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Or this:
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The latest here:
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.
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.
