 90 million years since the last common ancestor of mice and humans.)Rapamycin is known to inhibit an important protein kinase called mTOR (mammalian target of rapamycin). mTOR plays a key role in regulating cell growth, proliferation, and survival, so it's not all that surprising that rapamycin might affect cell biology relevant to aging and longevity. This same property of rapamycin makes it interesting as an anti-cancer agent. Rapamycin and similar compounds that inhibit mTOR have in fact been found to have anti-cancer properties in animal models. Several analogs of rapamycin have been investigated as anti-cancer therapies, and one has even been approved for human use (Torisel). But even in the anti-cancer setting, mTOR inhibitors haven't yet been slam-dunk successes.It is not clear that rapamycin in these experiments was working the same way as calorie restriction. None of the rapamycin-fed mice lost body weight, and calorie restriction usually works best when started relatively early in life.Experimental mice that received rapamycin got a dose of 2.24 mg per kg of body weight. That's quite a lot – about 30 to 60 times (per kg) what would be given to a 60 kg human for immunosuppression.The unfortunate truth is that cell signaling pathways that affect cell growth, proliferation, and survival are rather complicated, and any interventions in such pathways are very likely to not have the expected effects and/or to have various unexpected side-effects. Here's a diagram of just some of the important pathways mTOR is involved in. Imagine that were an electrical circuit and you made ad hoc changes to important components of the circuit.... Perhaps you can see how trying to affect mTOR in order either to control cancer or enhance longevity might be a dicey proposition.In spite of all the reservations, there are still promising signs for the role of mTOR inhibition in lifespan extension. The mechanism of action need not be the same as calorie restriction, even though that hasn't been ruled out either. For example, TOR is known from yeast and nematode studies to promote protein production in ribosomes and to inhibit protein degradation via autophagy. Invertebrate studies have shown that reversal of these TOR effects can increase lifespan. And TOR signaling is also known to influence cell growth, cell-cycle progression, mitochondrial metabolism, and insulin-analog signaling. Remember what we said about the diversity of effects of mTOR signaling? That's definitely a sword that can cut both ways – it's powerful, but hard to predict and control. We need to understand a lot more of the biological details – otherwise we're just swinging the sword in the dark.Harrison, D., Strong, R., Sharp, Z., Nelson, J., Astle, C., Flurkey, K., Nadon, N., Wilkinson, J., Frenkel, K., Carter, C., Pahor, M., Javors, M., Fernandez, E., & Miller, R. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice Nature DOI: 10.1038/nature08221Further reading: Tests raise life extension hopes (7/8/09) – BBC news storyImmune drug boosts lifespan (7/8/09) – TheScientist.com... Read more »