Most human nerve cells can last a lifetime without needing to be replaced. This is also true for some of the components within the cells, which can endure for as long as the organism itself. Recent research by Martin Hetzer, a molecular biologist and president of the Institute of Science and Technology Austria (ISTA), and his colleagues, found RNA, a molecule that is typically temporary, in the nerve cells of mice that remains stable for their entire lives. This discovery, published in Science, provides valuable insights into the longevity of nerve cells. The findings contribute to unraveling the mysteries of how nerve cells function over a lifetime.
Exploring the complexities of brain aging and associated diseases.
After twenty years in the United States, Martin Hetzer returned to Austria in 2023 to take on the role of the 2nd President of the Institute of Science and Technology Austria (ISTA). One year into his new position, the molecular biologist remains focused on aging research.
Hetzer is intrigued by the biological mysteries surrounding the aging processes in organs such as the brain, heart, and pancreas. Most cells in these organs are not regenerated throughout a person’s lifetime. For example, nerve cells (neurons) in the human brain.Neurodegenerative disorders like Alzheimer’s disease can be linked to the advanced age of neurons, which can last for over a century and must continue functioning throughout the organism’s lifetime. Understanding how nerve cells continue to function and maintain control as they age is crucial in addressing these diseases. This could lead to potential therapeutic interventions to counteract the aging process of these cells. The most recent publication by Hetzer and Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU), who is also affiliated with the Max Planck Center, explores this topic.Physics and Medicine, Erlangen, and colleagues have provided new insights into a field that has not been thoroughly explored before. Their study, for the first time in mammals, demonstrates that RNA, a crucial group of molecules that play a significant role in various biological processes within the cell, can last throughout an organism’s life. The researchers have identified specific RNAs with genome-protecting functions in the nuclei of nerve cells in mice that remain stable for up to two years, covering their entire lifespan. These findings, which have been published in the journal Science, highlight the importance of long-lived key molecules in maintaining the function of a cell.Key Molecules
The interior of cells is a highly dynamic environment. Some parts are constantly being replaced and refreshed, while others remain unchanged throughout their lifespan. It’s like a city where old buildings coexist with new ones. For example, the DNA found in the nucleus – the city’s core – is as old as the organism itself. “The DNA in our nerve cells is exactly the same as the DNA in the developing nerve cells in our mother’s womb,” explains Hetzer.
Unlike stable DNA, which is constantly undergoing repair, RNA, particularly messenger RNA (mRNA) responsible for producing proteins based on DNA’s instructions, is known for its temporary nature. The cellular scThe scope of this research extends beyond mRNA to a group of non-coding RNAs, which do not produce proteins but have specific roles in the overall organization and function of the cell. Their lifespan has been a mystery, until now.
To unravel this mystery, Hetzer and his team labeled RNAs in the brains of newborn mice using RNA analogs with chemical hooks that attach fluorescent molecules to the actual RNAs.Hetzer explains that the tracking of molecules and microscopic snapshots in the mice’s lives was efficient. They were able to capture powerful images at any given time point. They were surprised to discover the presence of long-lived RNAs in various cell types within the brain. Further analysis was needed to identify the ones in the nerve cells. Hetzer also mentions the fruitful collaboration with Toda’s lab, which helped make sense of the chaos during brain mapping. As a result, the researchers were able to focus solely on long-lived RNAs in neurons and quantify their concentration throughout a mouse’s life, as well as examine their composition.
Researchers studied the lifespan of mice and compared it to that of humans. While humans typically live for about 70 years, the average lifespan of a mouse is only 2.5 years. The study found that even after one year, long-lived RNAs were still present in the mice, although at slightly reduced levels compared to newborns. Even after two years, these long-lived RNAs remained detectable, indicating that they persist throughout the mouse’s lifetime.
The scientists also discovered that long-lived RNAs play a significant role in cellular longevity, particularly in neurons. They consist of both mRNAs and non-coding RNAs, and they accumulate near the heterochromatin, which is densely packed DNA.
The researchers focused on a specific part of the genome, which typically contains inactive genes. They then investigated the purpose of these long-lasting RNAs.
In the field of molecular biology, the most efficient method to achieve this is to decrease the abundance of the molecule in question and observe the resulting effects. “As their name and our previous experiments imply, these long-lasting RNAs are remarkably stable,” explains Hetzer. Therefore, the scientists used an in vitro (outside a living organism) approach, utilizing neuronal progenitor cells—stem cells with the ability to produce neural cells, such as neurons. This model system allowed them to effectively interact
Long-lasting RNAs play a critical role in maintaining the stability of genetic material within cells. Insufficient levels of these long-lived RNAs led to problems with the structure of heterochromatin and ultimately impacted cell viability. This research has shed light on the importance of long-lived RNAs in promoting cellular longevity.
The study suggests that long-lived RNAs may be involved in the ongoing regulation of genome stability. According to Hetzer, the lead researcher, “The extended lifespan of key molecules such as long-lived RNAs is essential for maintaining cellular health as we age.” However, the exact mechanism through which long-lived RNAs operate, potentially alongside unidentified proteins, remains to be fully understood.The Hetzer lab is focused on understanding the long-lived RNAs that persist in the mouse brain, as well as their biological characteristics. Specifically, they are interested in finding the missing links between nuclear RNAs and heterochromatin, a stable structure in the cell.
