A new way to measure ageing and disease risk with the protein aggregation clock

The protein aggregation clock. Image by Nike Heinss.

Could measuring protein clumps in our cells be a new way to find out our risk of getting age-related diseases? Dorothee Dormann and Edward Lemke, professors at Johannes Gutenberg University (JGU) and adjunct directors at the Institute of Molecular Biology (IMB) in Mainz, Germany, propose the concept of a “protein aggregation clock” to measure ageing and health in a new perspective article published in Nature Cell Biology.

As we age, the DNA and proteins that make up our bodies gradually undergo changes that cause our bodies to no longer work as well as before. This in turn makes us more prone to getting many age-related diseases, such as cardiovascular disease, cancer and Alzheimer’s disease. One important change is that the proteins in our cells can sometimes become misfolded and clump together to form aggregates (called amyloids). Misfolding and aggregation can happen to any protein, but a specific group of proteins—known as intrinsically disordered proteins (IDPs)—are especially prone to forming amyloids. IDPs make up around 30% of the proteins in our cells. And they are characterised by having no fixed structure. Instead, they are flexible and dynamic, flopping around like strands of cooked spaghetti. 

While the molecular mechanisms are widely debated and and important aspect of basic research, scientists know that aggregates formed from IDPs tend to accumulate in many long-lived cells (e.g. neurons or muscle cells) as we age. Moreover, they can cause many age-related diseases, particularly neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Thus, having many aggregates in a cell could be an indicator of how unhealthy the cell is, or if a person is likely to develop an age-related disease soon. In their recently published article, Dorothee Dormann and Edward Lemke propose that IDP aggregation could be used as a biological “clock” to measure a person’s health and age. 

If developed further into a sensitive diagnostic test, a protein aggregation clock could be extremely useful: firstly, doctors could use it to help diagnose age-related diseases at very early stages, or identify people who are not yet sick but have a higher risk of developing disease as they age. This would allow them to be given preventative treatments before they develop severe disease. Secondly, scientists could use it to assess the effects of new, experimental treatments to reduce protein aggregation in order to prevent or delay age-related diseases. 

“In practice, we are still far away from a routine diagnostic test, and it is important that we improve our understanding of the fundamental mechanisms leading to IDP aggregation”, says Dorothee. “However, we want to stimulate thinking and research in the direction of studying protein aggregates to measure biological ageing processes”. Edward adds, “We are optimistic that in the future we will be able to overcome the current challenges of reading a protein aggregation clock through more research on IDP dynamics and making further technological developments". 

Although there are other “clocks” to measure ageing and health, most of them are based on DNA. Dorothee and Edward think that a biological clock based on proteins would be a useful complement to these existing clocks, as proteins more accurately reflect the functional state of a cell. With the help of such a protein aggregation clock, Dorothee and Edward hope that scientists and doctors will be able to move one step closer towards helping people age healthily and preventing age-related diseases.

^{Further details}

^{Further information can be found at www.nature.com/articles/s41556-024-01423-w}

^{Dorothee Dormann is an Adjunct Director at IMB and a Professor of Molecular Cell Biology at Johannes Gutenberg University Mainz. Further information about research in the Dormann lab can be found at www.imb.de/dormann}

^{Edward Lemke is an Adjunct Director at IMB and a Professor of Synthetic Biophysics at Johannes Gutenberg University Mainz. Further information about research in the Lemke lab can be found at www.imb.de/lemke}

^{About the Institute of Molecular Biology gGmbH} 

^{The Institute of Molecular Biology gGmbH (IMB) is a centre of excellence in the life sciences that was established in 2011 on the campus of Johannes Gutenberg University Mainz (JGU). Research at IMB focuses on the cutting-edge fields of epigenetics, genome stability, ageing and RNA biology. The institute is a prime example of successful collaboration between a private foundation and government: The Boehringer Ingelheim Foundation has committed 154 million euros to be disbursed from 2009 until 2027 to cover the operating costs of research at IMB. The State of Rhineland-Palatinate has provided approximately 50 million euros for the construction of a state-of-the-art building and is giving a further 52 million in core funding from 2020 until 2027. For more information about IMB, please visit: www.imb.de}

^{About the Centre for Healthy Ageing}

^{The Centre for Healthy Ageing (CHA) is a virtual research centre launched in 2021 that brings together scientists in basic and clinical research from across Mainz that focus on ageing and age-related diseases. These findings should be used to promote healthy ageing and to find treatments that could prevent or cure age-related disease. For more information, please visit: www.cha-mainz.de}

^{About Johannes Gutenberg University Mainz} 

^{Johannes Gutenberg University Mainz (JGU) is a globally recognized research-driven university with around 31,000 students from over 120 nations. Its core research areas are in particle and hadron physics, the materials sciences, and translational medicine. JGU's success in Germany's Excellence Strategy program has confirmed its academic excellence: In 2018, the research network PRISMA+ (Precision Physics, Fundamental Interactions and Structure of Matter) was recognized as a Cluster of Excellence – building on its forerunner, PRISMA. Moreover, excellent placings in national and international rankings as well as numerous honors and awards demonstrate the research and teaching quality of Mainz-based researchers and academics. Further information at www.uni-mainz.de/eng}

^{Boehringer Ingelheim Foundation}

^{The Boehringer Ingelheim Foundation is an independent, non-profit organization that is committed to the promotion of the medical, biological, chemical, and pharmaceutical sciences. It was established in 1977 by Hubertus Liebrecht (1931–1991), a member of the shareholder family of the Boehringer Ingelheim company. Through its funding programmes Plus 3, Exploration Grants and Rise up!, the Foundation supports excellent scientists during critical stages of their careers. It also endows the international Heinrich Wieland Prize, as well as awards for up-and-coming scientists in Germany. In addition, the Foundation funds institutional projects in Germany, such as the Institute of Molecular Biology (IMB) and the European Molecular Biology Laboratory (EMBL) in Heidelberg. www.boehringer-ingelheim-stiftung.de/en} 

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