RESEARCHERS DISCOVER AN UNEXPECTED LINK BETWEEN DNA WINDING AND METABOLISM IN THE GUT TO AMELIORATE AGEING
Our genetic material is stored in our cells in a specific way to make the meter-long DNA molecule fit into the tiny cell nucleus of each body cell. An international team of researchers at the Max Planck Institute for Biology of Ageing, the CECAD Cluster of Excellence in Ageing research at the University of Cologne, the University College London and the University of Michigan have now been able to show that rapamycin, a well-known anti-ageing candidate, targets gut cells specifically to alter the way of DNA storage inside these cells, and thereby promotes gut health and longevity. This effect has been observed in flies and mice. The researchers believe this finding, which is published in the scientific journal eLife, will open up new possibilities for targeted therapeutic interventions against ageing.
Our genetic material lies in the form of DNA in every cell 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 micrometres in size. This is possible because the DNA is precisely stored. To do this, it is wound several times around certain proteins known as histones. How tightly the DNA is wound 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 is unclear whether changes in cellular histone levels could be utilized to improve the ageing process in living organisms.
Rapamycin is a well-known anti-ageing compound – with a new target
The drug rapamycin recently became one of the most promising anti-ageing substances and shows positive effects on health in old age. “Rapamycin turns down the TOR signalling pathway that regulates a wide spectrum of basic cellular activities such as energy, nutritional and stress status. In short, we use rapamycin to fine-tune the master regulator of cellular metabolism”, explains Yu-Xuan Lu, postdoc in the department of Linda Partridge and first author of the study. “Meanwhile, we know that histone levels have a critical impact on the ageing process. However, we had no idea whether there is a link between the TOR signalling pathway and histone levels, and more importantly, whether histone levels could be a druggable anti-ageing target.”
To study the effect of rapamycin on histone proteins, the researchers analysed various organs of the fruit fly Drosophila melanogaster. “We looked in different tissues and organs of the fly for noticeable changes in histone levels before and after treatment with rapamycin, this means before and after switching off the TOR signalling pathway”, explains Yu-Xuan Lu. “Surprisingly, we observed an increase in histone proteins after rapamycin treatment. This effect occurred exclusively in the gut 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 specific gut cell type called enterocytes reduced tumour growth, improved gut health and extended lifespan of the animals. Similar observations were made in mouse gut enterocytes after rapamycin treatment.
“Our results show for the first time a link between the TOR signalling pathway and histone levels that determines longevity”, says Yu-Xuan Lu. “The increased levels of histone proteins subsequently change how 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 finding not only broadens our knowledge on the ageing process, but also provides new possibilities for targeted therapeutic interventions against ageing.”
This project has received funding from the European Union’s Horizon 2020 research, the Glenn Foundation for Medical Research, and the Max-Planck-Gesellschaft. Yu-Xuan Lu was supported by an EMBO Long-Term Fellowship.
Yu-Xuan Lu, Jennifer C. Regan, Jacqueline Eßer, Lisa F. Drews, Thomas Weinseis, Julia Stinn, Oliver Hahn, Richard A. Miller, Sebastian Grönke and Linda Partridge.
A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing.
Online: 14.05.2021, DOI: 10.7554/eLife.62233
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Learn more about the research at the department of Linda Partridge.
DO WOMEN AGE DIFFERENTLY FROM MEN?
Studies in fruit flies reveal how the sex determines the responses to the anti-ageing drug rapamycin
The effect of medicines on women and men can differ significantly. This also applies to the currently most promising anti-ageing drug rapamycin, as researchers from the Max Planck Institute for Biology of Ageing in Cologne and University College London have now shown. They report in Nature Aging that the drug only prolongs the lifespan of female fruit flies, but not that of males. In addition, rapamycin only slowed the development of age-related pathological changes in the gut in female flies. The researchers conclude that the biological sex is a crucial factor in the effectiveness of anti-ageing drugs.
The life expectancy of women is significantly higher than that of men. However, women also suffer more often from age-related diseases and adverse drug reactions. “Our long-term goal is to make men live as long as women and also women as healthy as men in late life. But for that, we need to understand where the differences come from”, explains Yu-Xuan Lu, one of the leading authors of the study.
Rapamycin extends lifespan only in female flies
The researchers gave the anti-ageing drug rapamycin to male and female fruit flies to study the effect on the different sexes. Rapamycin is a cell growth inhibitor and immune regulator that is normally used in cancer therapy and after organ transplantations. They found that rapamycin extended the lifespan and slowed age-related intestinal pathologies in female flies but not in males.
Healthier life due to more autophagy
The researchers observed that rapamycin increased autophagy – the cell’s waste disposal process – in the female intestinal cells. Male intestinal cells, however, already seem to have a high basal autophagy activity, which cannot be further increased by rapamycin. The scientists could also see this effect of rapamycin in mice. Female mice showed increased autophagy activity after treatment with rapamycin. “Previous studies found that females had greater responses to rapamycin on lifespan extension than did males in mice, we now uncover an underlying mechanism of these differences using flies”, says Yu-Xuan Lu.
Sex-specific, personalised treatments
“Sex can be a decisive factor for the effectiveness of anti-ageing drugs. Understanding the processes that are sex-specific and determine response to therapeutics will improve the development of personalised treatments”, explains Linda Partridge, senior author of the study.
The research for this study was conducted at the Max Planck Institute for Biology of Ageing and the University College London. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 741989).
Jennifer C Regan*, Yu-Xuan Lu*, Enric Ureña, Ralf L Meilenbrock, James H Catterson, Disna Kißler, Jenny Fröhlich, Emilie Funk, Linda Partridge
Sexual identity of enterocytes regulates autophagy to determin intestinal health, lifespan and responses to rapamycin
Nature Aging, December 1st, 2022
*authors contributed equally to the study
Learn more about the work in the Partridge lab.