How telomeres contribute to the cellular mechanisms of aging – Medical News Today

Every time a cell divides, its chromosomes — the bundles of DNA that encode genes — get a little shorter.
This is because the cellular machinery for duplicating DNA cannot copy the molecule to the very ends of each strand.
To prevent vital genetic information from being lost every time the cell divides, structures called telomeres protect the ends of the chromosomes.
These are strips of expendable DNA that don’t encode any important information.
However, with every cell division, the telomeres erode until they can no longer protect the chromosome.
At this point, a control mechanism kicks in that stops the cell from dividing any further. Although the cell remains alive and active, it enters into senescence.
Over time, as people age, the body accumulates these senescent cells.
The downside is that senescent cells promote the inflammation that researchers think underlies many diseases of aging, including cardiovascular disease, diabetes, and Alzheimer’s disease.
After studying cultures of human skin cells in their lab, researchers at the Université de Montréal in Montreal, Canada, have outlined a new theory about how cells become senescent.
Their model updates the leading theory of senescence, which proposes that cells stop dividing simply because their telomeres become too short and no longer function properly.
Instead, the scientists claim that cells only stop dividing after chromosomal instability due to loss of telomeres has resulted in irreparable genomic damage during cell division.
“What’s most surprising is that before really entering senescence, the cells divide one last time,” says senior author and cancer researcher Francis Rodier, Ph.D.
“In fact, the cell division caused by telomere dysfunction is so unstable that it ends up creating genetic defects,” he adds.
As a result, the researchers believe the genome of senescent cells is faulty.
“Contrary to what was believed, senescent cells have an abnormal genome,” says Professor Rodier.
Their study appears in the journal Nucleic Acids Research.
According to the established model of cell senescence, if a telomere becomes faulty, it activates a “DNA damage response” mechanism.
In turn, this switches on a protein called p53, which shuts down cell division. The protein is known to play a vital role in suppressing the growth of cancerous tumors.
The theory suggests that a single damaged telomere should be sufficient to shut off cell division.
However, several groups of scientists have noticed that normal mammalian cells can harbor several damaged telomeres and yet continue dividing.
To find out more, Prof. Rodier and his colleagues took a series of pictures of individual skin cells as they divided and became senescent.
They observed that, at first, faulty telomeres only slowed down cell division.
A cell only stopped dividing after its chromosomes began to stick together, which functional telomeres usually prevent from happening, causing permanent damage.
Functioning telomeres are double strands of DNA, like the main body of the chromosome.
When the cell divides, the double strands of each chromosome unzip to form two single strands of DNA. These pair up with individual DNA building blocks (or nucleotides) to create two copies of each chromosome, meaning a copy of each chromosome goes into each half of the dividing cell to make two whole new cells.
The two daughter chromosomes are known as sister chromatids.
A broken telomere, however, has a sticky “loose end.” This is a single strand of DNA that, like the loose end of a roll of sticky tape, can loop back on itself or stick to another damaged telomere.
The scientists observed that a cell only became senescent after the damaged telomeres of two sister chromatids permanently fused during cell division.
The research may have implications for preventing age-related disease.
In their paper, the scientists conclude:
“Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability.”
Senescent cells may contribute to the low-level inflammation or “inflammaging” that underlies age-related diseases.
“We think that the genomic instability plays a key role in activating the senescence-associated inflammation,” Prof. Rodier told Medical News Today.
“[I]t is possible that therapies aiming at protecting telomere ends before fusions occur would prevent genomic instability and senescence,” he said.
However, cells that harbor defective telomeres that have yet to fuse may have other characteristics, such as altered gene expression, that also play a role in inflammaging.
“If they do, then simple telomeric correction might not be enough to completely bring them back to normality,” Prof. Rodier added.
Joachim Lingner, Ph.D., who heads a lab at the Swiss Federal Institute of Technology in Lausanne, Switzerland, that studies telomeres, sounded another note of caution.
Telomere shortening imposes a limit on the number of times a cell can divide.
Sperm and egg cells are exceptions to this rule. In these cases, an enzyme called telomerase rebuilds telomeres to ensure that a complete, working genome passes on to the next generation.
Cancer cells are another exception and can attain “immortality” by switching on the gene that makes telomerase.
“Telomerase is upregulated in 90% of tumors, being responsible for cancer immortality,” Prof. Lingner told MNT.
A person’s telomere length also positively correlates with their likelihood of developing cancer, he said.
So preventing telomere shortening would almost certainly promote the development of cancer.
“Thus, this strategy to counteract senescence-related disease would be extremely risky,” Prof. Lingner concluded.





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