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Rapamycin changes the way our DNA is stored

Rapamycin changes the way our DNA is stored

The anti-aging compound rapamycin affects DNA winding. Credit: Hanna Salmonowicz, Monney Medical Media, 2021

Our genetic material is stored in our cells in a certain way to make the meter-long DNA molecule fit into the small cell nucleus in each body cell. An international team of researchers at the Max Planck Institute for Biology of Aging, the CECAD Cluster of Excellence in Aging Research at the University of Cologne, University College London and the University of Michigan has now been able to demonstrate that rapamycin, a well-known anti -aging candidate, is targeted at intestinal cells specifically to alter DNA storage in these cells, thereby promoting intestinal health and longevity. This effect has been observed in flies and mice. The researchers believe that this finding will open up new possibilities for targeted therapeutic interventions against aging.

Our genetic material is in the form of DNA in every nucleus of our body cells. In humans, this DNA molecule is two meters long – yet it fits into the cell nucleus, which is only a few micrometers in size. This is possible because the DNA is accurately stored. To do this, it is repeatedly wrapped around certain proteins known as histones. How tightly DNA is wrapped around the histones also determines which genes can be read from our genome. In many species, the amount of histones changes with age. Until now, however, it has been unclear 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 goal

The drug rapamycin recently became one of the most promising drugs against aging and shows positive effects on health in old age. “Rapamycin turns down the TOR signaling pathway, which regulates a wide range of basic cellular activities such as energy, nutrition and stress status. In short, we use rapamycin to fine-tune the master regulator of cellular metabolism,” explains Yu-Xuan Lu, postdoc in Linda’s department. Partridge and first author of the study. “Meanwhile, we know that histone levels have a critical impact on the aging process. However, we had no idea whether there is a link between the TOR signaling pathway and histone levels, and more importantly, whether histone levels could be a drugable anti-aging target.”

To investigate the effect of rapamycin on histone proteins, the researchers analyzed various organs of the fruit fly Drosophila melanogaster. “We looked at different tissues and organs in the fly for noticeable changes in histone levels before and after treatment with rapamycin; that means before and after disconnecting the TOR signaling pathway,” explains Yu-Xuan Lu. “Surprisingly, we observed an increase in histone proteins after treatment with rapamycin. This effect occurred exclusively in the intestines of the flies, but not in other tissues.”

In further experiments, Yu-Xuan Lu and his colleagues were able to show that the increased levels of certain histone proteins in a particular intestinal cell type called enterocytes reduced tumor growth, improved intestinal health, and prolonged life of the animals. Similar observations were made in mouse gut enterocytes after rapamycin treatment.

“For the first time, our results show a correlation between the TOR signaling pathway and histone levels that determine lifetime,” says Yu-Xuan Lu. “The increased levels of histone proteins subsequently change how 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 histone’s central role in DNA storage in the cell, this finding not only expands our knowledge of the aging process, but also provides new opportunities for targeted therapeutic interventions against aging.”

Protein can release trapped histones in the cell

More information:
Yu-Xuan Lu et al., A TORC1 histone axis regulates chromatin organization and non-canonical induction of autophagy to improve aging, eLife (2021). DOI: 10.7554 / eLife.62233

Journal information:

Provided by the Max Planck Society

Citation: Rapamycin changes the way our DNA is stored (2021, June 9) Retrieved June 9, 2021 from https://phys.org/news/2021-06-rapamycin-dna.html

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