From Nature magazine:
A pill for longer life?
A drug slows the march of time in middle-aged mice.
Kerri Smith
Could a pill one day slow ageing in humans?
Rapamycin, a drug commonly used in humans to prevent transplanted organs from being rejected, has been found to extend the lives of mice by up to 14% — even when given to the mice late in life.
In flies and worms, drug treatments have been shown to prolong lifespan, but until now, the only robust way to extend life in mammals has been to heavily restrict diet.
The researchers caution, however, that using this drug to extend the lifespan of humans might be problematic because it suppresses the immune system — potentially making people who take it more susceptible to infectious diseases.
Research teams at three different US institutions — the University of Texas Health Science Center in San Antonio, the University of Michigan in Ann Arbor and the Jackson Laboratory in Bar Harbor, Maine — ran the same experiment in parallel, splitting nearly 2,000 mice between them. The mice were bred to ensure that they were genetically different enough that no single strain would be more or less susceptible to ageing-related diseases or the effects of the drug. They then gave the mice food that included rapamycin.
Problems formulating the feed meant that the teams couldn't start the treatment until the mice were rather older than they had planned — 20 months of age, or the equivalent of about 60 years in human terms.
As it happened, this delay was a fortuitous accident. Compared with the non-drug-taking group, the lifespans of the mice given rapamycin increased by up to 14%, even though they were middle-aged when treatment began. Their life expectancy at 20 months shot up by 28% for the males and 38% for the females.1
"You've probably heard the phrase 'chance favours the prepared mind', and this is an example of it," says David Harrison, who led the arm of the experiment that took place at the Jackson Laboratory.
Calorie control link?
An independent initiative, the Interventions Testing Program overseen by the US National Institute of Aging, chose rapamycin for the three labs to test because it's known to have effects on a cellular pathway called TOR (for target of rapamycin). This pathway is known from studies in mice, flies and worms to be involved in the age-defying effects of calorie-restricted diets.
“I wouldn't do it myself and wouldn't encourage anyone to do it at this point.”
David Harrison
Jackson Laboratory
This link could mean that rapamycin is mimicking the effects of dietary restriction, says Matt Kaeberlein, whose group at the University of Washington in Seattle works on ageing in mice, yeast and worms. "All the arrows are going in the right direction," he says.
Harrison isn't so sure, however — none of the mice lost body weight during their experiments, he says, and dietary restriction usually works best when started early in life, not in middle age as the rapamycin treatment was.
The big question, of course, is whether this drug could extend human life. Both Harrison and Kaeberlein are cautious. "I wouldn't do it myself and wouldn't encourage anyone to do it at this point," says Harrison.
Getting the dose correct is another problem. A normal human dose of rapamycin is between 2 and 5 milligrams per day, much lower than the dose given to the mice, which was 2.24 milligrams per kilogram of body weight per day.
Perhaps rapamycin could be altered somehow, to reduce its effects in the immune system while keeping its anti-ageing effects? "It's an open question whether you can uncouple that from immune suppression," Kaeberlein says. But in future, he says, it's likely that it will be possible to tweak rapamycin in this way, or to target the other molecules in the pathway instead. Kaeberlein's lab is already working on these downstream targets.
Several other compounds are currently being tested by the three US centres as part of the Interventions Testing Program, including resveratrol, a compound found in red wine and thought to have beneficial effects on the heart, and simvastatin, one of a family of compounds called statins, also used for heart conditions.
For now, the researchers won't be trying out their anti-ageing drug on themselves. But that hasn't stopped them daydreaming about it. "Of course, you can imagine we've been considering it ourselves," laughs Harrison. "I'm 67, so it's just about time for me to start my treatment, isn't it?"
References
Harrison, D. E. et al. Nature advance online publication doi:10.1038/nature08221 (2009).
Abstract:
Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies1, 2, 3, 4, 5; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.
