Senescent cells — those that have lost the ability to divide — accumulate with age and are key drivers of age-related diseases, such as cancer, dementia and cardiovascular disease. In a new study, a team of researchers has uncovered a mechanism by which senescent, or “zombie,” cells develop.
Published in Nature Structural & Molecular Biology, the study shows for the first time that oxidative damage to telomeres —the protective tips of chromosomes that act like plastic caps at the end of a shoelace — can trigger cellular senescence. These findings could eventually point to new therapeutics that promote healthy aging or combat cancer.
“Zombie cells are still alive, but they can’t divide, so they don’t help replenish tissues,” said the senior author. “Although zombie cells don’t function properly, they’re not couch potatoes — they actively secrete chemicals that promote inflammation and damage neighboring cells. Our study helps answer two big questions: How do senescent cells accumulate with age, and how do telomeres contribute to that?”
When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosome’s tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a person’s lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a zombie-like state. Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could turn cells into zombies.
Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome.
“Our new tool is like a molecular sniper,” explained first author. “It creates oxidative damage exclusively at the telomeres.”
To develop such marksman-like precision, the team used a special protein that binds exclusively to telomeres. This protein acts like a catcher’s mitt, grabbing hold of light-sensitive dye “baseballs” that the researchers tossed into the cell. When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.
Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a zombie state after just four days — much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab.
“We found a new mechanism for inducing senescent cells that is completely dependent on telomeres,” explained a co-lead. “These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones.”
Sunlight, alcohol, smoking, poor diet and other factors generate reactive oxygen molecules that damage DNA. Cells have repair pathways to patch up DNA lesions, but, according to the author, telomeres are “exquisitely sensitive” to oxidative damage. The researchers found that damage at telomeres disrupted DNA replication and induced stress signaling pathways that led to senescence.
“Now that we understand this mechanism, we can start to test interventions to prevent senescence,” said the senior author. “For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.”
The findings could also inform the development of new drugs called senolytics that home in on zombie cells and kill them.
“By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we might be able to promote ‘healthspan’ — the length of time that a person is healthy,” the author added.
https://www.nature.com/articles/s41594-022-00790-y
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Ftelomeric-8-oxo-guanine&filter=22
New pathway for accumulation of age-promoting 'zombie cells'
- 847 views
- Added
Latest News
Abusive drugs hijack natura…
By newseditor
Posted 23 Apr
Mechanism of action of the…
By newseditor
Posted 23 Apr
Role of fat in rare neurolo…
By newseditor
Posted 23 Apr
How protein synthesis in de…
By newseditor
Posted 22 Apr
Atlas of mRNA variants in d…
By newseditor
Posted 22 Apr
Other Top Stories
Novel mechanism to inactivate kinases
Read more
Osteocyte transcriptome reveals genes that control the skeleton
Read more
A new lysine-cysteine redox switch with an NOS bridge regulates enz…
Read more
How dendritic spines change size during learning and memory
Read more
Amyloid beta generation at the mitochondria-associated endoplasmic…
Read more
Protocols
A programmable targeted pro…
By newseditor
Posted 23 Apr
MemPrep, a new technology f…
By newseditor
Posted 08 Apr
A tangible method to assess…
By newseditor
Posted 08 Apr
Stem cell-derived vessels-o…
By newseditor
Posted 06 Apr
Single-cell biclustering fo…
By newseditor
Posted 01 Apr
Publications
Exploiting pancreatic cance…
By newseditor
Posted 23 Apr
Structure of antiviral drug…
By newseditor
Posted 23 Apr
Type-I-interferon-responsiv…
By newseditor
Posted 23 Apr
Selenium, diabetes, and the…
By newseditor
Posted 23 Apr
Long-term neuropsychologica…
By newseditor
Posted 23 Apr
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar