Researchers have successfully restored fading memories in older rats by reactivating silenced genes and adjusting molecular switches in the brain, demonstrating that specific age-related changes driving cognitive decline can be reversed.
Two complementary studies from Virginia Tech used CRISPR gene-editing tools to manipulate age-related molecular processes in rat brains, improving memory performance in animals that had already begun showing signs of decline. Memory loss affects more than a third of people over 70 and represents a major risk factor for Alzheimer’s disease.
The first study, published in Neuroscience, examined K63 polyubiquitination—a molecular tagging system that directs protein behaviour in brain cells. Researchers discovered opposing patterns in different brain regions: the hippocampus showed increased K63 levels with age whilst the amygdala exhibited decreased levels.
Using CRISPR-dCas13 RNA editing to reduce K63 polyubiquitination in the hippocampus improved memory in older rats. Paradoxically, further reducing the already-lowered levels in the amygdala also enhanced memory performance, suggesting region-specific roles for this molecular process.
“Memory loss affects more than a third of people over 70, and it’s a major risk factor for Alzheimer’s disease,” said Timothy Jarome, associate professor in the School of Animal Sciences who led both studies. “If we can understand what’s driving it at the molecular level, we can start to understand what goes wrong in dementia.”
Impactful insights
The second study, published in Brain Research Bulletin, targeted IGF2, a growth-factor gene supporting memory formation that becomes silenced through DNA methylation as brains age. The gene’s unusual imprinted status means it expresses from only one parental copy, making its age-related shutdown particularly impactful.
Researchers employed CRISPR-dCas9 to remove methylation tags and reactivate IGF2 in the hippocampus. Older rats with existing memory problems showed significant improvement, whilst middle-aged animals without cognitive issues remained unaffected—indicating intervention timing matters.
“We essentially turned the gene back on,” Jarome said. “When we did that, the older animals performed much better.”
The dual findings reveal that aging-related cognitive decline involves multiple molecular systems working simultaneously, requiring broader therapeutic approaches than targeting individual molecules. Both studies suggest memory loss stems from specific, potentially reversible molecular changes rather than general brain deterioration.
Graduate students drove both research projects, with doctoral student Yeeun Bae leading the K63 polyubiquitination study and Shannon Kincaid heading the IGF2 investigation. Collaborations included scientists from Rosalind Franklin University, Indiana University and Penn State.
The National Institutes of Health and American Federation for Aging Research supported the research. The identification of specific targetable mechanisms marks progress toward understanding what Jarome describes as correctable molecular changes that “give us a path forward to potential treatments.”
