Memory loss may not simply be a symptom of getting older. New research from Virginia Tech shows that it's tied to specific molecular changes in the brain and that adjusting those processes can improve memory.
In two complementary studies, Timothy Jarome , associate professor in the College of Agriculture and Life Sciences ' School of Animal Sciences , and his graduate students used gene-editing tools to target those age-related changes to improve memory performance in older subjects. The work was conducted on rats, a standard model for studying how memory changes with age.
"Memory loss affects more than a third of people over 70, and it's a major risk factor for Alzheimer's disease," said Jarome, who also holds an appointment in the School of Neuroscience . "This work shows that memory decline is linked to specific molecular changes that can be targeted and studied. If we can understand what's driving it at the molecular level, we can start to understand what goes wrong in dementia and eventually use that knowledge to guide new approaches to treatment."
Targeting memory loss in two key brain regions
In the first study , published in the journal Neuroscience and led by Jarome and doctoral student Yeeun Bae, the team examined a process called K63 polyubiquitination. This process acts as a molecular tagging system that tells proteins inside the brain how to behave. When the system functions normally, it helps brain cells communicate and form memories.
Jarome and his team found that aging disrupts K63 polyubiquitination in two distinct areas of the brain. In the hippocampus, which helps form and retrieve memories, levels of K63 polyubiquitination increase with age. Using the CRISPR-dCas13 RNA editing system to reduce these levels, the researchers were able to improve memory in older rats.
In the amygdala, which is important for emotional memory, the researchers noted that K63 polyubiquitination declines with age. By reducing it even further, they were able to boost memory in older rats.
"Together, these findings reveal the important functions of K63 polyubiquitination in the brain's aging process," Jarome said. "In both regions, adjusting this one molecular process helped improve memory."
Reactivating a gene that supports memory
A second study , published in the Brain Research Bulletin and led by Jarome with doctoral student Shannon Kincaid, focused on IGF2, a growth-factor gene that supports memory formation. As the brain ages, IGF2 activity drops as the gene becomes chemically silenced in the hippocampus.
"IGF2 is one of a small number of genes in our DNA that's imprinted, which means it's expressed from only one parental copy," Jarome said. "When that single copy starts to shut down with age, you lose its benefit."
The researchers found that this silencing happens through DNA methylation, a natural process in which chemical tags accumulate on the gene and switch it off. Using a precise gene-editing tool, CRISPR-dCas9, they removed those tags and reactivated the gene. The result was better memory in older rats.
"We essentially turned the gene back on," Jarome said. "When we did that, the older animals performed much better. Middle-aged animals that didn't yet have memory problems weren't affected, which tells us timing matters. You have to intervene when things start to go wrong."
Together, the two studies show that memory loss is not caused by a single molecule or pathway and that multiple molecular systems likely contribute to how the brain ages.
"We tend to look at one molecule at a time, but the reality is that many things are happening at once," he said. "If we want to understand why memory declines with age or why we develop Alzheimer's disease, we have to look at the broader picture."
Collaborative, graduate-led research
Both studies were driven by graduate researchers in Jarome's lab and supported through collaborations with scientists at Rosalind Franklin University, Indiana University, and Penn State. Yeeun Bae, who completed her doctoral work with Jarome in the School of Animal Sciences , led the study on K63 polyubiquitination. Shannon Kincaid, a doctoral student in the same program, led the study on IGF2.
"These projects represent the kind of graduate-led, collaborative research that defines our work," Jarome said. "Our students are deeply involved in designing experiments, analyzing data, and helping shape the scientific questions we pursue."
The research was supported by the National Institutes of Health and the American Federation for Aging Research.
"Everyone has some memory decline as they get older," he said. "But when it becomes abnormal, the risk for Alzheimer's disease rises. What we're learning is that some of those changes happening at a molecular level can be corrected — and that gives us a path forward to potential treatments."
Original study: https://doi.org/10.1016/j.neuroscience.2025.06.032
Original study: https://doi.org/10.1016/j.brainresbull.2025.111509
