Our genetic material is stored in our cells in a specific way so that the meter-long DNA molecule fits into the tiny cell nucleus of every cell in the body. An international team of researchers from the Max Planck Institute for the Biology of Aging, the CECAD Center of Excellence in Aging Research at the University of Cologne, University College London and the University of Michigan have now been able to show that rapamycin, a well-known anti-aging candidate, specifically targets intestinal cells to alter the way DNA is stored inside these cells, thereby promoting intestinal health and longevity. This effect has been observed in flies and mice. Researchers believe this discovery will open up new possibilities for targeted therapeutic interventions against aging.
Our genetic material is found in the form of DNA in every cell nucleus of our body cells. In humans, this DNA molecule is two meters long, but it fits into the nucleus of the cell, which is only a few microns in size. This is possible because DNA is stored with precision. To do this, it is wrapped several times around certain proteins called histones. The way the DNA is wrapped around histones also determines which genes can be read in our genome. In many species, the amount of histones changes with age. So far, however, it is not clear whether changes in cellular histone levels could be used to improve the aging process in living organisms.
A well-known anti-aging compound with a new target
The drug rapamycin has recently become one of the most promising anti-aging substances and shows positive effects on the health of the elderly. “Rapamycin blocks the TOR signaling pathway that regulates a wide range of basic cellular activities such as energy, nutritional and stress status. In short, we use rapamycin to refine the primary regulator of cell metabolism,” explains Yu-Xuan Lu, postdoc in Linda Partridge’s department and first author of the study. “In the meantime, we know that histone levels have a critical impact on the aging process. However, we weren’t sure if there was a link between the TOR signaling pathway and histone levels, and more importantly. again, if histone levels could be an anti-drug. aging target. “
To study the effect of rapamycin on histone proteins, the researchers analyzed various organs of the fruit fly Drosophila melanogaster. “We looked for noticeable changes in histone levels in different tissues and organs of the fly before and after treatment with rapamycin, that is to say before and after the deactivation of the TOR signaling pathway”, Yu-Xuan Lu explains. “Surprisingly, we observed an increase in histone proteins after treatment with rapamycin. This effect occurred exclusively in the gut of flies, but not in other tissues.” In other experiments, Yu-Xuan Lu and his colleagues were able to show that the increased levels of certain histone proteins in a specific type of gut cell called enterocytes reduced tumor growth, improved gut health, and prolonged the lifespan of animals. . Similar observations were made in mouse intestinal enterocytes after treatment with rapamycin.
“Our results show for the first time a link between the TOR signaling pathway and the levels of histones that determine longevity,” says Yu-Xuan Lu. “The increased levels of histone proteins subsequently alter the way the DNA is stored in the nucleus. The fact that we were also able to make similar observations in mice shows that this is a widespread mechanism. ” Looking ahead to future experiments, he adds: “Given the central role of histones on DNA storage in the cell, this discovery not only expands our knowledge about the aging process, but also offers new possibilities for targeted therapeutic interventions against aging. “
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