Researchers reveal how aging rewires the proteome in human cells
16 October 2026
PRESS RELEASE OF THE INSTITUTE OF MOLECULAR BIOLOGY
What happens inside a cell when it grows old? A new study led by Professor Petra Beli and Professor Helle Ulrich at the Institute of Molecular Biology (IMB) in Mainz provides one of the most detailed answers to date. In collaboration with Professor Christian Behl from the Mainz University Medical Center and Dr. Jia-Xuan Chen from IMB's Proteomics Core Facility, they show that human cells experience a widespread and coordinated change in thousands of proteins as they enter senescence, a process closely linked to aging. Proteins involved in chromatin organization, gene expression, as well as protein production and disposal were particularly affected. Their findings, which were published in Nature Communications, provide new insights into the basic molecular mechanisms of aging and could reveal new targets for therapies against age-related disease.
Age-related diseases due to the gradual accumulation of senescent cells
Our bodies continuously produce new cells to grow, to repair damage, and to replace worn-out cells. However, most cells cannot divide forever. Cells that have divided repeatedly eventually stop proliferating, entering a state of arrest called senescence. As we get older, more senescent cells accumulate in our tissues. While this is important for preventing old, damaged cells from multiplying, senescent cells also produce inflammatory compounds that contribute to aging. As a result, the gradual accumulation of senescent cells impairs organ function and leads to age-related diseases such as cancer, cardiovascular disease, arthritis, and neurodegenerative disorders.
One way to combat this is to develop drugs that target and remove senescent cells. In animal models, this can slow age-related diseases, improving health and longevity. Understanding the molecular changes that occur in human cells during senescence is essential for finding better ways to detect and target them.
Following changes across the proteome in senescent cells
Using mass-spectrometry-based proteomics, the research teams quantified nearly 6,000 proteins in human lung fibroblast cells at four successive stages, from actively dividing to fully senescent. The analysis revealed widespread, coordinated changes across many proteins during senescence.
"We applied a systematic and temporally resolved multi-omics approach that revealed the coordinated rewiring of cellular networks, providing a valuable systems-level view of the molecular processes that shape and sustain the senescent state," explained PhD student Nádia Da Silva Fernandes, first author of the study.
Widespread reorganization of chromatin and protein regulatory networks
One of the clearest patterns was the loss of proteins associated with chromatin. Proteins involved in gene transcription, RNA processing, and chromosome organization declined at different stages, suggesting an ordered restructuring of the nucleus and gene regulation. Another major change took place in proteins involved in proteostasis – the systems responsible for protein synthesis, maintenance, and removing damaged proteins. Malfunctions in these systems are two of the primary hallmarks of aging.
"We found that senescence involves a broad reorganization of proteostasis, affecting not only how cells remove damaged proteins, but also how they produce new ones," stated Professor Petra Beli, Adjunct Director at IMB and Professor for Quantitative Proteomics in the Institute of Developmental Biology and Neurobiology at Johannes Gutenberg University Mainz (JGU).
The researchers found that components of the cell machinery that make new proteins became depleted, while the cell's two main protein disposal systems – autophagy and the proteasome – showed reduced activity. More than 500 proteins also became less soluble, a hallmark of protein aggregation that is common in senescent cells and contributes to neurodegenerative disease.
Senescence changes how cells tag proteins for disposal
The team also surveyed the abundance of two chemical protein tags, ubiquitin and SUMO, which cells use to modify protein stability, direct them to different locations, or mark them for disposal. They found an increase in two specific ubiquitin tags, namely K11- and K27-linked ubiquitin chains. This may reflect attempts by senescent cells to manage damaged proteins and reorganize their cellular quality-control systems.
A distinctive signature of senescence
The changes in senescent cells were distinct from those triggered by other types of cellular stress, such as oxidative stress, starvation, and the disruption of protein folding or degradation. The researchers assume that this shows senescence is not simply a general stress response, but a distinctive process.
"The qualitative differences between the patterns triggered by the various types of stress suggest that senescence might leave a specific 'fingerprint' on the cellular proteome. But senescence can be induced by many different conditions. It will therefore be extremely interesting to compare our results to situations where senescence is driven by other means, for example by DNA damage or oncogenes," emphasized Professor Helle Ulrich, Scientific Director at IMB and Professor in the Department of Biology at Mainz University.
Overall, the study reveals that multiple gene and protein regulatory networks are rewired in a highly coordinated way during senescence. The findings deepen our understanding of the molecular mechanisms of cellular aging and create a wealth of information that could reveal new targets for future therapies against age-related disease.
This study was part of the Science of Healthy Aging Research Program (SHARP) funded by the Ministry of Science, Continuing Education, and Health of Rhineland-Palatinate. Funding was also provided by the German Research Foundation via the Collaborative Research Centers on "Regulation of DNA repair and genome stability" (CRC 1361) and on "Systems-level consequences of fidelity changes in mRNA and protein biosynthesis" (CRC 1678).