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Sunday, July 26, 2009

LIVE DECADES LONGER WITH A PILL?

26 july 2009--“A wonder pill could extend the lifespan of people by up to 23 years,” the Daily Express has reported on its front page. Most other newspapers have also featured stories on an ‘anti-ageing drug’, which contains a chemical made by insects in the soil on Easter Island. They say that it stops cells in mice from ageing by blocking the damaging proteins thought to be responsible for the ageing process.

The lifespan of mice (up to the point where 90% had died) was extended by up to 38% if measured from the time that they were given the drug. The newspapers say this raises the possibility that a similar drug might delay ageing in people by several years. However, it is based on several assumptions, such as equating 10 mouse days to one year of a human life. The research also raises the possibility that the survival rates might vary due to different diets given to mice before they were given the drug.

The drug rapamycin has already been used in humans to prevent rejection after transplants, but the researchers say it is not licensed for healthy people, and may increase risk of infections. The main appeal of this research is the benefit seen in mice that were given the drug later in life. It means that researchers now have a target for the development of new drugs aimed at treating age-related diseases and extending healthy life in humans.

Where did the story come from?

This research was carried out by Dr David E. Harrison from the Jackson Laboratory in Maine, US. Other colleagues from departments and institutes of ageing around the US co-authored the paper, which was supported by grants from the National Institutes of Ageing and the Department of Veterans Affairs in the US. The study was published in Nature, the peer-reviewed scientific journal.

What kind of scientific study was this?

This animal study testing how the drug rapamycin might affect lifespan in specially bred mice.

Rapamycin, which was discovered in the 1970s in the hunt for new antibiotics, is a drug that inhibits the ‘TOR signalling pathway’. The TOR signalling pathway has been studied in yeasts and invertebrates, and it controls cell growth by activating and inhibiting important cell processes. In the laboratory, parts of this pathway have been inhibited by several things, such as low nutrient levels, caffeine and rapamycin. New TOR inhibitor drugs might potentially have roles in several areas of disease, particularly in the fight against cancer.

Rapamycin is currently used to suppress immune systems of patients who have had transplant operations, to prevent their bodies rejecting organs. It is also used in heart operations, and is being tested for its anti-cancer properties. It is not licensed for use in healthy people.

The research was conducted at three test sites in the US: The Jackson Laboratory, the University of Michigan and the University of Texas Health Science Center. All the mice were supplied by the Jackson Laboratory, and had been bred to be genetically unique despite the fact that they were all siblings. The researchers say that a 600-day-old mouse is roughly equivalent to a 60-year-old human. The initial research, which began in 2005, looked at 1,960 mice.

The researchers weaned the mice on a standard, specially formulated diet (mouse chow) until they were 600 days old, and then added rapamycin to the feed of the “rapamycin-fed group”. The remainder, “the control group”, continued to be fed on their normal diet. Rapamycin was prepared in capsule form so that it could pass through to the intestine undigested.

After the mice had been divided into the two groups at 600 days, they were followed until they died naturally or were judged to be too sick and “euthanised”. The researchers measured the average (median) survival and the number alive up to the last tenth of expected lifespan for a mouse. This was calculated by recording the day on which 90% of the mice had died. This is a measure of the mouse maximum survival, but not the actual length of time that all the mice lived.

What were the results of the study?

The researchers say that rapamycin extended the median and maximal lifespans of both male and female mice when fed the drug from 600 days of age. Combining results from the three test sites showed that rapamycin led to an increased survival time of 14% for females and 9% for males when measured from the start of the study to the point where 90% of the mice had died. The control female mice lived 1,094 days, which increased to 1,245 days in the treated females. The respective lifespan for males was 1,078 days, which increased to 1,179 days with treatment.

Patterns of disease did not differ between control mice and normal mice.

What interpretations did the researchers draw from these results?

The researchers say that “these are the first results to demonstrate a role for the mTOR signalling in the regulation of mammalian lifespan” and the “pharmacological extension of lifespan in both genders”.

They suggest that their findings have implications for the further development of interventions which target the mTOR pathway for the treatment and prevention of age-related diseases. They also suggest that rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or through a combination of the two.

What does the NHS Knowledge Service make of this study?

This study has several interesting features and will provide an added impetus to research in this area. However, there are important points to consider when interpreting this study.

Across the groups mice actually had about the same lifespan, about 1,250 days, and the survival improvements reported are due to the measures used in this study, and the fact that fewer mice in the treated group died in the first 90% of their lifespan, and instead died in the last 10%. This difference is apparent from an examination of the survival curves reported in the study. Survival curves simply report the proportion of mice surviving at all time points throughout the study.

Looking at these curves, it is apparent that in two of the laboratories the survival curves begin to separate before the 600-day point. This suggests that there was a difference in the number of mice surviving in the control and treated groups, even before they were given the active drug.

This is a puzzling finding, which indicates that a factor other than the drug had affected their rates of survival. The researchers say that this difference was partly due to the control mice in the two labs receiving a different formula of mouse feed.

On this basis, the researchers say they cannot rule out the possibility that improved survival among these two groups of males might reflect differences in nutritional or health status between control and rapamycin groups before 600 days, rather than solely the effects of rapamycin.

Finally, it should be noted that this was an experiment in mice, therefore the benefit of longer lifespan found in this study may not translate directly into humans. On this basis, rapamycin should not yet be considered to ‘extend life by 20 years’. A further consideration of potentially extending lifespans must also be the quality of life experienced during any extra years gained.