Rejuvenating cocktails

Researchers at the National University of Singapore, working under the guidance of Dr. Jan Gruber, have compiled several combinations of pharmaceutical drugs that not only increase the healthy life expectancy of microscopic roundworms Caenorhabditis elegans, but also slows down the rate of their aging.

Initially, the aim of the authors' work was to develop a method for increasing the duration of a healthy life by combining drugs that affect various signaling mechanisms that affect life expectancy. For example, rapamycin is currently used to prevent rejection of donor organs, but earlier experiments have shown that it increases the life expectancy of many organisms, including C.elegans nematodes, fruit flies of fruit flies and mice.

First, the researchers, based on the literature data, identified the most well-studied mechanisms of increasing life expectancy, after which they selected drugs that affect these mechanisms. A total of 12 compounds were tested on roundworms, of which 5 of the most promising were selected: rapamycin, rifampicin, psora-4, metformin and allantoin. All these drugs significantly increased both the average (blue bars) and maximum (orange) life expectancy of nematodes.

After that, the selected 5 compounds were tested in pairs. The combination of optimal dosages of metformin and rapamycin did not provide an additional increase in life expectancy, however, the desired effect was achieved by combining suboptimal dosages of these compounds. Two combinations – rapamycin + rifampicin and rifampicin + psora-4 – in optimal concentrations provided a synergistic effect on life expectancy.

At the next stage, the researchers tested combinations of 3 drugs. Since testing all possible variants (220 combinations) was a very difficult task, they decided to start with a combination of 3 of the most well-proven compounds: rapamycin, rifampicin and psora-4.

However, this combination even reduced life expectancy compared to the two most successful two-component combinations. After that, they decided to add allantoin to these two-component combinations. Both three-component variants provided a significant increase in average and maximum life expectancy, and the most successful of them (rapamycin + rifampicin + allantoin) doubled the average life expectancy. The authors note that this approach is more effective than all previously tested pharmacological interventions aimed at increasing the life expectancy of adult nematodes.

In addition, the tested three-component combinations not only did not reduce fertility, which is typical for a number of methods of increasing life expectancy, but also slightly increased the duration of the reproductive period. Moreover, the addition of both combinations of drugs to the medium containing worms increased the duration of a healthy life. In fact, according to the frequency of spontaneous movements, the old individuals of the experimental groups did not differ from the young individuals of the control group. Finally, both successful three-component combinations of drugs increased the resistance of nematodes to oxidative and thermal stress.

The researchers also analyzed the effect of three-component therapy on the age and non-age mortality of nematodes. An interesting fact is that the combination of rifampicin + psora-4+allantoin significantly reduced both age and non-age mortality. This suggests that therapy not only improves the condition of the worms at an early age, but also slows down their aging.

Subsequent experiments have shown that three-component combinations of drugs also significantly increase the life expectancy of fruit flies Drosophila (Drosophila melanogaster). The fact that such evolutionarily distant organisms as nematodes and fruit flies react equally to the effects of tested drug combinations testifies to the antiquity of the molecular mechanisms underlying aging.

In the future, the authors plan to develop their work in three directions. First, they will expand their approach to develop even more effective interventions. The second direction will be devoted to the study of molecular and biological mechanisms of drug interactions that slow down aging and increase life expectancy. This will allow the development of computer models to simulate these interactions, with the help of which it will be possible to test thousands of combinations of promising drugs before conducting experiments on animals. The third and main direction will be the development of safe pharmacological interventions to slow down human aging.

Article by Tesfahun Dessale Admasu et al. Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling published in the journal Developmental Cell.

Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Yale-NUS College: Yale-NUS researchers discover drug cocktail that increases lifespan.