The mystery of cellular youthfulness and longevity might be tied to the size of the nucleolus, a small structure within the core of a cell, as discovered by researchers at Weill Cornell Medicine. This study conducted on yeast, an organism that shares surprising cellular similarities with humans, was published on November 25 in the journal Nature Aging.

The study could be a significant step towards the development of new treatments to increase human lifespan. It also uncovers a sort of cellular “countdown clock” that can indicate how much time a cell has before it ceases to function.

As age increases, so does the risk of developing various health conditions such as cancer, cardiovascular disease, and neurodegenerative diseases. “The highest risk factor for these diseases is aging,” explained Dr. Jessica Tyler, professor of pathology and laboratory medicine at Weill Cornell Medicine. She suggested that instead of treating each disease individually, a more effective approach would be to prevent the molecular defects that cause them in the first place, and the nucleolus could be the key.

The nucleus of a cell houses its chromosomes and the nucleolus is the location of the ribosomal DNA (rDNA), which is integral to building proteins. The rDNA is particularly prone to damage due to its complex, repetitive structure, and if the damage is not properly repaired, it can lead to cell death.

Interestingly, the nucleoli in organisms ranging from yeast to humans tend to expand as they age. However, anti-aging strategies such as calorie restriction can result in smaller nucleoli. The precise mechanism of how calorie restriction extends lifespan is still unknown, noted Dr. Tyler.

To understand whether maintaining small nucleoli could delay aging, Dr. Tyler and Dr. J. Ignacio Gutierrez, a postdoctoral fellow, engineered a method to control the size of nucleoli in yeast cells. Their findings revealed that keeping the nucleolus compact effectively delayed aging, akin to the effects of calorie restriction.

In a fascinating observation, the researchers noted that the nucleoli did not expand evenly throughout their lifespan. They remained small for most of their life, but after reaching a certain size threshold, they began to expand rapidly. After this threshold was reached, cells only survived for roughly five more divisions on average, serving as a kind of cellular mortality clock.

The team found that larger nucleoli had less stable rDNA than smaller ones, and their larger size allowed unwanted elements to enter, causing damage to the delicate rDNA. This instability can lead to serious issues such as chromosomal rearrangements.

The next step for the researchers is to study the impact of nucleolar size on aging in human stem cells. As stem cells have the unique ability to replace other types of cells as they die, the researchers aim to use their findings to prolong the lifespan of these vital cells.

Dr. Gutierrez expressed excitement at the prospect of linking the structure of the nucleolus to the repair process in a way that could be applicable from yeast to humans.