Crazy Grad Student Idea Results in Major Aging Discovery

One potential key to treating many diseases may lie in targeting senescent cells, sometimes called “zombie cells.” These cells stop dividing but fail to die off as normal cells do, and they accumulate in the body over time. Their presence has been linked to aging and several major illnesses, including cancer and Alzheimer’s disease, the journal Aging Cell reported.

While scientists have been exploring ways to remove or repair these malfunctioning cells, one major obstacle has been finding a reliable way to spot them among healthy cells in living tissues.

In a new study, researchers at Mayo Clinic have developed a promising method to identify senescent cells. The team used molecules called “aptamers” (short strands of synthetic DNA that naturally fold into complex three-dimensional shapes).

Aptamers can bind to proteins found on the outer surfaces of cells, allowing scientists to distinguish between cell types. In experiments using mouse cells, the researchers discovered several rare aptamers—selected from more than 100 trillion DNA sequences—that could specifically attach to proteins unique to senescent cells, effectively tagging them for detection.

“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.”

The project began with the quirky idea of a Mayo Clinic graduate student who had a chance conversation with a classmate.

Keenan Pearson, Ph.D. — who recently received his degree from Mayo Clinic Graduate School of Biomedical Sciences — was working under the mentorship of Dr. Maher, studying how aptamers might address neurodegenerative diseases or brain cancer.

A few floors away, Sarah Jachim, Ph.D., — who was also then conducting her graduate research — was working in the lab of researcher Nathan LeBrasseur, Ph.D., who studies senescent cells and aging.

At a scientific event, the two happened to chat about their graduate thesis projects. Dr. Pearson thought aptamer technology might be able to identify 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.

They pitched the idea to their mentors and to researcher Darren Baker, Ph.D., who investigates therapies to treat senescent cells. At first, Dr. Maher acknowledges, the students’ idea seemed “crazy” but worth pursuing. The three mentors were excited about the plan. “We frankly loved that it was the students’ idea and a real synergy of two research areas,” says Dr. Maher.

The students obtained compelling results sooner than they expected and quickly recruited other student participants from the labs. Then-graduate students Brandon Wilbanks, Ph.D., Luis Prieto, Ph.D., and M.D.-Ph.D. student Caroline Doherty, each contributed additional approaches, including special microscopy techniques and more varied 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.”

The study has provided new information about senescent cells beyond a way to tag them. “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.”

The study found several aptamers latched onto a variant of a specific molecule on the surface of mouse cells, a protein called fibronectin. The role of this variant fibronectin in senescence is not yet understood. The finding means that aptamers may be a tool to further define unique characteristics of senescent cells.

Additional studies will be necessary to find aptamers that can identify senescent cells in humans. Aptamers with the ability to latch onto senescent cells could potentially deliver a therapy directly to those cells. Dr. Pearson notes aptamer technology is less expensive and more versatile than conventional antibodies, proteins that are typically used to differentiate cells from one another.

“This project demonstrated a novel concept,” says Dr. Maher. “Future studies may extend the approach to applications related to senescent cells in human disease.”

4155/v