Scientists May Have Found a Way to Reverse Memory Loss in Aging Brains

Memory problems may not be an inevitable part of aging. New findings from Virginia Tech show that age-related memory loss is due to specific molecular changes in the brain and that fine-tuning these processes can help restore memory function.

In two complementary studies, Timothy Jarome, associate professor in the School of Animal Sciences at the College of Agriculture and Life Sciences, and his doctoral students used advanced gene-editing tools to specifically target these molecular changes and improve memory performance in older rats. Rats are often used as models to understand how memory declines with age.

Modifying Memory Pathways in the Hippocampus and Amygdala

“Memory loss affects more than one-third of people over the age of 70 and is a major risk factor for Alzheimer’s disease,” said Jarome, who is also affiliated with the School of Neuroscience. “This work shows that memory loss is linked to specific molecular changes that can be targeted. If we understand what’s going on at the molecular level, we can begin to understand what goes wrong in dementia and ultimately use that knowledge to develop new treatment approaches.”

In the first study, published in Neuroscience and led by Jarome and doctoral student Yeeun Bae, the researchers examined a molecular process called K63 polyubiquitination. This process acts like a tagging system that dictates how proteins in brain cells should behave. When it functions properly, it helps neurons communicate effectively and form memories. The researchers discovered that aging alters this process in two important brain regions. In the hippocampus, which is responsible for forming and retrieving memories, the level of K63 polyubiquitination increases with age. Using a gene editing system called CRISPR-dCas13, the team lowered this level and observed an improvement in memory in older rats.

In contrast, K63 polyubiquitination decreases with age in the amygdala, a region critical for emotional memory. When the researchers further reduced this activity, memory performance also improved. Together, these findings demonstrate the important functions of K63 polyubiquitination in the aging brain, according to the researchers. In both regions, the adjustment of this single molecular process contributed to memory improvement.

Reactivating a Dormant Gene to Improve Memory

The second study, published in the Brain Research Bulletin and led by Jarome and doctoral student Shannon Kincaid, focused on IGF2, a growth factor gene known to support memory formation. As the brain ages, IGF2 activity declines because the gene is chemically silenced in the hippocampus. “IGF2 is one of the few genes in our DNA that is imprinted, meaning it is expressed from only one parental copy,” Jarome said. “When that single copy begins to decline with age, you lose its benefit.”

The team found that this shutdown occurs through DNA methylation, a natural process in which chemical tags are attached to the DNA, turning the gene off. Using the CRISPR-dCas9 gene editing system, they removed these tags and successfully reactivated IGF2. Older rats showed a marked improvement in their memory once the gene was reactivated. The researchers essentially reactivated the gene. When they did so, the older animals performed much better. Middle-aged animals that did not yet have memory problems were not affected, showing that timing plays a role. You have to intervene when things start to go wrong.

Multiple Molecular Systems Influence Brain Aging

Taken together, these studies show that memory loss in old age is not due to a single cause. Rather, multiple molecular systems are involved that change over time. “We tend to look at only one molecule at a time, but in reality, many things are happening simultaneously,” Jarome said. “If we want to understand why memory declines with age or why we develop Alzheimer’s disease, we need to look at the big picture.”

Both projects were spearheaded by doctoral researchers in Jarome’s lab and conducted in collaboration with Rosalind Franklin University, Indiana University, and Penn State University. Yeeun Bae led the K63 polyubiquitination study, while Shannon Kincaid led the IGF2 project. “These projects are representative of the type of collaborative research led by doctoral students that characterizes our work,” Jarome said. “Our students are deeply involved in designing experiments, analyzing data, and formulating the scientific questions we pursue. Everyone experiences some memory loss as they age. However, when this becomes abnormal, the risk of Alzheimer’s disease increases. We have learned that some of these changes can be corrected at the molecular level—and that opens up a path to potential treatments.”