When it comes to treating disease, one promising avenue is addressing the presence of senescent cells. These cells - also known as "zombie cells" - stop dividing but don't die off as cells typically do. They turn up in numerous diseases, including cancer and Alzheimer's disease, and in the process of aging. While potential treatments aim to remove or repair the cells, one hurdle has been finding a way to identify them among healthy cells in living tissue.
In the journal Aging Cell, Mayo Clinic researchers report finding a new technique to tag senescent cells. The team used molecules known as "aptamers" - small segments of synthetic DNA that fold into three-dimensional shapes. Aptamers have the ability to attach themselves to proteins on the surfaces of cells. In mouse cells, the team found several rare aptamers, identified from among more than 100 trillion random DNA sequences, that can latch onto specific cell surface proteins and flag senescent cells.
"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."
From a quirky idea to collaboration
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."
Identifying attributes of senescent cells
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."
See the study for a complete list of authors, disclosures and funding.
