Smaller nucleoli slow aging, acting as a “mortality timer,” while larger nucleoli lead to cell death by destabilizing rDNA.
The secret to cellular youth may lie in maintaining a small nucleolus—a dense structure within the cell nucleus—according to investigators at Weill Cornell Medicine. These findings were uncovered in yeast, a model organism renowned for its role in making bread and beer, 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 lifespan. It also establishes a mortality timer that reveals how long a cell has left before it dies.
As people get older, 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. “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.
Small Packages
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, or eating less, result in smaller nucleoli. “Calorie restriction does so many different things, and no one knows the precise way that it is extending lifespan,” Dr. Tyler said.
Dr. Tyler and postdoctoral fellow Dr. J. Ignacio Gutierrez, the first author of the paper, 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 advantage of our system is that we could isolate the nucleolus size from all of the other effects of anti-aging strategies,” Dr. Gutierrez said.
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.
Final Moments
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.
“When we saw it wasn’t a linear size increase, we knew something really important was happening,” said Dr. Gutierrez. 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, the team 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.
“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 said. These proteins can cause catastrophic problems, such as chromosomal rearrangements, to build up.
Next, the researchers plan to study nucleolar effects on aging in human stem cells. Stem cells are special because they have the potential to replace other cell types as they die. But eventually, the stem cells stop dividing, so the researchers hope to use the knowledge gained from this project to make them last longer.
“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,” said Dr. Gutierrez.
Reference: “A mortality timer based on nucleolar size triggers nucleolar integrity loss and catastrophic genomic instability” by J. Ignacio Gutierrez, and Jessica K. Tyler, 25 November 2024, Nature Aging.
DOI: 10.1038/s43587-024-00754-5
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18 Comments
I just love it can’t get enough enjoy reading about science and technology
I concur!
Great info
As someone with just a basic understanding of science, I really appreciate how Scitechdaily keeps their articles concise yet easy to understand. They provide enough information for curious readers to explore the topic further if they want.
That said, I found this article particularly interesting and timely for me personally. With the way algorithms and targeted advertising work, who knows if it’s just a coincidence that I came across it. Either way, in the simplest terms, this article left me feeling hopeful about what the future might hold.
So if reduction and caloric intake keeps the nucleolus(i) smaller, would not burning calories also accomplish the same thing through exercise and activity?
this is indeed a fascinating discovery and imo the first true longevity stepping stone of importance !
Ray B, I’d assume not – as limiting calories intake leads to a slower metabolism (thus slowing all associated processes, including shortening of telomeres), while consuming and burning more can lead to faster metabolism… with opposite effects.
It’d still be helpful for many other ailments that potentially limit our lifespan before our cells clock/timer had a chance to deteriorate, though!
The cell clock used to be measured by telomeres on the chromosomes.
I believe it’s more complicated than that, as apparently there are other “normal” senescence processes which can occur that involve aspects other than telomeres shortening. Not a biologist here, just remember reading about cellular senescence and causes/mitigations.
Well done telomeres was the standard I enjoy the articles but the comments add to the presentation keep it up people
This. Was thinking this the entire article.
I appreciate articles that are well comments! Many stories that deserve comments do not entertain them and should!
Calorie restriction is kinda vague. I imagine if done too regularly it would decrease heart n other muscular function, decrease energy levels thus preventing regular exercise, cause insomnia (bc I sleep best when I have eaten a lot personally), cause organs to atrophy, induce infertility and reproductive issues, hormonal issues (hormones are built with sat fats and cholesterol), nutritional deficiencies etc…In a culture unusually obsessed with being overly thin compared to much of the world, linking undereating to longevity seems a little problematic, although I’m guessing overeating doesn’t increase longevity either. Focusing on restricting calories as an avg person seems a little pseudoscientific, yet I see esp women and girls do it all the time as some sorta measure of responsibility. But it’s actually very hard for women to get all their necessary nutrients bc of the added toll of reproduction and related processes. And the efficacy of supplements questionable compared to actual whole foods we’ve evolved with. I read thrs no evidence any supplement prolongs lifespan. It’s int to look at the results of the 90 yr old plus study, in which medical researchers tracked an aging community for decades. Those we were underweight or of normal weight had lower longevity, which was quite counterintuitive culturally.
Not arguing your other points, I’d just like to point out that “culture unusually obsessed with being overly thin compared to much of the world” – being “unusually obsessed” about it is only because the nation, on the whole, has unusual levels of obesity, comparing to the rest of the world!
And “overly thin” – not many people here in the States are in danger of being TRULY “overly thin”, only those with legit eating disorders and those whose employment depends on being underweight, like certain models, etc. (even though on them, too, the pressure is a lot less than it used to be).
What’s more likely is that our sense of what’s normal is shifting, as it largely depends on what we see as “average” around us – not necessarily what’s true for a human body, biologically! (I still remember what people used to look like, naturally, with more walking and less processed foods, in my childhood/youth what would pass as “healthy” now, would be considered quite chubby, back then!)
Furthermore, the efficacy of limiting calories as beneficial to longevity, comes from slowing down metabolism, and therefore all associated processes… not just from end result of being thin/normal, as that could also be achieved by burning more calories, yet as far as aging goes on a CELLULAR level, won’t be nearly as effective!
There’s a drug called rapamycin that simulates calorie restriction. It inhibits the MTOR complex, which is part of the signaling pathway that informs the cell that nutrition is available. Rapamycin has been shown to increase lifespan in many species, including yeast, mice, and more recently in rhesus monkeys. Maybe one of the ways it is achieving that is by preventing increase in the size of the nucleolus? It’s also been shown to trigger “mitophogy”, a process that causes a cell’s mitochondria to be recycled and replaced, thus renewed. Unfortunately rapamycin is in the public domain, so it’s impossible to get funding to do the clinical studies needed to make it available for people to use…
Interesting
rDNA (Ribosomal DNA)
Definition: rDNA refers to the DNA sequences in the genome that encode for ribosomal RNA (rRNA).
Function: These sequences are part of the nucleolus organizer regions (NORs) in chromosomes and are transcribed to produce rRNA.
Structure: rDNA consists of repetitive units, each containing the genes for 18S, 5.8S, and 28S rRNA, along with non-coding spacer regions.
Location: Found in specific regions of the genome, often in multiple copies to meet the high demand for rRNA production.
rRNA (Ribosomal RNA)
Definition: rRNA is a type of RNA molecule that is a structural and functional component of ribosomes.
Function:
rRNA plays a critical role in protein synthesis by forming the ribosome’s core structure and catalyzing peptide bond formation during translation.
It interacts with messenger RNA (mRNA) and transfer RNA (tRNA) to facilitate translation.
Types in Eukaryotes:
18S rRNA (small subunit)
28S rRNA, 5.8S rRNA, and 5S rRNA (large subunit)
Types in Prokaryotes:
16S rRNA (small subunit)
23S rRNA and 5S rRNA (large subunit)
Relationship Between rDNA and rRNA
rDNA is the template from which rRNA is transcribed. Through transcription in the nucleolus, rDNA produces precursor rRNA (pre-rRNA), which is processed to form the functional rRNA molecules that assemble into ribosomes.
To my knowledge (PhD in cell and Molecular Biology) in this context there is no such thing as rDNA, I think you meant to say rRNA