Why do cells react abnormally as we age? The reason lies in the cell nucleus, the seat of some aging-related symptoms. An improper response to external stimuli could, over time, foster the emergence of age-associated diseases.
It is what researchers at the Paul Scherrer Institute (PSI) in Switzerland explain, in a study published in PNAS (Proceedings of the National Academy of Sciences of the United States of America).
The aging process
Cells, following human biology, as they age become less efficient themselves: DNA loses compaction, remaining active while continuing to function in a “senescent” mode. At the heart of this mechanism would be the aging of the cell nucleus, specifically the chromatin, the complex of DNA, histones and non-histone proteins located in the nucleus of eukaryotic cells, responsible for the packing of the genome.
However, the mechanisms and its interaction with the environmental context are not yet clear: the current study sought to provide some initial answers, using fibroblasts, specific connective-tissue cells, from people of different ages, comparing, for example, cells from ten-year-old children with those from 75-year-old adults.
From these, under the microscope, using biological techniques, researchers observed the different reaction to a particular signaling molecule under mechanical stress. As per protocol, following biological laws, cells from older individuals responded in a much more attenuated way than younger ones to the same stimuli. This would support the idea that with age the chromatin inside the cell nucleus undergoes changes, especially in certain specific DNA sequences that constitute a functional unit.
This means that certain genes can no longer be read with the same precision. Yet gene expression is crucial for the organism to produce the proteins it needs, the instructions for their synthesis stored precisely in the genes.
In essence, chromatin performs a filtering action on potential gene expressions; if the activation of the right genes no longer works properly, some processes are compromised, such as wound healing or brain repair processes, while if aging alters the shape of chromatin, it can also trigger processes that damage the organism, with the onset of aging-related diseases.
The experiment conducted
The researchers incorporated the fibroblasts into a three-dimensional collagen gel matrix, then subjected the gel to mechanical tension, where a particular strategy, a kind of ring, kept it taut on the surface. They also added the transforming growth factor beta (TGF-β) as a signaling molecule, which regulates maturation, division, and the immune response of the cells. The experiment was, in fact, aimed at demonstrating if and to what extent cells respond to a biochemical signal, in a way that varies with age.
It was observed that young cells contract against the ring’s traction force, increasing their division rate, and that older cells, while still responding to the stimulus, did so in a more attenuated manner, and that, once the ring was removed, older cells maintained their contraction, whereas younger ones relaxed again to adapt.
To explain the reason for this phenomenon, using advanced imaging techniques and molecular biology methods, the researchers analyzed the three-dimensional structure of chromatin at molecular resolution, observing that with age, regions of the genome that had previously been strongly compacted, and thus inaccessible, tend to open up and become more pervasive. In practical terms this translates into an increase in erroneous activations, for example with more frequent transcription of inappropriate genes, resulting in the production of unwanted proteins. In case this phenomenon develops excessively, there is the possibility of the emergence of major diseases, including cancer.
Next steps
The aim is to evaluate whether this discovery could be applicable to the development of new therapeutic approaches, for instance that influence chromatin changes or that could restore it to a youthful appearance. It is clear that cellular aging cannot be halted, yet for some tissue types it might be possible to slow down or postpone age-related degeneration, thereby delaying the onset of specific pathologies.
Parallel to this, researchers have developed, in collaboration with other research groups, new imaging techniques that, with the support of artificial intelligence, are capable of identifying chromatin structures altered at a pathological level in high-resolution images.
The artificial intelligence approach, for example, compares the chromatin of blood cells, which play a central role in the body’s immune response against a wide range of diseases, with the chromatin of healthy blood cells, based on hundreds of features such as shape, structure and spectral signature. These models are building a large reference database. In combination with such early detection, targeted actions on chromatin structure could, in the long term, open up new possibilities that would enable healthier longevity.
Source
Liao Y, Yuan L, Sornapudi TR et al. Chromatin accessibility regulates age-dependent nuclear mechanotransduction. PNAS, 2026, 123(13):e2522217123. Doi: 10.1073/pnas.2522217123
Abbonati a Karla Miller
