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G. V. Shivashankar (left) and Yawen Liao from the PSI Center for Life Sciences have investigated how chromatin in human cell nuclei changes with age.
Photo Credit: © Paul Scherrer Institute PSI/Markus Fischer
Scientific Frontline: Extended "At a Glance" Summary: Chromatin Alteration in Cellular Aging
The Core Concept: As human cells age, the packaged form of DNA within the cell nucleus, known as chromatin, undergoes structural degradation and physically opens up. This alteration causes older cells to respond weakly or incorrectly to external mechanical and biochemical stimuli, leading to impaired cellular function.
Key Distinction/Mechanism: Unlike young cells, where tightly packed chromatin effectively restricts access to irrelevant genes, the relaxed chromatin structure in older cells fails to act as an accurate filter. When subjected to mechanical tension or growth factors (such as TGF-β), this disorganized state triggers incorrect gene expression, resulting in the production of unwanted proteins instead of those necessary for appropriate cellular responses.
Major Frameworks/Components:
- Chromatin Architecture: The three-dimensional structural packaging of DNA that regulates genome accessibility for transcription.
- Cellular Mechanotransduction: The mechanism through which cells translate mechanical forces (such as tension within a 3D collagen matrix) into biochemical signals and genetic responses.
- Aberrant Gene Expression: The age-induced misregulation where previously inaccessible, irrelevant genes are inappropriately activated due to chromatin degradation.
Branch of Science: Molecular Biology, Cell Biology, Mechanobiology, and Biogerontology.
Future Application: Insights from this research aim to inform therapeutic interventions designed to selectively modify chromatin shape, potentially returning it to a youthful state to delay age-related tissue degeneration. Additionally, this knowledge is being integrated with artificial intelligence (AI) imaging to detect pathologically modified chromatin for the early diagnosis of diseases, including cancer.
Why It Matters: This structural understanding of cellular aging explains why fundamental physiological processes, such as wound healing and tissue repair, inevitably degrade over time. Addressing the root cause of these incorrect cellular responses offers a viable pathway to extending human healthspan and mitigating severe age-related pathologies.
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| “It seems as though chromatin opens up with age, so to speak,” says PSI scientist Yawen Liao. “The result is an increase in incorrect activations.” Photo Credit: © Paul Scherrer Institute PSI/Markus Fischer |
As we age, our cells age with us. Although they remain active, they become less flexible, stop dividing, and sometimes respond incorrectly to signals. The reason for this lies in the cell nuclei, specifically in the chromatin – the packaged form of our DNA. This is the finding of a study by researchers at PSI, who analyzed samples of skin cells taken from people of different ages in the laboratory. They have now published their findings in the scientific journal PNAS.
Using a microscope and molecular biological methods, the scientists led by G. V. Shivashankar examined how various skin cells reacted to a specific chemical messenger when mechanical tension was applied. They compared skin cells from ten-year-old children with those from 75-year-olds. As expected, the response of older people’s cells to the same stimuli was different and significantly weaker. The scientists were able to attribute this to a specific cause: the chromatin in the cell nucleus changes with age. As a result, certain genes – sections of DNA that belong together – can no longer be read accurately. This process, known as gene expression, is important in order to produce the proteins required by the organism, because the genes store the instructions for building those proteins. However, if the shape of the chromatin changes with age, other processes may be triggered instead, which can harm the organism.
“Chromatin acts like a filter for potential gene expression,” explains lead researcher G. V. Shivashankar from the PSI Center for Life Sciences. “Processes such as wound healing or tissue repair in the brain are impaired if the activation of the appropriate genes no longer works properly.”
Young cells versus old
Shivashankar’s team, which also includes the PhD student Yawen Liao, the first author of the study, used connective tissue cells known as fibroblasts for their research. “We could just as easily have used brain or muscle cells,” Shivashankar points out. “The mechanisms are basically comparable in all cells.” The researchers embedded the cells in a three-dimensional matrix of collagen gel, as is common practice when working with tissue samples. They then subjected this gel to mechanical tension. Normally the gel would contract like a drop of water, but a surrounding ring of glass kept it taut across its surface. They also added the growth factor TGF-β, which regulates the maturation, division, and immune response of cells, as a chemical messenger. This was intended to show how the cells reacted to a biochemical signal.
“The response to the signal that we observed in the older cells was different and significantly weaker, even though the signal was exactly the same in both cases,” Yawen Liao reports. Young cells contracted against the tensile force exerted by the ring and increased their division rate. Older cells did the same, but their response was much weaker. When the ring was removed, the older cells maintained their contraction while the young cells adapted and relaxed again.
The researchers then investigated the changes in the old cells that might explain such pronounced differences in behavior compared with the young cells. They used special imaging techniques and molecular biological methods to determine the three-dimensional structure of the chromatin at the molecular level. “Here we saw the decisive difference,” says Liao. “It seems as though chromatin opens up with age, so to speak.” Areas of the genome that were previously tightly packed and therefore inaccessible, because they contain genes that are irrelevant for that particular cell type, now become more easily accessible. “The result is an increase in incorrect activations. Instead of reading the appropriate genes for the process in question, there is an increase in the expression of unsuitable genes and the production of unwanted proteins, for example,” Liao continues. “If this gets out of hand, it can lead to diseases, including cancer.”
Can ageing cells be brought back into shape?
Shivashankar’s team wants to carry out additional experiments to investigate whether and how these findings can be used for new therapeutic approaches. “Perhaps we can selectively modify the shape of the chromatin and prevent it from changing in this way,” says Shivashankar. “Or else it might be possible to return it to a youth-like state.” Although this would certainly not stop ageing itself, it might be possible to slow down or delay age-related degeneration in specific types of tissue.
In another project, Shivashankar and other researchers have developed a new imaging technique that uses artificial intelligence to identify pathologically modified chromatin structures in high-resolution images. The AI system compares the chromatin of blood cells – which play a key role in the body’s immune response to various diseases – with the chromatin of healthy blood cells based on hundreds of characteristics such as shape, texture and light spectrum. These patterns are currently being recorded in a comprehensive reference database. In combination with this type of early detection, selectively modifying the structure of the chromatin could open up new possibilities for healthier ageing in the long term.
Reference material: What Is: Cellular Senescence
Published in journal: Proceedings of the National Academy of Sciences
Title: Chromatin accessibility regulates age-dependent nuclear mechanotransduction
Authors: Yawen Liao, Luezhen Yuan, Trinadha Rao Sornapudi, Max Land, Rajshikhar Gupta, and G. V. Shivashankar
Source/Credit: Paul Scherrer Institute | Jan Berndorff
Reference Number: mbio032626_01