One of the biggest challenges in aging and disease research is tracking down senescent cells. These cells — often called “zombie cells” — stop dividing but refuse to die off normally. Over time, they can build up in the body and have been linked to conditions including cancer, Alzheimer’s disease, and the aging process itself.
Scientists have been exploring ways to remove or repair these harmful cells, but there has been a major obstacle. Researchers have struggled to reliably identify senescent cells hiding among healthy cells in living tissue.
DNA Aptamers Help Researchers Identify Senescent Cells
A team at Mayo Clinic now says it has found a promising new strategy. Writing in the journal Aging Cell, the researchers describe a technique that uses molecules called “aptamers” to tag senescent cells.
Aptamers are short strands of synthetic DNA that naturally fold into complex three dimensional shapes. Those shapes allow them to attach to specific proteins found on the surfaces of cells.
Working with mouse cells, the scientists screened more than 100 trillion random DNA sequences and identified several rare aptamers capable of binding to proteins associated with senescent cells. Once attached, the aptamers effectively flagged the cells for identification.
“This approach established the principle that aptamers are a technology that can be used to distinguish senescent cells from healthy ones,” says biochemist and molecular biologist Jim Maher, III, Ph.D., a principal investigator of the study. “Though this study is a first step, the results suggest the approach could eventually apply to human cells.”
A Chance Conversation Sparked the Discovery
The project began with an unexpected idea shared during a casual conversation between graduate students at Mayo Clinic.
Keenan Pearson, Ph.D. — who recently earned his degree from Mayo Clinic Graduate School of Biomedical Sciences — had been studying how aptamers might be used against brain cancer or neurodegenerative diseases while working with Dr. Maher.
Elsewhere on campus, Sarah Jachim, Ph.D., — who was also completing graduate research at the time — was studying aging and senescent cells in the laboratory of Nathan LeBrasseur, Ph.D.
The two students crossed paths during a scientific event and started discussing their thesis projects. Dr. Pearson began wondering whether aptamer technology could be adapted to recognize senescent cells.
“I thought the idea was a good one, but I didn’t know about the process of preparing senescent cells to test them, and that was Sarah’s expertise,” says Dr. Pearson, who became lead author of the publication.
Researchers Pursue a “Crazy” Idea
The students presented the idea to their mentors as well as researcher Darren Baker, Ph.D., whose work focuses on therapies targeting senescent cells.
Dr. Maher says the concept initially sounded “crazy,” but intriguing enough to investigate further. The mentors ultimately embraced the collaboration.
“We frankly loved that it was the students’ idea and a real synergy of two research areas,” says Dr. Maher.
The research advanced quickly. Early experiments produced encouraging findings sooner than expected, leading the team to bring in additional students from several labs.
Then-graduate students Brandon Wilbanks, Ph.D., Luis Prieto, Ph.D., and M.D.-Ph.D. student Caroline Doherty contributed specialized techniques, including advanced microscopy and analysis of a wider variety of tissue samples.
“It became encouraging to expend more effort,” Dr. Jachim says, “because we could tell it was a project that was going to succeed.”
New Clues About the Biology of Zombie Cells
The study may offer more than just a new way to identify senescent cells. It also uncovered information about the cells themselves.
“To date, there aren’t universal markers that characterize senescent cells,” says Dr. Maher. “Our study was set up to be open-ended about the target surface molecules on senescent cells. The beauty of this approach is that we let the aptamers choose the molecules to bind to.”
Several of the aptamers attached to a variation of fibronectin, a protein found on the surface of mouse cells. Researchers do not yet understand exactly how this fibronectin variant relates to senescence, but the finding could help scientists better define what makes senescent cells unique.
Future Potential for Aging and Disease Treatments
The researchers caution that additional studies will be needed before aptamers can reliably identify senescent cells in humans.
Still, the technology could eventually become much more than a detection tool. Scientists believe aptamers might one day carry therapies directly to senescent cells, allowing highly targeted treatment approaches.
Dr. Pearson says aptamers are also less expensive and more adaptable than traditional antibodies, which are commonly used to distinguish different types of cells.
“This project demonstrated a novel concept,” says Dr. Maher. “Future studies may extend the approach to applications related to senescent cells in human disease.”
