Could measuring protein clumps in cells offer a new way to investigate the risk of developing age-related diseases? In a New Perspective article published in Nature Cell Biology, Professors Dorothee Dollmann and Edward Lemke from the Johannes Gutenberg University Mainz (JGU), who are also adjunct directors of the Institute of Molecular Biology (IMB) in Mainz, propose the concept of a “protein aggregation clock” to measure ageing and health.
Visualization of the protein aggregation clock (Illustration/©: Nike Heinss / JGU)
As we age, the DNA and proteins that make up our bodies undergo gradual changes that cause our bodies to not function as well as they used to. As a result, we become more susceptible to age-related diseases such as cardiovascular disease, cancer, and Alzheimer's. One key change is that proteins in our cells can misfold and form aggregates, so-called amyloids. While misfolding and aggregation can occur in any protein, a certain group of proteins, called intrinsically disordered proteins (IDPs), are particularly prone to forming amyloids. IDPs make up about 30 percent of the proteins in our cells and are characterized by the fact that they have no fixed structure. Instead, IDPs are flexible and dynamic, flopping around like boiled spaghetti.
Although the molecular mechanisms are widely debated and an important aspect of basic research, scientists know that aggregates formed from IDPs tend to accumulate in many long-lived cells, such as neurons and muscle cells, with age. Moreover, they can cause many age-related diseases, especially neurodegenerative diseases such as Alzheimer's and Parkinson's. Thus, the presence of many aggregates in a cell could be an indicator of how unhealthy the cell is or whether a person may soon develop age-related diseases. In a recently published paper, Dolman and Lemke propose that IDP aggregates could potentially be used as a biological “clock” to measure a person's health and age.
The protein aggregation clock will be extremely useful once it is further developed and expanded into a sensitive diagnostic test. Firstly, doctors could use it to diagnose age-related diseases at a very early stage or to identify people who are not yet sick but are at high risk of developing diseases as they age. This would allow preventative treatments to be administered before they develop severe illness. Secondly, scientists could use it to evaluate the effectiveness of new experimental treatments that reduce protein aggregation to prevent or delay age-related diseases.
“In reality, we are still far from having a routine diagnostic test, so it is important to improve our understanding of the underlying mechanisms that lead to IDP aggregation,” Dolman said.
“However, we hope to stimulate thinking and research in the direction of studying protein aggregates to measure biological aging processes. In the future, we are optimistic that with further research into IDP dynamics and further technological developments, we will be able to overcome the current challenges of reading the protein aggregation clock.”
Edward Lemke, Professor at Johannes Gutenberg University Mainz (JGU)
There are other “clocks” that measure aging and health, but most of them are based on nucleic acids such as DNA. Dorman and Lemke believe that protein-based biological clocks can serve as a complement to existing clocks, because proteins are among the most abundant molecules in cells and are important for all cellular functions. With the help of these protein aggregation clocks, scientists and doctors hope to get one step closer to helping people age healthily and prevent age-related diseases.
Dorothee Dolmann and Edward Lemke contribute to research at the Center for Healthy Aging (CHA), a virtual research center that opened in 2021. The CHA brings together scientists from basic and clinical research across Mainz with a focus on aging and age-related diseases. Their research findings will be used to find therapies that can promote healthy aging and help prevent or treat age-related diseases.
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Johannes Gutenberg University Mainz (JGU)
Journal References:
Dormann, D., & Lemke, EA (2024). Adding intrinsically disordered proteins to the biological aging clock. Nature Cell Biology. doi.org/10.1038/s41556-024-01423-w.
