RNA and DNA are distinguished by gray (EU; 5-ethynyluridine) and blue (DAPI) staining, respectively in the research. Brain regions that are visible include the olfactory bulb (OB), rostral migratory stream (RMS), subventricular zone (SVZ), and the dentate gyrus (DG).
After spending twenty years in the United States, Martin Hetzer returned to Austria in 2023 to assume the role of the 2nd President of the Institute of Science and Technology Austria (ISTA). One year into his tenure, the molecular biologist remains actively involved in the field of aging research.
Hetzer’s interest lies in the biological enigmas surrounding the aging mechanisms in organs such as the brain, heart, and pancreas. The majority of cells in these organs are not regenerated throughout a human’s lifespan. Neurons, for example, can persist for the entire lifespan of an individual, even exceeding a century, highlighting the necessity for their sustained functionality.
The extended lifespan of neurons poses a significant risk for neurodegenerative conditions like Alzheimer’s disease. Understanding these disorders hinges on gaining deeper insights into the maintenance and functionality of these cells over time, potentially paving the way for therapeutic interventions to counteract the aging processes affecting these specific cells.
A recent collaborative publication authored by Hetzer, Tomohisa Toda from the Friedrich-Alexander University Erlangen-Nürnberg (FAU) and the Max Planck Center for Physics and Medicine, Erlangen, along with their colleagues, sheds new light on this relatively unexplored domain of intricate mechanisms.
In a groundbreaking study involving mammals, the research reveals that RNA—a vital group of molecules crucial for various cellular processes—can endure throughout an organism’s life. The scientists pinpointed specific RNAs with genome-protecting functions in the nuclei of mouse nerve cells that remain stable for two years, spanning their entire lifespan. These findings, published in the journal Science, underscore the significance of long-lived key molecules in preserving cellular functionality.
Persistence of Essential Molecules
Within cells, there exists a dynamic interplay where certain components undergo continuous renewal and updating, while others remain constant throughout their existence. This dynamic is akin to a cityscape where old structures coexist with new developments. For instance, DNA housed in the nucleus—the city’s core—is as old as the organism itself. Hetzer elucidates that “DNA in our nerve cells retains its original blueprint from the developmental stages in our mother’s womb.”
In contrast to stable DNA, which undergoes constant repair, RNA, particularly messenger RNA (mRNA) responsible for protein synthesis based on DNA instructions, is known for its transient nature. Beyond mRNA, the cellular landscape encompasses a group of non-coding RNAs that do not encode proteins but play specific roles in cellular organization and function. The longevity of these non-coding RNAs has long been a puzzle, until now.
Enduring RNAs in a Lifespan
Hetzer and his team embarked on unraveling this mystery by labeling RNAs in the brains of newborn mice. Through the use of RNA analogs—structurally akin molecules with chemical markers that attach fluorescent molecules to the actual RNAs—the researchers could effectively track these molecules and capture detailed microscopic snapshots at various stages of the mice’s lives.
“Surprisingly, our initial observations unveiled the presence of long-lived RNAs across diverse cell types in the brain. Subsequent data analysis honed in on these molecules within nerve cells,” explains Hetzer. Collaborating with Toda’s lab facilitated the meticulous mapping of these long-lived RNAs in the brain.
The researchers focused their efforts on long-lived RNAs within neurons, quantifying their concentrations throughout a mouse’s lifespan, scrutinizing their compositions, and delving into their spatial distribution.
While humans boast an average lifespan of around 70 years, mice typically live for 2.5 years. After a year, the concentration of long-lived RNAs exhibited a slight decline compared to newborns. Nevertheless, even after two years, these molecules remained detectable, indicating their enduring presence throughout the lifespan.
Role of RNAs in Genome Protection
Furthermore, the study underscores the pivotal role of long-lived RNAs in cellular longevity. The researchers elucidated that long-lived RNAs in neurons comprise both mRNAs and non-coding RNAs, accumulating near the heterochromatin—a densely packed genomic region housing inactive genes. Subsequent investigations delved into the functionalities of these long-lived RNAs.
“In research, a key strategy involves reducing the molecule of interest to observe its downstream effects,” Hetzer explains. As suggested by their name and prior experiments, these long-lived RNAs exhibit remarkable stability. Leveraging an in vitro approach using neuronal progenitor cells—stem cells capable of generating neural cells including neurons—the scientists could manipulate these long-lived RNAs effectively. Diminished levels of long-lived RNAs disrupted the heterochromatin architecture and genomic stability, ultimately impacting cellular viability. This elucidated the crucial role of long-lived RNAs in promoting cellular longevity.
The study highlights the potential of long-lived RNAs in regulating genome stability over an organism’s lifespan.
“Lifelong maintenance of cellular functions, particularly during aging, hinges on the sustained presence of key molecules like the long-lived RNAs we’ve uncovered,” Hetzer emphasizes. The precise mechanisms underlying this phenomenon remain to be fully elucidated. “Together with unidentified proteins, long-lived RNAs likely form a stable structure that interacts with the heterochromatin.”
Future research endeavors in Hetzer’s laboratory are dedicated to bridging these gaps and unraveling the biological intricacies surrounding these long-lived RNAs.
More information:
S. Zocher, Lifelong persistence of nuclear RNAs in the mouse brain, Science (2024).
Citation:
New research shows key molecules within nerve cells persist throughout life (2024, April 4)
retrieved 4 April 2024 from https://phys.org/news/2024-04-key-molecules-nerve-cells-persist.html
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