Rapamycin: prolonging life without side effects?
As a result of joint work, a group of scientists from several research institutions in the United States, working under the guidance of associate Professor Joseph A. Baur from the University of Pennsylvania, explained how rapamycin, a drug that increases the life expectancy of model organisms, simultaneously causes cell resistance to insulin, which increases the body's predisposition to diabetes. The results of the work carried out on an animal model showed that theoretically it is possible to separate these two effects mediated by inhibition of two protein complexes mTORC1 and mTORC2, respectively.
Rapamycin, used as an immunosuppressant in organ transplantation, as well as an antitumor drug, became a celebrity after the discovery of its ability to prolong the life of yeast, fruit flies and mice. It was first discovered as a byproduct of the vital activity of Streptomyces hygroscopicus bacteria isolated from a soil sample of Easter Island, also known as Rapa Nui (hence rapamycin). Initially, rapamycin was developed as an antifungal drug, but the situation changed radically after the discovery of its immunosuppressive effect.
Rapamycin exerts its effect through interaction with the mTORC1 and mTORC2 complexes, which are based on a single mTOR protein (the target of mammalian rapamycin), whose functions are determined by associated proteins. These complexes regulate cell growth, movement and survival, as well as protein synthesis and transcription. In certain types of cancer, inadequate activation of one or both mTOR complexes is observed, therefore, double-acting mTOR complex inhibitors are being developed as chemotherapeutic agents.
Specialists were alerted that patients taking rapamycin have an increased predisposition to glucose intolerance, which is a risk factor for diabetes mellitus. At the same time, chronic rapamycin therapy aimed at increasing life expectancy also disrupted glucose metabolism and insulin functioning in the body of mice.
In search of an explanation for this pattern, the researchers analyzed several hypotheses. As a result, they demonstrated in a mouse model that rapamycin disrupts the normal functioning of the mTORC2 complex, which is a necessary condition for insulin-mediated suppression of glucose metabolism in the liver.
On the other hand, in a line of mice with reduced activity of the mTORC1 complex, they demonstrated that inhibition of this mechanism is sufficient to increase life expectancy, not accompanied by changes in glucose metabolism. Such animals lived 14% longer than normal mice and had normal levels of glucose metabolism and insulin sensitivity.
According to the researchers, in addition to developing selective mTORC1 inhibitors, they are primarily very interested in understanding the mechanisms by which mTORC1 inhibition increases life expectancy. Currently, they are studying the interactions between mTORC1 and other mechanisms of longevity, as well as the influence exerted by this complex on processes such as free radical synthesis and quality control of protein synthesis.
Article by Dudley W. Lamming et al. Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity published in the journal Science.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the University of Pennsylvania:
Duality of Longevity Drug Explained by Perelman School of Medicine Researchers02.04.2012