Antibodies destroy infected cells

‘Zombie cells’ that accelerate aging – a new study reveals these unique cells

Senescent cells, or “zombie cells,” are unique in that they eventually stop reproducing, but don’t die as expected.

Researchers have discovered a new pathway that promotes the accumulation of aging “zombie cells”.

Senescent cells, or cells that lose the ability to divide, increase with age and are a major cause of age-related diseases such as cancer, dementia and cardiovascular disease. In a new study, a team led by researchers at the University of Pittsburgh and UPMC Hillman Cancer Center has discovered a way for senescent or “zombie” cells to develop.

Patricia Opresco

Patricia Opresko, Ph.D., professor of environmental and occupational health, pharmacology, and chemical biology at the University of Pittsburgh, and co-director of the Genome Stability Program at UPMC Hillman Cancer Center.Credit: Patricia Opresco

The study was recently published in the journal Nature Structural and Molecular Biology, For the first time, it has been shown that oxidative damage to telomeres — the protective tips of chromosomes that behave like the plastic caps at the ends of shoelaces — can lead to cellular senescence. The findings could eventually lead to new treatments that promote healthy aging or fight cancer.

“Zombie cells are still alive, but they can’t divide, so they don’t help replenish tissue,” said senior author Patricia Opresko, Ph.D., professor of environmental and occupational health and pharmacology and chemical biology at Pitt. “While zombie cells don’t work 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 senescent cells age as they age. accumulation, and how do telomeres contribute to this?”

When a healthy human cell divides to produce two identical cells,

DNA
DNA or deoxyribonucleic acid is a molecule made up of two long chains of nucleotides that twist around each other to form a double helix. It is the genetic material in humans and almost all other organisms, with genetic instructions for development, function, growth and reproduction. Almost every cell in the human body has the same DNA. Most DNA is located in the nucleus (called nuclear DNA), but small amounts of DNA can also be found in mitochondria (called mitochondrial DNA or mtDNA).

“data-gt-translation-attributes=”[{” attribute=””>DNA is shaved off the tip of each chromosome, causing telomeres to get shorter with each division. However, it is unknown if a cell may divide so often in a person’s lifetime that its telomeres fully degrade, resulting in a zombie-like condition. For decades, scientists have known that telomere shortening causes senescence in lab-grown cells, but they could only assume that DNA damage at telomeres could convert cells into zombies.

This hypothesis could not previously be tested since the techniques used to damage DNA were non-specific, creating lesions across the entire chromosome.

“Our new tool is like a molecular sniper,” explained first author Ryan Barnes, Ph.D., a postdoctoral fellow in Opresko’s lab. “It creates oxidative damage exclusively at the telomeres.”

Chromosome Fragile Telomeres

X-shaped chromosomes are stained purple, and telomeres appear as green spots at chromosome tips. When researchers used a novel tool to induce oxidative damage specifically at telomeres, they can become fragile (green arrows), sending cells into senescence. The inset shows an enlarged chromosome with fragile telomeres, indicated by multiple green spots at chromosome tips. Credit: Barnes et al., Nature Structural & Molecular Biology, (2022)

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.

Ryan Barnes

Ryan Barnes, Ph.D., a postdoctoral fellow at the University of Pittsburgh. Credit: Ryan Barnes

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 Opresko, who also co-leads the Genome Stability Program at UPMC Hillman. “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 Opresko, 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 Barnes. “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,” he added.

Reference: “Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening” by Ryan P. Barnes, Mariarosaria de Rosa, Sanjana A. Thosar, Ariana C. Detwiler, Vera Roginskaya, Bennett Van Houten, Marcel P. Bruchez, Jacob Stewart-Ornstein, and Patricia L. Opresko, 30 June 2022, Nature Structural & Molecular Biology.
DOI: 10.1038/s41594-022-00790-y

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