Almost one and a half times
A cocktail of three drugs extended the life of fruit flies by 48 percent
Polina Loseva, N+1
Scientists have extended the life of fruit flies drosophila, using a mixture of three drugs: lithium, rapamycin and antitumor drug trametinib. Each of the substances individually increased life expectancy by an average of 11 percent, in pairs – by 30 percent, and all together – by 48 percent. At the same time, lithium saved the flies from the side effects of rapamycin.
The work was published in the journal Proceedings of the National Academy of Sciences (Castillo-Quan et al., A triple drug combination targeting components of the nutrient-sensing network maximizes longevity).
The life span of the fruit fly of drosophila is only about 3 months, which makes it a convenient object for aging research. Scientists have repeatedly managed to lengthen the life of fruit flies, but the most effective methods have always been genetic. Mutant animals can live several times longer than wild-type flies. Of the non–genetic methods, the restriction in food has shown itself well - up to 50 percent. But with the help of drugs, it has so far been possible to prolong the life of drosophila by only 5-20 percent.
Jorge Castillo-Quan and his colleagues from University College in London decided to try a comprehensive approach on the flies: prolong their lives not with one medicine, but with several at once.
The first drug is rapamycin. First discovered as an antibiotic, it was further used as an immunosuppressor, and its analogues still serve as cancer drugs, and it is also often used in aging research. Rapamycin blocks the TOR protein, which coordinates the cellular response to food intake and causes the cell to grow and store resources. It is believed that it is the work of TOR that leads to the fact that cells wear out and age, that is, they stop dividing and performing their functions in the tissue.
The second substance is trametinib. It blocks MEK kinase, a regulatory protein that is involved in cell division. Trametinib is used in medicine as an antitumor drug.
The third substance is lithium. It blocks another kinase – GSK-3.
All three drug targets are involved in the cell's response to the intake of nutrients. The signal to them comes from the cell surface from insulin-like peptides. Flies deprived of these peptides live 25 percent longer – about 100 days instead of the required 80. However, the drug targets are located in different parts of the signaling pathway. Therefore, the researchers assumed that one drug would not be enough to completely prohibit the cell from activating in the presence of food, and decided to try first a couple of drugs, and then a full-fledged cocktail of three drugs.
They found that each of the substances individually increased the average lifespan of flies by 11 percent. Vapors of substances – on average by 30 percent. And a cocktail of three – by 48 percent.
A – survival of flies under the influence of different combinations of drugs.
Q – comparison of life expectancy: maximum (bright points) and minimum (pale).
Each dot represents one repeat of the experiment. The number of flies in the experiment and the number of researchers who independently confirmed the result are indicated in parentheses. A drawing from an article in PNAS.
Judging by the ratio of these values, it's not a simple addition of effects. Probably, the drugs enhance the effect of each other. In particular, it is known that rapamycin as a side effect increases the amount of fat in human blood and in the hemolymph of flies. But in combination with lithium, it did not have such an effect: the researchers measured the amount of fat, and it did not differ from the control group, which did not receive any drugs.
The observed change in life expectancy could be associated with a change in eating behavior. However, the experimental insects consumed as much food as the control ones. One could also explain this effect by the redistribution of resources: for example, it could be assumed that insects began to reproduce less, and therefore they had enough energy for a long life. Indeed, the drug trametinib reduced the number of eggs laid by flies by half, both by itself and in combination with other substances. However, rapamycin and lithium did not affect the ability to reproduce in any way.
Thus, scientists have created a cocktail, each of the components of which acts on independent targets and probably enhances the effect of others. Researchers have achieved a record result for a drug intervention to increase life expectancy and believe that such cocktails may one day become a means with a similar effect for people.
Recently, scientists have tried to apply another three-component anti-aging cocktail on humans. It was completely different in composition: it included growth hormone, metformin and dihydroepiandrosterone – however, with its help, it was possible to reverse the epigenetic age of patients.
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