Could the key to aging gracefully be as simple as keeping your cells’ nucleoli small? Science says yes, and the findings are groundbreaking.

The key to cellular youth may be to keep the nucleolus- a compacted structure inside a cell’s nucleus- small, according to researchers at Weill Cornell Medicine. The discoveries were revealed in yeast, a model organism known for producing bread and beer that is remarkably comparable to humans at the molecular level.

The findings, published in Nature Aging, could lead to new longevity treatments that lengthen human life (1). It also creates a mortality timer that shows how long a cell has before it dies.

As people age, they are more likely to suffer health problems like cancer, cardiovascular disease, and neurological illnesses.

“Aging is the highest risk factor for these diseases,” said Dr. Jessica Tyler, a pathology and laboratory medicine professor at Weill Cornell. “Rather than treating each disease separately, a better approach would be to develop a therapeutic or supplement that will delay the onset of diseases by preventing the underlying molecular defects that cause them.” The nucleolus may hold the key.

Nucleolus: A Key to Aging and Lifespan Regulation

The nucleus contains the cell’s chromosomes, while the nucleolus houses the ribosomal DNA (rDNA). The nucleolus isolates rDNA, which encodes the RNA components of ribosomes, the protein-building machinery. The rDNA is one of the most fragile regions of the genome because of its repeating nature, making it difficult to maintain and repair if damaged. If rDNA damage is not properly repaired, it might result in chromosomal rearrangements and cell death.

Nucleoli expand as organisms age, ranging from yeast to worms to humans. Anti-aging measures, such as calorie restriction or eating less, produce smaller nucleoli. “Calorie restriction does so many different things, and no one knows the precise way that it is extending lifespan,” a professor said.

Dr. Tyler and the paper’s first author, postdoctoral fellow Dr. J. Ignacio Gutierrez, suspected that keeping nucleoli small could prevent aging. To put this theory to the test, scientists created an artificial method for attaching rDNA to the membrane surrounding the nucleus of yeast cells, allowing them to control when it was anchored and when it was not. “The advantage of our system is that we could isolate the nucleolus size from all of the other effects of anti-aging strategies,” said Gutierrez, the researcher.

The researchers discovered that anchoring the nucleolus was sufficient to keep it compact and that tiny nucleoli prevented aging to a degree comparable to calorie restriction.

Nucleolar Growth: A Tipping Point in Cellular Aging and Lifespan

Surprisingly, nucleoli did not increase at the same pace throughout the lifespan as cells aged. They remained small for most of the yeast’s life, but when the nucleoli reached a certain size threshold, they suddenly began to develop rapidly and expand to a considerably greater size. Cells survived for an average of five additional cell divisions after reaching this threshold.

“When we saw it wasn’t a linear size increase, we knew something really important was happening,” Dr. Gutierrez said. Passing the barrier appears to act as a mortality meter, counting down the final moments of a cell’s existence.

During aging, DNA accumulates damage, some of which can be lethal to cells. During testing, the team discovered that larger nucleoli had less stable rDNA than smaller ones. Furthermore, when the structure is big, proteins and other components normally excluded from the nucleolus are no longer kept out. It’s as if the nucleolus is leaking, allowing chemicals to wreak havoc on the fragile rDNA.

“The whole point of condensates is to separate biological reactions to help them work efficiently, but now when you have other proteins coming into the nucleolus, it leads to genome instability, which triggers the end of the lifespan,” Dr. Tyler told me. These proteins can accumulate and produce catastrophic consequences including chromosomal rearrangements.

The researchers then intend to investigate nucleolar effects on aging in human stem cells. Stem cells are unique in that they have the ability to replace other cell types as they perish. However, the stem cells will ultimately cease dividing, so the researchers intend to use the knowledge gathered from this effort to extend their lifespan.

“I was excited that we could connect the structure of the nucleolus with the repair process in a way that could be conserved from yeast to humans,” according to Dr. Gutierrez.

References:

1. A mortality timer based on nucleolar size triggers nucleolar integrity loss and catastrophic genomic instability
   (Gutierrez, J.I., Tyler, J.K. A mortality timer based on nucleolar size triggers nucleolar integrity loss and catastrophic genomic instability. Nat Aging (2024). https://doi.org/10.1038/s43587-024-00754-5)

Source-Medindia