OKLAHOMA CITY – While chemotherapy can be lifesaving, it also damages DNA and leads to cognitive issues known as "chemo brain." These effects resemble the memory and learning problems seen in older adults, prompting University of Oklahoma researchers to investigate this unique overlap of cognitive decline.
Their work has resulted in three recent publications in the journals Geroscience and Aging Cell. Lead author Anna Csiszar, M.D., Ph.D., a professor of neurosurgery at the University of Oklahoma College of Medicine, said that the similarities between the aging brain and chemo brain may yield answers that apply to both.
"There are several parallels in these two situations," Csiszar said. "In both, there is decreased blood flow in the brain when it is at rest and a smaller increase in blood flow when the brain is active. In addition, the blood-brain barrier, a protective layer that prevents harmful substances from entering the brain, is disrupted, which triggers inflammation in the brain. Finally, there is an accumulation of senescent cells in both brains. Senescent cells, sometimes called 'zombie cells,' are in a suspended state of not being dead nor being able to fulfill their normal function, which also causes inflammation."
When people receive chemotherapy, the drug kills cells that are dividing rapidly. While this can eliminate cancer cells, it also damages healthy cells, leading to side effects like chemo brain. In a Geroscience paper , the research team studied several chemotherapy drugs in mice for their effects on the brain, including the commonly used paclitaxel and cisplatin. They found that even though the chemo drugs caused DNA damage in different ways, their characteristics were the same in how they affected cognition.
Because of the blood-brain barrier, chemotherapy drugs do not directly enter and damage the brain. Instead, chemotherapy harms endothelial cells, the type of vascular cell most susceptible to damage. When the endothelial cells are impaired, they become senescent and produce inflammatory substances that compromise the blood-brain barrier.
Csiszar and her team also studied ways to improve cognition. In a study published in Aging Cell, they tested senolytics in aging mice. Senolytics are drugs that can induce senescent cells to die through apoptosis, the typical process by which cells are removed. By selectively removing senescent cells, cognition improved.
"Our study demonstrated that if we remove these senescent cells, we can improve cerebral blood flow and the health of the blood-brain barrier, and eventually improve cognition," she said.
Researchers took the study a step further to determine the ideal time window for administering senolytics to have the most positive effect on the brain's vasculature and cognition. They tested senolytics in mice of all ages and ultimately discovered the drug was most effective when the mice were about 16 months old, which researchers believe equates to 50 to 55 years old in humans.
"We found that to be the best time frame to eliminate senescent cells and protect cognitive health," she said. "You can give senolytics later and still eliminate the cells and protect the brain's vasculature, but by then, the cognitive changes are irreversible."
Whether a result of chemotherapy or as part of normal aging, cognitive impairment can affect quality of life. Csiszar said she hopes this intersecting field of study yields answers that will ultimately improve troubling gaps in cognition.
"There is truly an intersection between aging research and cancer research," she said. "These teams represent the future of research, and we have wonderful momentum on our campus."
