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Researchers discover new avenue for accumulation of age-promoting ‘zombie cells’

Overview: Oxidative damage to telomeres can cause cellular aging. The findings could lead to the development of new therapies for healthy aging and cancer control.

Source: University of Pittsburgh

Age cells – cells that have lost the ability to divide – accumulate with age and are the main drivers of age-related diseases, such as cancer, dementia and cardiovascular disease.

In a new study, a team led by University of Pittsburgh and UPMC Hillman Cancer Center researchers has discovered a mechanism by which senescent or “zombie” cells develop.

Published today in Nature Structural and Molecular Biology, the study shows for the first time that oxidative damage to telomeres — the protective ends of chromosomes that act like plastic caps on the end of a shoelace — can cause cellular aging. These findings could ultimately point to new therapies that promote healthy aging or fight cancer.

“Zombie cells are still alive, but they can’t divide, so they don’t help replenish tissues,” said senior author Patricia Opresko, Ph.D., a professor of environmental and occupational health and pharmacology and chemical biology at Pitt.

“While 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 stack up as they age, and how do they wear down? telomeres to that?”

When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off the tip of each chromosome so that the telomeres gradually shorten with each division. However, it remains unclear whether a cell can divide so many times over a person’s life that the telomeres completely erode, leading to a transition into a zombie-like state.

Researchers have known for decades that telomere shortening causes senescence in lab-grown cells, but they could only hypothesize that DNA damage to telomere could turn cells into zombies.

Until now, testing this hypothesis hadn’t been possible because the tools used to damage DNA were non-specific, causing lesions all over the chromosome.

“Our new tool is like a molecular sniper,” explains first author Ryan Barnes, Ph.D., a postdoctoral researcher in Opresko’s lab. “It only causes oxidative damage to the telomeres.”

To develop such sniper-like precision, the team used a special protein that binds exclusively to telomeres. This protein acts like a catcher’s glove, grabbing 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-capturing protein only binds to telomeres, the tool creates DNA lesions specifically on chromosome ends.

Using human cells grown in a dish, the researchers found that damage to telomeres put the cells into a zombie state after just four days — much faster than the weeks or months of repeated cell divisions needed to trigger aging through telomere shortening in the laboratory .

This shows the zombie cells
X-shaped chromosomes are colored purple and telomeres appear as green spots on chromosome ends. When researchers used a new tool to cause oxidative damage, specifically at telomeres, they can become fragile (green arrows), causing cells to age. The inset shows an enlarged chromosome with fragile telomeres, indicated by multiple green spots on chromosome ends. Credit: Barnes et al., Nature Structural & Molecular Biology

“We have found a novel mechanism for inducing senescent cells that is completely dependent on telomeres,” explains Opresko, who is also co-leader of 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 repair DNA lesions, but according to Opresko, telomeres are “excellently sensitive” to oxidative damage. The researchers found that damage to telomeres disrupted DNA replication and induced stress signaling pathways that lead to aging.

“Now that we understand this mechanism, we can start testing interventions to prevent aging,” says Barnes. “For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage.”

The findings could also help develop new drugs called senolytics that target and kill zombie cells.

“By reducing the accumulation of zombie cells, which contribute to degenerative diseases, we can promote the ‘healthspan’ – the length of time a person is healthy,” he added.

Other authors who contributed to the study were Mariarosaria de Rosa, Ph.D., Sanjana A. Thosar, MS, Ariana C. Detwiler, MS, Vera Roginskaya, BS, Bennett Van Houten, Ph.D., and Jacob Stewart- Ornstein, Ph.D., Jolly Pitt and UPMC, and Marcel P. Bruchez, Ph.D., Carnegie Mellon University.

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Financing: This research was supported by the National Institutes of Health (F32AG067710-01, K99ES033771, R35ES030396, R01CA207342, and R01EB017268), the Glenn Foundation for Medical Research, the UPMC Hillman Cancer Center Cytometry Facility (P30CA047904), and the UPMC Hillman Cancer Center Postdoctoral Fellowship for Innovative cancer research.

About this genetics research news

Author: Asher Jones
Source: University of Pittsburgh
Contact: Asher Jones – University of Pittsburgh
Image: The image is attributed to Barnes et al., Nature Structural & Molecular Biology

Original research: Open access.
Telomere 8-oxo-guanine provides rapid premature aging in the absence of telomere shorteningby Barnes et al. Nature Structural and Molecular Biology


Telomere 8-oxo-guanine provides rapid premature aging in the absence of telomere shortening

Oxidative stress is a primary cause of cellular aging and contributes to the etiology of numerous human diseases. It has been proposed that oxidative damage to telomere DNA causes premature aging by accelerating telomere shortening.

Here we directly tested this model using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to induce multiple features of p53-dependent senescence.

Telomeric 8oxoG activates ATM and ATR signaling and enriches for markers of telomere dysfunction in replicating, but not resting cells. Acute 8oxoG production cannot shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis on telomeres, indicating impaired replication.

Based on our results, we propose that oxidative stress promotes rapid aging by producing oxidative basal lesions that cause replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

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