Recycling is the way to prolong life
Scientists from Brown University, USA, led by Louis Lapierre, have developed a new strategy to stimulate autophagy – the process of self-renewal of cells by recycling worn parts. The method has been tested in experiments on nematodes, fruit flies and human cell culture.
Violation of autophagy accompanies a number of neurodegenerative and other age-related diseases. The authors suggested that if they can control this process with the help of drugs, they will be able to influence the progression of age-related diseases.
The study of autophagy attracts more and more researchers around the world. In 2016, Yoshinori Osumi, a biologist from Japan who described it, was awarded the Nobel Prize in Physiology or Medicine. The process involves the absorption of defective proteins and worn-out cellular structures by autophagosomes. After that, they merge with lysosomes, enzymes break down the contents of autophagosomes to components that can be reused by the cell.
The researchers decided to stimulate autophagy by influencing the transcription factor – a protein that enables and disables gene expression. To do this, it had to be localized in the cell nucleus. They started looking for genes responsible for the synthesis of autophagic activity transcription factor (TFEB).
In a study on C.elegans nematodes, the search showed that the weakening of the expression of the transport protein XPO1, which transports proteins from the nucleus to the cell body, leads to the accumulation of TFEB in the nucleus and increased autophagy. As markers of autophagic activity, the authors evaluated the number of autophagosomes, autolysosomes and the degree of lysosomal biogenesis. There was also an increase in the life expectancy of worms after the intervention by 15-45%.
Thus, it has been demonstrated that limiting the transport of TFEB from the cell nucleus leads to prolongation of life.
The next step is to search for a drug that could have an effect identical to the shutdown of genes in the previous experiment. Scientists found that selective nuclear export inhibitors (SINE), previously developed for the treatment of cancer, had the desired effect – they accumulated TFEB in the cell nucleus, enhanced autophagy and increased the life expectancy of roundworms.
The researchers tested SINE on fruit flies genetically modified to create a model of a neurodegenerative disease – amyotrophic lateral sclerosis. As a result of the experiment, life expectancy increased slightly, but significantly.
Finally, SINE was tested in human HeLa cell culture: the concentration of TFEB protein in the nucleus increased, autophagy markers showed increased activity of the process.
The work done demonstrates the effectiveness of the strategy of increasing autophagy. It is necessary to conduct research on clinically more significant models of neurodegenerative diseases.
Article by M. J. Silvestrini et al. Nuclear Export Inhibition Enhancements HLH-30/TFEB Activity, Autophagy, and Lifespan is published in the journal Cell Reports.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Brown University: Researchers find a new way to stimulate cellular recycling process.