16 July 2009

An immunosuppressant will not help to live up to a hundred years :(

Rapamycin slows down aging in miceAlexander Markov, Elements
Rapamycin was first detected in soil samples from Easter Island.

The local name of the island is Rapa Nui, hence the name of the medicine. Photo from the discussed Kaeberlein & Kennedy article in Nature

Rapamycin, a substance secreted by soil bacteria and first discovered in the soil of Easter Island, prolongs the life of not only yeast, flies and worms (this was previously known), but also mice. Experiments conducted independently in three laboratories showed that male mice who started taking rapamycin in old age (600 days) live 9% longer, and females - 13% longer than control mice who did not take medications. However, rapamycin has harmful side effects that do not allow it to be used to prolong people's lives.

Rapamycin is produced by the soil bacteria Streptomyces hygroscopicus. Previously, it was found that this substance prolongs the life of yeast and invertebrates (flies, worms). Studying the causes of this effect, scientists found that rapamycin suppresses the activity of an important regulatory protein, which is called TOR (target of rapamycin, "target of rapamycin"). As it turned out, TOR regulates a number of vital processes in the cell, including the rate of cell division and the rate of protein synthesis. Mammals have their own version of the TOR protein, but so far almost nothing has been known about its effect on life expectancy.

Moreover, all attempts by pharmacological methods to increase the life expectancy of laboratory mammals (such experiments are usually carried out on mice) have so far either proved unsuccessful, or allowed only one of the sexes (males or females) to prolong the life a little, or extended the life exclusively of some pure genetic line of mice - for example, by reducing the frequency of specific "age-related diseases" characteristic of this particular genetic line, but not for all old mice in general.

Currently, the National Institute of Aging (USA) is making great efforts to find ways to prolong the life of mice, regardless of their belonging to a particular genetic lineage. As part of the Interventions Testing Program (ITP), experiments with genetically heterogeneous (diverse) mice are conducted in parallel at three research centers: at the Universities of Michigan and Texas and at The Jackson Laboratory.

Rapamycin was included in the research program because it was previously shown that the suppression of TOR activity in short-lived model animals (flies and roundworms) leads to an increase in average life expectancy. Mice were given rapamycin when they were already in old age – 600 days, which corresponds to about 60 years of age in humans. It wasn't planned that way. When experimental groups of mice in all three institutes were already born, technical problems arose with the addition of rapamycin to food. It turned out that this substance breaks down too quickly when mixed with standard mouse food. Therefore, it was necessary to urgently develop a technology for packaging rapamycin in small capsules, from which the substance gradually enters the blood of mice that have eaten it. As a result, when everything was ready, the mice had already aged. However, thanks to this technical overlay, the results obtained have become even more interesting, because slowing down aging in the later stages is obviously even more difficult than achieving the same effect by affecting animals from a young age.

Survival of mice in experiments.
On the horizontal axis – the age of mice in days, on the vertical axis – the proportion of mice who lived to this age. Lines with red triangles are mice that have taken rapamycin since the age of 600 days; lines with blue triangles are control mice. The upper graphs are males, the lower ones are females. The two left graphs are the results obtained in the Jackson Laboratory, the middle graphs are the University of Michigan, the right graphs are the University of Texas.
Fig. from the article under discussion by Harrison et al. in Nature

Similar results were obtained in all three institutes, showing that rapamycin really prolongs the life of mice. The average life expectancy of females at the Jackson Laboratory, the University of Michigan and the University of Texas increased by 15, 16 and 7%, respectively (an average of 13%); males – by 5, 8 and 15% (an average of 9%). The results become even more impressive if they are expressed through an increase in the life expectancy of mice who have reached the age of 600 days (when they began to be given rapamycin). This indicator increased in females taking the medicine by 45, 48 and 22%, in males – by 16, 23 and 52%. However, at the University of Michigan and the University of Texas, the results for males were not quite "clean", because the composition of the feed in the experimental and control groups was slightly different from the very beginning. Perhaps that is why the survival rate of males in the experimental and control groups began to differ even before the experimental group began receiving rapamycin (see the middle and upper right graphs). The Jackson laboratory did not make this mistake: the composition of the feed in all mice was absolutely identical.

Three more groups of mice started receiving rapamycin at an earlier age – 270 days, but this experiment is not over yet. By February 2009, when the results were processed, 49% of females and 32% of males were still alive. At this point, in all three laboratories, the mortality rate in females treated with rapamycin was significantly lower than in controls, and in males, rapamycin significantly reduced mortality in two out of three laboratories. Apparently, rapamycin not only prolongs the life of elderly mice, but also reduces mortality in "middle-aged" mice.

To make sure that the mechanism of action of rapamycin in mice is the same as in invertebrates, the researchers measured the level of phosphorylation of ribosomal protein S6. In invertebrates, rapamycin, as we remember, suppresses the activity of TOR. This leads (through a number of intermediate steps) to a reduced level of phosphorylation of the S6 protein. This is one of the mechanisms by which rapamycin ultimately slows down the work of ribosomes, that is, protein synthesis. It turned out that in mice receiving rapamycin, the level of S6 phosphorylation was reduced by 4-5 times. This suggests that the mechanism of action of rapamycin in mice is most likely the same as in invertebrates. The drug slows down the vital activity of cells, which leads, in particular, to a decrease in the likelihood of the formation of malignant tumors (which are the main cause of death in old mice).

There is another reliable way to prolong the life of laboratory animals (flies, worms and mice) – a restrictive diet. If you don't let animals overeat, they live longer. One of the likely reasons for the beneficial effects of a restrictive diet is that it reduces the activity of TOR. Therefore, we can say that rapamycin in some sense "imitates" a restrictive diet. The authors, however, point out two fundamental differences. Firstly, a restrictive diet always leads to a decrease in the weight of animals compared to the control, and the weight does not decrease from rapamycin. Secondly, a restrictive diet prolongs life only if mice are put on this diet at an early age. Mice who have lived the first 600 days on a regular diet, no food restrictions will help in the future.

Unfortunately, this study is still of purely theoretical interest. The creation of effective "medicines for old age" is still far away. Rapamycin has many side effects and therefore cannot be used to prolong people's lives. In particular, it has an immunosuppressive effect (weakens the immune defense of the body). Currently, doctors use drugs based on rapamycin to suppress immunity during organ transplantation, as well as for the treatment of late-stage kidney cancer.

1) David E. Harrison et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice // Nature (16 July 2009). V. 460. P. 392–395. Doi:10.1038/nature08221.
2) Matt Kaeberlein, Brian K. Kennedy. Ageing: A midlife longevity drug? // Nature (16 July 2009). V. 460. P. 360–361. Doi:10.1038/nature08246.

Portal "Eternal youth" http://vechnayamolodost.ru16.07.2009

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