The relationship between muscles and aging is revealed
Researchers at Brown University, working under the guidance of Professor Marc Tatar, have deciphered a complex sequence of events at the molecular level, leading from insulin to the degradation of muscle proteins and significantly reducing the lifespan of fruit flies drosophila. A key role in this molecular cascade belongs to the mammalian protein analog activin.
The life expectancy of fruit flies is very small, but scientists specializing in the study of the biology of aging are already gradually beginning to understand the mechanisms by which some individuals live much longer than others. They clearly demonstrated the existence of a relationship between insulin and life expectancy, and also described a compromise between high fertility and longevity. A new study, the results of which can be applied to a wide range of living organisms, has revealed a close relationship between these two observations, going from an insulin-mediated signaling cascade to "quality control" of muscle tissue proteins and shortening of life expectancy.
The authors began their study inspired by the understanding that a decrease in the activity of the insulin-mediated signaling mechanism increases the lifespan of fruit flies due to the fact that a decrease in insulin levels entails an increase in the level of the dFOXO protein. The primary task for them was to search for genes, by influencing which dFOXO increases life expectancy.
In the process, the search field was narrowed to three genes, the suppression of the activity of which using the method of RNA interference increased the lifespan of fruit flies. At the same time, suppression of the activity of the dawdle gene – an analogue of the mammalian gene encoding the activin protein – increased life expectancy by 12-35%.
The life of fruit flies. Individuals in whose cells the dawdle gene was inactivated lived significantly longer than the flies of the control group. Approximately on the 40th day of the experiment, only a small part of the drosophila of the control group remained alive, while almost all flies with the inactivated dawdle gene were alive.
In earlier experiments on fruit flies, it was shown that dawdle is involved in the development of the nervous system. In the human body, one of the functions of activin is the stimulation of ovarian follicles in women.
However, when researchers began searching for the role of dawdle in life expectancy, it turned out that the answer lies in muscle tissue. It was found that dawdle suppresses the activity of the Atg8a gene, whose function is to stimulate autophagy – the process of splitting and reuse of abnormal and damaged proteins. The accumulation of such proteins in myocytes weakens muscles in the same way as the accumulation of abnormal beta-amyloid in brain tissue leads to the development of Alzheimer's disease.
In the drosophila muscle fibers of the control group (upper row) at 1, 3 and 5 weeks of life, more protein aggregates (green dots) accumulated compared to the drosophila muscle fibers in whose cells the dawdle gene was inactivated, making it difficult to remove these aggregates (lower row).Suppression of dawdle activity provided more effective removal of damaged proteins from the muscle fibers of fruit flies.
It has also been shown that overexpression of the Atg8a gene slightly increases the lifespan of fruit flies.
In addition, the authors found that suppression of dawdle activity also reduced insulin secretion by the neurosecretory cells of the drosophila brain, which led to a decrease in the activity of the insulin-mediated signaling cascade at the systemic level. This mechanism was the last link that closed the feedback loop, in which the suppression of insulin-mediated signals increases the activity of dFOXO suppressing dawdle, which in turn leads to further suppression of insulin secretion in the brain. The same process ensured the maintenance of better muscle tissue functionality by increasing the expression of Atg8a.
According to the authors, they have not yet figured out why the deterioration of muscle function due to reduced autophagy activity shortens life expectancy. One possible explanation is the loss of mobility by aging flies, which deprives them of the ability to find food. However, researchers have already begun to look for an answer in another direction. They are conducting experiments aimed at testing the hypothesis that an autophagy-blocking signaling cascade can negatively affect the work of the heart muscle.
In addition, they are studying the signaling mechanisms mediated by the activin protein in mammalian cells and hope that the data obtained in the future will provide specialists with new therapeutic targets and information necessary for the development of drugs to slow aging.
Article by Hua Bai et al. Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila is published in the journal PLoS Genetics.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Brown University: Protein interplay in muscle tied to life span.
18.11.2013