Brain rejuvenation breakthrough: How limiting glucose could spark new neuron growth

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Brain rejuvenation breakthrough: How limiting glucose could spark new neuron growth

STANFORD, Calif. — Could the secret to maintaining a youthful, sharp mind be as simple as watching our sugar intake? A new study from Stanford Medicine suggests that glucose plays a surprising role in the aging brain’s ability to produce new neurons.

As we age, our brains become less adept at producing new neurons, a process known as neurogenesis. This decline can have far-reaching consequences, contributing to memory loss, reduced cognitive function, and potentially exacerbating neurodegenerative diseases like Alzheimer’s and Parkinson’s. It also hinders recovery from stroke and other brain injuries. However, this new research, led by Anne Brunet, PhD, professor of genetics, offers hope by shedding light on why neural stem cells – the precursors to new neurons – become less active with age.

Using cutting-edge CRISPR technology, Brunet and her team conducted a comprehensive genetic screen to identify genes that, when inhibited, could reactivate dormant neural stem cells in aged mice. Among the 300 genes they discovered, one stood out: Slc2a4, which codes for the glucose transporter protein GLUT4.

“We first found 300 genes that had this ability— which is a lot,” Brunet explains in a statement. “One in particular caught our attention. It was the gene for the glucose transporter known as the GLUT4 protein, suggesting that elevated glucose levels in and around old neural stem cells could be keeping those cells inactive.”

To validate their findings in living animals, the researchers developed an innovative in vivo screening technique. They injected viruses carrying genetic instructions to knock out specific genes into the subventricular zone of aged mouse brains – an area rich in neural stem cells. After five weeks, they examined the olfactory bulb, where newly generated neurons typically migrate.

The results, published in the journal Nature, were dramatic. Knocking out the Slc2a4 gene led to a more than two-fold increase in new neuron production in the olfactory bulbs of old mice. This boost in neurogenesis was accompanied by an increase in both quiescent and activated neural stem cells in the subventricular zone, indicating that the treatment was stimulating the stem cell population itself.

Among the 300 genes researchers discovered, one stood out: Slc2a4, which codes for the glucose transporter protein GLUT4. (© vegefox.com – stock.adobe.com)

Further investigation revealed that neural stem cells from older mice take up about twice as much glucose as those from young mice. This increased glucose uptake appears to push the stem cells into a more dormant state. By knocking out Slc2a4 and reducing glucose influx, the aged stem cells became more likely to activate and produce new neurons.

“It’s allowing us to observe three key functions of the neural stem cells. First, we can tell they are proliferating. Second, we can see that they’re migrating to the olfactory bulb, where they’re supposed to be. And third, we can see they are forming new neurons in that site,” explains Tyson Ruetz, PhD, lead author of the study and former post-doctoral scholar in Brunet’s lab, in a media release.

The glucose transporter connection opens up exciting possibilities for future interventions. Brunet described it as “a hopeful finding,” suggesting that it could lead to the development of pharmaceutical or genetic therapies to stimulate new neuron growth in aged or injured brains. Perhaps even more intriguingly, it raises the possibility of simpler behavioral interventions, such as a low-carbohydrate diet, that might adjust the amount of glucose taken up by old neural stem cells.

While this research marks a significant step forward in our understanding of brain aging and regeneration, it’s important to note that the study was conducted in mice. Further research is needed to determine if these findings translate to humans and to explore the long-term effects and potential side-effects of manipulating glucose uptake in neural stem cells.

Nevertheless, this study provides a promising new direction for addressing age-related cognitive decline and potentially treating neurodegenerative diseases. By identifying GLUT4 and other key regulators of neural stem cell aging, scientists now have promising new targets for developing therapies to rejuvenate the aging brain.

Paper Summary

Methodology

The researchers used CRISPR-Cas9 gene editing technology to systematically knock out over 20,000 genes in cultured neural stem cells from young and old mice. They then assessed which gene knockouts enhanced the stem cells’ ability to activate and divide. To test the most promising gene candidates in living mouse brains, they developed a novel in vivo screening technique. This involved injecting viruses carrying CRISPR components to knock out specific genes in the subventricular zone of aged mouse brains. Five weeks later, they examined the olfactory bulb to quantify newly generated neurons containing the genetic knockouts.

Key Results

The in vitro screen identified over 300 genes that, when inhibited, boosted the activation of aged neural stem cells. The in vivo screen validated 24 of these genes, with Slc2a4 consistently emerging as a top hit. Knocking out Slc2a4 in the brains of old mice increased new neuron production in the olfactory bulb by more than two-fold. It also increased the numbers of both quiescent and activated neural stem cells in the subventricular zone. Further experiments revealed that aged neural stem cells take up about twice as much glucose as young ones and that this elevated glucose uptake appears to promote quiescence.

Study Limitations

The study was conducted in mice, so it remains to be seen if the findings will translate to humans. The researchers focused on the subventricular zone, but it’s unclear if similar mechanisms apply to other neurogenic regions like the hippocampus. The long-term effects and potential side effects of Slc2a4 inhibition were not evaluated. Additionally, while the screening approach was powerful, it may have missed some important genes.

Discussion & Takeaways

This study provides strong evidence that elevated glucose uptake contributes to the decline in neural stem cell function during aging. By identifying GLUT4 as a key regulator of this process, the researchers have uncovered a promising new target for potential therapies to enhance neurogenesis in aged brains. The fact that brief glucose starvation could activate aged stem cells suggests dietary interventions might offer a non-invasive way to boost neurogenesis. However, much more research is needed to determine if modulating glucose uptake in neural stem cells could safely and effectively enhance cognitive function or treat neurodegenerative diseases in humans.

Funding & Disclosures

The study was supported by grants from the National Institutes of Health (grants P01AG036695 and R01AG056290), the Stanford Brain Rejuvenation Project and a Larry L. Hillblom Foundation Postdoctoral Fellowship. Tyson Ruetz, the lead author, is now the scientific advisor and co-founder of ReneuBio.