A Molecular Approach to Reversing Cognitive Decline
Researchers at Virginia Tech have made a discovery that could change how we think about aging and memory. Led by Associate Professor Timothy Jarome, scientists have found that specific molecular changes in the brain cause age-related memory loss—and that these changes can be reversed using advanced gene-editing techniques. The findings suggest memory loss might not be an unavoidable part of growing older, but rather a treatable biological process.
Jarome’s work centers on two interconnected studies that reveal how memory declines with age in different parts of the brain. The research focused on the hippocampus, which manages learning and memory recall, and the amygdala, which processes emotional memory. Both regions experience molecular disruptions as the brain ages, but in distinct ways that can be corrected with precise genetic tools.
How the Studies Were Conducted
The first study, published in Neuroscience, examined a molecular tagging system known as K63 polyubiquitination. This process helps regulate how proteins behave and communicate within neurons. Jarome and doctoral student Yeeun Bae discovered that K63 polyubiquitination becomes unbalanced with age—increasing in the hippocampus and decreasing in the amygdala. Using a CRISPR-dCas13 RNA editing system, they adjusted these levels in older rats, which led to significantly improved memory performance.
In the hippocampus, reducing excessive K63 tagging restored the ability to form and retrieve memories. In the amygdala, decreasing already low levels further enhanced emotional memory. The results showed that manipulating this single molecular mechanism could improve memory in aged rats without affecting younger ones.
The second study, published in the Brain Research Bulletin, focused on a different but related problem: the silencing of the IGF2 gene, a key player in memory formation. As the brain ages, IGF2 becomes chemically shut down through a process called DNA methylation, which prevents it from supporting memory retention. Jarome and doctoral student Shannon Kincaid used a CRISPR-dCas9 tool to remove the methylation marks, effectively “turning the gene back on.” The older rats regained much of their lost memory capacity, while middle-aged rats with normal memory showed no change.
Together, these experiments demonstrate that age-related memory decline can be traced to distinct, correctable molecular disruptions.
Gene Editing at Work: Restoring the Brain’s Communication
Both studies rely on CRISPR-based systems—genetic tools capable of targeting specific RNA or DNA sequences with extreme precision. Instead of editing the genome permanently, these CRISPR variants modify gene activity or chemical marks that affect expression. This allows scientists to fine-tune how brain cells communicate and store information.
In the hippocampus and amygdala, these gene edits restored normal signaling between neurons. The researchers used behavioral tests to assess how well the rats learned and remembered tasks before and after treatment. Rats receiving the gene edits performed markedly better, confirming that the molecular repairs directly translated into cognitive improvement.
“Memory loss affects more than a third of people over 70,” said Jarome. “What we’ve shown is that some of those changes at the molecular level can be corrected. That gives us a path forward to potential treatments.”
A Broader Understanding of Memory and Aging
Jarome’s team emphasizes that memory loss is not caused by one molecule or one pathway alone. Rather, it is a web of interrelated systems that deteriorate over time. His lab, in collaboration with Rosalind Franklin University, Indiana University, and Penn State, continues to investigate how these molecular systems interact.
Their findings add to a growing body of evidence that the brain’s proteasome complex—a molecular machine responsible for recycling proteins—also plays a role in age-related cognitive decline. In a related project funded by the National Institute on Aging, Jarome and Purdue University researcher Sydney Trask are exploring how stimulating the proteasome could prevent memory loss altogether. Using CRISPR-Cas9 to increase proteasome activity in the hippocampus, they hope to show that memory capacity can be preserved or restored.
The Role of RPT6: A Dual-Function Memory Protein
Another discovery from Jarome’s lab revealed that a protein known as RPT6 has a previously unknown function. Traditionally seen as part of the proteasome complex that degrades proteins, RPT6 also binds to DNA to activate genes during memory formation. This dual role was reported in the Journal of Neuroscience by research scientist Kayla Farrell.
“This discovery opens up new possibilities for understanding how memory is built and maintained,” Jarome explained. “If we can learn how RPT6 regulates gene expression during memory formation, we may be able to enhance memory or reduce the effects of disorders like Alzheimer’s and PTSD.”
The Outlook for Human Treatments
While the experiments were conducted in rats, the implications for humans are profound. The research indicates that cognitive decline with aging can be reversed by reprogramming molecular systems, not just slowed. Future therapies could use targeted gene editing to correct chemical changes in the brain before they lead to dementia or Alzheimer’s disease.
The next steps include verifying safety and effectiveness in larger animal models and eventually translating the techniques into human applications. Jarome’s work, supported by the National Institutes of Health and the American Federation for Aging Research, offers new hope that age-related memory loss may one day be preventable—or even reversible.
As Jarome summarized, “We’re learning that memory decline is not inevitable. If we can fix these molecular mechanisms, we might be able to restore memory across the lifespan. It gives us a clear therapeutic target and a new vision for healthy aging.”
