Probing the Undead to Understand the Aging Process

<p>Denis Tsygankov</p>

Denis Tsygankov

Sometimes, cells permanently stop dividing but remain active — you could even say they are undead. Scientists have appropriately nicknamed them “zombie” cells, which is a much more colorful description than the biological term, senescence.

Resistant to the natural process of cell death, or apoptosis, they no longer contribute to tissue repair or homeostasis and instead are known to release harmful substances, causing inflammation and damage to cells nearby and in distant organs.

So-called zombie cells increase as we age, and they are thought to be a central cause of age-related diseases and frailty. That’s why Denis Tsygankov and his collaborators are trying to dig up the underlying workings of senescence with the help of the National Institutes of Health.

The NIH has awarded Tsygankov, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, a two-year, $275,000 R21 grant for his project, “Patterns of Aging and the Role of Biomarkers in Senescence.” R21 grants are designed to support exploratory research with potential to lead to advances in biomedical research.

“This project will build the first mathematical model to characterize senescence in the entire human organism, unveiling its regulation and dynamics, and its role in the physiological or pathological processes during human aging,” said Tsygankov, an expert in computational biology and mathematical modeling.

His collaborators include Dr. Hyman Muss, clinical researcher from the University of North Carolina, and Dr. Natalia Mitin, former cancer researcher at UNC, who is now CEO and co-founder of Sapere Bio, a company focused on studying senescence and interpreting its clinical significance. Dr. Muss has been interested in understanding senescence in his clinical practice for over a decade and published numerous papers on the connection between a central biomarker of senescence, p16, and chemotherapy-induced age-acceleration.

“The company is built around measuring a protein and tumor suppressor called p16,” said Tsygankov, who also is a researcher in the Petit Institute for Bioengineering and Bioscience at Georgia Tech, and who has experience with that particular protein. “There is very strong evidence that p16 is a true biomarker of aging, perhaps the most trustworthy biomarker, and with great clinical value.”

Research interest in p16 has grown in the past 10 years or so, since Ned Sharpless’ lab at UNC identified the protein in human T cells as an easily measured biomarker of human senescence or molecular age. The researchers identified a subset of blood cells that express p16, “which made it possible to measure p16 efficiently and precisely, unlike the attempts of measuring in whole blood,” said Tsygankov, who was a postdoc at UNC before coming to Georgia Tech/Emory BME in 2015.

“Our top goal in this project is to develop quantitative, mechanistic models of p16 dynamics at the cellular and the whole organism scales, and determine if the p16 measured in T cells actually reflects the overall senescence load at the systems level,” Tysgankov added.

Tsygankov and his collaborators are working under the broad theme that aging may not be reversed, but it can be slowed down. A quantitative understanding of p16’s role as a biomarker of senescence, and the ability to control it, could improve health care, particularly when it comes to guiding clinical decisions.

“Treatment plans such as chemotherapy can be dependent on a patient’s age,” Tsygankov said. “But chronological age and molecular or biological age are different things. We all age differently.”

Preliminary analysis of data from studies by Muss and Sapere Bio has shown that p16 levels — those indicators of senescence — can be used to predict patient risk for adverse side effects of treatment, such as kidney failure in patients undergoing cardiovascular surgery or peripheral neuropathy in breast cancer patients undergoing chemotherapy.

“Better data and predictive mathematical models on p16’s role in senescence could lead to better personalized treatment,” Tsygankov said. “Then we can expand the scope of our research, potentially leading to a precise, reliable set of clinically important biomarkers of aging.”


Tsygankov lab