Rapamycin has again confirmed its geroprotective properties
A short course of immunosuppressant prolonged the life of mice
Oleg Lischuk, N+1
American scientists managed to prolong the life of mice with a limited course of rapamycin in old age. The results of the work are published in the journal eLife (Bitto et al., Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice).
Rapamycin (sirolimus) is an immunosuppressant that is used to prevent rejection after kidney transplantation and for several other indications. In a number of experiments, it has been shown that regular intake of relatively small doses of this drug significantly prolongs the life of mice and some other animals. The drug also slowed down aging-related processes such as weakening of mental functions, cardiac disorders, decreased immunity and the development of cancer. Pilot clinical trials have demonstrated that a six-week course of rapamycin derivative RAD001 improves the immune response in the elderly. At the same time, the optimal prescribing schemes, the duration of the course and the dosage of the drug to slow down aging have not yet been clarified.
Employees of the Fred Hutchinson Cancer Research Center, the Universities of Washington and Missouri administered rapamycin to mice aged 20-21 months for 90 days (this approximately corresponds to the 60-year age of a person). The dose used was relatively large – eight milligrams per kilogram of body weight per day intraperitoneally (this is 27 times more than was used in previous studies with constant intake of rapamycin). The effects of the drug in males and females were evaluated separately.
During the course of therapy, male mice had a significant decrease in body weight when consuming the same amount of food, and this effect persisted for several weeks after discontinuation of the drug. Their life expectancy after the end of treatment increased by 60 percent compared to mice from the control group. Total life expectancy from birth increased by 16 percent. The male mouse, who lived the longest after the course of therapy, lived another 710 days until the age of about 1400 days (about 140 human years), which made him one of the longest-lived mice in the entire history of observations.
Weight loss was also observed in female mice, but a significant prolongation of life was not achieved in them. According to the researchers, this is due to the observed increase in the incidence of aggressive forms of cancer of the hematopoietic system (while the risk of cancer of other organs decreased significantly) compared with the control group. No such increase in cancer incidence was observed in males.
At the second stage of the experiment, when the dose of the drug was tripled in mice of the same age, life expectancy after a three–month course of treatment increased in animals of both sexes: after treatment – by an average of 42 percent, absolute - by 13 percent. Also, the mice taking rapamycin had higher indicators of muscle strength and endurance than in the control group for at least six months.
In addition, it turned out that taking the drug caused significant changes in the intestinal microbiome of animals. The most significant of them was an increase in the proportion and total number of segmented filamentous bacteria in the small intestine. These gram-positive microorganisms are low-virulent and non-invasive, but their interaction with the intestinal epithelium activates the differentiation of immune cells, enhancing the immune response. Normally, elderly animals do not have a significant number of them. The significance of such an impact on the microbiome for general health and life expectancy has not yet been clarified.
Rapamycin inhibits the signaling pathway of the most important cell growth regulator mTOR (a mechanistic target of rapamycin). This leads to various changes in metabolism and energy in cells, as well as their reactions to the action of biologically active substances (hormones, cytokines, etc.). How exactly these changes increase life expectancy remains generally unknown.
Many laboratories around the world are working on the problem of healthy aging and prolongation of life, which investigate various pharmacological and non-pharmacological approaches. In addition to tacrolimus, nicotinamide riboside (a derivative of vitamin B3), as well as inhibitors of the transcription-regulating JAK-STAT signaling pathway and insulin-like growth factor type 1 (IGF-1) are considered the most promising drugs. Also, in order to prolong a healthy life, gene, cellular and tissue therapy, restriction of calories consumed, the appointment of hormones and antioxidants, "cleansing" the body of aged cells, activation of the enzyme telomerase, removal of damaged mitochondria from cells and other techniques are being investigated. Most of them are in the stage of laboratory study or preclinical testing.
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29.08.2016