The secret of cellular youth may depend on keeping the nucleolus—a condensed structure inside a cell’s nucleus—small, according to Weill Cornell Medicine researchers. The findings were clarified in yeast, a model organism famous for making bread and beer and yet surprisingly similar to humans at the cellular level.
The study, published Nov. 25 in Nature Aging, may lead to new longevity treatments that could extend human lifespans. It also establishes a mortality timer that reveals how long a cell has left before it dies.
As people age, they are more likely to develop health conditions such as cancer, cardiovascular disease and neurodegenerative diseases.
“Aging is the highest risk factor for these diseases,” said Dr. Jessica Tyler, professor of pathology and laboratory medicine at Weill Cornell Medicine. “Instead of treating each disease individually, a better approach would be to develop a therapeutic or supplement that delays the onset of diseases by preventing the underlying molecular defects that cause them.” The kernel may hold the key.
Small packages
The nucleus holds the cell’s chromosomes and the nucleus where the ribosomal DNA (rDNA) resides. The nucleus isolates the rDNA that codes for the RNA segments of ribosomes, the protein-making machinery. rDNA is one of the most fragile parts of the genome, due to its repetitive nature that makes it more difficult to maintain and repair if damaged. If rDNA damage is not accurately repaired, it can lead to chromosomal rearrangements and cell death.
In organisms from yeast to worms to humans, nuclei expand during aging. On the other hand, anti-aging strategies, such as calorie restriction or eating less, result in smaller cores. “Calorie restriction does so many different things, and no one knows exactly how it extends life,” Dr. Tyler said.
Dr. Tyler and postdoctoral fellow Dr. J. Ignacio Gutierrez, the paper’s first author, suspected that keeping the nuclei small could delay aging. To test this idea, they engineered an artificial way to secure rDNA to the membrane surrounding the nucleus of yeast cells so they could control when it was anchored and when it wasn’t.
The advantage of our system is that we can isolate core size from all other effects of antiaging strategies.”
Dr. J. Ignacio Gutierrez, Postdoctoral Fellow
The researchers found that core tethering was enough to keep it compact, and small cores delayed aging to about the same extent as calorie restriction.
Last moments
Interestingly, nuclei did not expand at the same rate throughout life as cells aged. They remained small for most of the yeast’s life, but at a nuclear size threshold, the nuclei suddenly began to grow rapidly and expand to a much larger size. Cells only survived for about five additional cell divisions on average after reaching this threshold.
“When we saw that it wasn’t a linear increase in size, we knew something very important was going on,” Dr. Gutierrez said. Exceeding the threshold appears to serve as a mortality timer, marking the final moments of a cell’s life.
During aging, DNA accumulates damage, some of which can be destructive to the cell. In tests, the team found that large nuclei had less stable rDNA than smaller ones. Also, when the structure is large, proteins and other factors that are normally excluded from the nucleus are no longer kept out. It’s as if the nucleus is leaking, leaving behind molecules that can wreak havoc on the fragile rDNA.
“The whole point of the condensates is to separate biological reactions to help them work efficiently, but now when there are other proteins entering the nucleus, it leads to genome instability, which triggers the end of life,” said Dr. Tyler. These proteins can cause devastating problems, such as chromosomal rearrangements, to accumulate.
Next, the researchers plan to study nuclear effects on aging in human stem cells. Stem cells are special because they have the ability to replace other types of cells as they die. But eventually, the stem cells stop dividing, so the researchers hope to use the knowledge gained from this work to make them last longer.
Dr. Tyler and Dr. Gutierrez are excited about how different aspects of biology and aging have come together in this work, which may lead to new treatments. “I was excited that we could link the core structure to the repair process in a way that could be conserved from yeast to humans,” said Dr. Gutierrez.
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Journal Reference:
Ignacio, GJ, & Tyler, JK (2024). A nuclear size-based lethality timer causes loss of nuclear integrity and catastrophic genomic instability. Aging Nature. doi.org/10.1038/s43587-024-00754-5.
