The nucleolus resides in the cell nucleus, and is where ribosomes are assembled. It is known that the nucleolus grows larger with age, and in cells that have undergone a sufficient number of divisions to approach the Hayflick limit. Here, researchers provide evidence for harms caused by enlargement of the nucleolus in aging, using a novel approach that prevents the nucleous from enlarging without manipulating other aspects of cell function. It remains to be seen as to how one might progress from this engineering exercise to interventions that target the nucleolus, and whether other approaches to rejuvenation might prevent this from being needed in the first place. Enlargement of the nucleolus may be a downstream consequence of molecular damage that is easier to fix than the nucleolus itself.
The nucleus holds the cell’s chromosomes and the nucleolus where the ribosomal DNA (rDNA) is housed. The nucleolus isolates the rDNA which encodes the RNA portions of the ribosomes, the protein-building machinery. The rDNA is one of the most fragile parts of the genome, due to its repetitive nature making it more difficult to maintain and fix if damaged. If damage in the rDNA is not accurately repaired, it can lead to chromosomal rearrangements and cell death. In organisms from yeast to worms to humans, nucleoli expand during aging. On the flip side, anti-aging strategies like calorie restriction result in smaller nucleoli.
Researchers suspected that keeping nucleoli 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 was not. The researchers discovered that tethering the nucleolus was enough to keep it compact, and small nucleoli delayed aging to about the same extent as calorie restriction.
Interestingly, nucleoli did not expand at the same rate during the entire lifespan as cells aged. They remained small for most of the yeast’s life, but at a nucleolar size threshold, the nucleoli suddenly began to grow quickly and expand to a much larger size. Cells only survived for an average of about five more cell divisions after hitting this threshold. Passing the threshold appears to serve as a mortality timer, ticking down the final moments of a cell’s life. During aging, DNA accumulates damage, some of which can be devastating to the cell. In tests, researchers found that large nucleoli had less stable rDNA than smaller ones. Also, when the structure is large, proteins and other factors that are usually excluded from the nucleolus are no longer kept out. It’s as if the nucleolus becomes leaky, letting in molecules that can wreak havoc on the fragile rDNA.
Link: https://news.weill.cornell.edu/news/2024/11/fighting-aging-by-staying-compact
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