The key to maintaining cellular youth might lie in keeping the nucleolus—a compact structure found within a cell’s nucleus—small, according to researchers from Weill Cornell Medicine. This discovery was made using yeast, an organism known for its roles in baking and brewing, and surprisingly bears a resemblance to human cells.
The key to maintaining cellular youth might lie in keeping the nucleolus—a compact structure found within a cell’s nucleus—small, according to Weill Cornell Medicine researchers. This discovery was made using yeast, an organism known for its roles in baking and brewing, and surprisingly bears a resemblance to human cells.
Published on November 25 in Nature Aging, this study could pave the way for new treatments aimed at enhancing human longevity. It also provides insights into a mortality indicator, revealing how much longer a cell can survive before it dies.
As individuals age, they are more prone to various health issues, including cancer, heart diseases, and neurological disorders.
“Aging significantly raises the risk of these conditions,” noted Dr. Jessica Tyler, a pathology and laboratory medicine professor at Weill Cornell Medicine. “Instead of tackling each disease individually, a more effective strategy would be to create a treatment or supplement that halts the onset of diseases by addressing the fundamental molecular issues that lead to them.” The nucleolus might be central to this solution.
Small Is Key
The cell’s nucleus contains chromosomes and the nucleolus, the latter housing ribosomal DNA (rDNA). The nucleolus isolates rDNA, which encodes RNA components needed for ribosomes, the cell’s protein production factories. The rDNA is one of the genome’s more vulnerable sections, as its repetitive sequence makes repair tougher. If rDNA damage goes unrepaired, it can lead to cell death and chromosomal abnormalities.
In various organisms, from yeast to worms and humans, nucleoli grow larger with age. Conversely, anti-aging methods like calorie restriction lead to reduced nucleoli size. “Caloric restriction impacts many aspects, but we still don’t fully understand its exact mechanism for lifespan extension,” Dr. Tyler remarked.
Dr. Tyler and postdoctoral fellow Dr. J. Ignacio Gutierrez, the paper’s lead author, hypothesized that smaller nucleoli could postpone aging. To explore this, they devised a method to anchor rDNA to the nuclear membrane in yeast cells, allowing them to control when this anchoring occurred. “Our system enables us to isolate nucleolus size from all other anti-aging influences,” Dr. Gutierrez explained.
The research team found that securing the nucleolus kept it compact, and smaller nucleoli delayed aging similarly to caloric restriction.
Critical Threshold
Remarkably, nucleoli did not grow consistently throughout a cell’s lifespan. They remained small for most of the yeast’s life but then rapidly expanded once a certain nucleolar size was reached. After surpassing this limit, cells could only survive about five additional divisions.
“The non-linear increase in size was a clear signal that something significant was occurring,” Dr. Gutierrez stated. Surpassing this threshold appears to function as a mortality timer, counting down the cell’s final days.
As aging progresses, DNA experiences accumulating damage, some of which can severely threaten cell viability. The team discovered that larger nucleoli had less stable rDNA compared to smaller nucleoli. When the nucleolus expands, it allows proteins and other factors, typically excluded, to enter, leading to a ‘leaky’ state that can harm fragile rDNA.
“The primary purpose of condensates is to compartmentalize biological reactions for efficiency, but with unwanted proteins infiltrating the nucleolus, it results in genome instability, hastening cell lifespan termination,” Dr. Tyler explained. Such proteins can lead to significant issues, including damaging chromosomal rearrangements.
Moving forward, the researchers intend to investigate how nucleoli impact aging in human stem cells. Stem cells are unique as they have the capacity to regenerate as other cells perish. However, eventually, these stem cells cease division. The researchers aim to apply insights from this study to improve the longevity of stem cells.
“I was thrilled that we could connect the nucleolus’s structure with the repair process in a way that is preserved from yeast to humans,” Dr. Gutierrez expressed.
