Summary: Researchers have identified molecular mechanisms that contribute to age-related memory decline and demonstrated that those changes can be reversed in animal models. Two studies from Virginia Tech show that correcting specific molecular processes in the hippocampus and amygdala, and reactivating a silenced memory-supporting gene (IGF2), improved memory performance in older rats.
Using CRISPR-based gene-editing tools, scientists restored more normal signaling and communication between neurons involved in memory storage and recall. These results suggest that some forms of memory loss may not be an inevitable consequence of aging and that targeted molecular interventions could eventually become therapeutic options.
Key facts:
- Molecular targets identified: Dysregulation of K63 polyubiquitination and age-related silencing of the IGF2 gene are linked to memory decline.
- CRISPR interventions: Precise editing of these pathways in older rats improved memory on behavioral tests.
- Therapeutic potential: The findings support the possibility that gene-focused treatments might prevent or reverse some age-related memory impairments.
Source: Virginia Tech
Memory decline tied to specific molecular changes
New research from Virginia Tech indicates that memory loss with age is connected to distinct molecular alterations in the brain, and that intervening at that level can restore memory function. In two complementary studies led by Timothy Jarome and doctoral students in his lab, teams used CRISPR-based tools to modify those age-related changes and improve memory in older rats, a well-established model for investigating aging and cognition.
“Memory loss affects more than a third of people over 70 and is a major risk factor for Alzheimer’s disease,” said Timothy Jarome, associate professor in the School of Animal Sciences and the School of Neuroscience. “This work shows memory decline is linked to specific molecular changes that can be targeted. Understanding those drivers can help us identify what goes wrong in dementia and guide new treatment strategies.”
Targeting memory loss in two key brain regions
In the first study, Jarome and doctoral student Yeeun Bae investigated K63 polyubiquitination, a form of protein tagging that regulates cellular behavior without directing proteins for degradation. The team found age-dependent, region-specific changes in K63 polyubiquitination: levels rose in the hippocampus but fell in the amygdala across the lifespan.
Using the CRISPR-dCas13 RNA editing system to reduce excessive K63 polyubiquitination in the hippocampus of aged rats, researchers improved contextual memory performance. In the amygdala—important for emotional memory—further reducing already lowered K63 polyubiquitination also enhanced memory retention in older animals. Manipulations in middle-aged rats that had not yet developed memory deficits produced little or no effect, highlighting an age-dependent window for intervention.
Reactivating a gene that supports memory
The second study, led by Jarome and doctoral student Shannon Kincaid, focused on IGF2, an imprinted growth-factor gene that supports synaptic plasticity and memory formation. The researchers observed increased DNA methylation at the IGF2 promoter in the hippocampus of aged male rats, which corresponded with reduced gene expression and poorer memory.
Using CRISPR-dCas9 targeted to modify DNA methylation marks and increase a transcriptionally active modification (5-hydroxymethylation) at the IGF2 promoter, the team reactivated the gene in aged animals and restored memory performance and synaptic plasticity measures. Middle-aged rats without memory impairments were unaffected by the manipulation, indicating that timing matters and that intervention is most effective once specific molecular changes have begun.
“We essentially turned the gene back on,” Jarome said. “When we did that, older animals performed much better. The results show that some molecular changes underlying age-related memory loss can be corrected.”
Collaborative, graduate-led research
Both studies were driven by graduate researchers in Jarome’s laboratory and carried out in collaboration with colleagues at other institutions. The projects exemplify graduate-led, team-based research in which students design experiments, analyze data, and shape scientific questions. The research was supported by the National Institutes of Health and the American Federation for Aging Research.
Frequently asked questions
Q: What causes memory loss with age?
A: The studies show that age alters key molecular processes—specifically K63 polyubiquitination and DNA methylation-mediated silencing of the IGF2 gene—that are critical for synaptic plasticity and memory.
Q: How did researchers improve memory in older animals?
A: They used CRISPR-based editing systems to normalize K63 polyubiquitination in the hippocampus and amygdala and to remove repressive DNA marks on the IGF2 gene, restoring its activity. Both approaches led to improved memory in aged rats.
Q: Could these findings lead to human treatments?
A: While preliminary and conducted in animal models, the results indicate that targeting specific molecular changes could inform future gene-based therapies for age-related memory decline and potentially dementia. Further research is required before clinical application.
About this research
Author: Margaret Ashburn (Virginia Tech)
Source: Virginia Tech
Contact: Margaret Ashburn – Virginia Tech
Image credit: Neuroscience News
Selected abstracts
1) Increased DNA methylation of Igf2 in the male hippocampus regulates age-related deficits in synaptic plasticity and memory
Aged male rats showed increased CpG-site promoter methylation and reduced hippocampal expression of Igf2 compared with young and middle-aged animals. Targeted CRISPR-dCas9 editing that increased DNA 5-hydroxymethylation at the Igf2 promoter restored gene expression, improved long-term potentiation, and enhanced memory in aged but not middle-aged rats. These findings implicate increased Igf2 methylation as a contributor to age-related synaptic and cognitive decline.
2) Age-related dysregulation of proteasome-independent K63 polyubiquitination in the hippocampus and amygdala
Using proteomics, researchers found a lifespan-associated increase in K63 polyubiquitination in the hippocampus and a decline in K63 targets in the amygdala. Reducing K63 polyubiquitination in aged hippocampus or further reducing it in aged amygdala improved memory, while similar manipulations in middle-aged animals had no effect. The work highlights region-specific and age-dependent roles for K63 polyubiquitination in brain aging and memory loss.