Scientists have long been searching for the factors in young blood that give it its rejuvenating powers to drug form for widespread public use.
A team of researchers led by Saul Villeda, Ph.D., an assistant professor of anatomy at UC San Francisco discovered a brain-rejuvenating enzyme that improved memory in adult mice when restored to youthful levels. The researchers say the new protein could lead to new therapies for maintaining the healthy brain function of humans.
While the molecule only works in mice and hasn’t been tested in humans, it brings us one step closer to drugs that replicate the beneficial effects of parabiosis without requiring costly young blood transfusions, costing about $8000 a pop.
Using a technique called parabiosis, in which the vascular systems of two mice are surgically connected, Villeda’s team had previously discovered that infusing old mice with the blood of younger ones leads to brain rejuvenation, including improvements in memory and learning. On the flip side, infusions of old blood cause premature brain aging in the younger mice. Since then, the UCSF lab has been searching for the rejuvenating factors. The researchers published their results on February 20, 2018, in the journal Cell Reports.
The Elusive Tet2 Factor
Geraldine Gontier, Ph.D., a postdoctoral researcher in the lab, discovered that infusions of young blood caused levels a molecule called Tet2 go up in the hippocampus – a part of the brain involved in learning and memory. This result suggested that Tet2 might be the elusive factor that in young blood that produces rejuvenating cognitive benefits.
“This was amazing because it’s like improving memory in a healthy, 30-year-old human,” Dr. Villeda said. “I always assumed that because there are no overt cognitive impairments in middle-aged mice, we wouldn’t be able to improve their brain function, but here we see that, no, you can improve cognition to make it better than normal.”
Tet2 is an epigenetic regulator that marks DNA to alter the activity of different genes. Gontier and her team found that Tet2 levels in the hippocampus decline as mice age, along with a decrease in the epigenetic tags Tet2 makes on DNA.
The genes that produce new brain cells during adulthood lose these tags leading to a decline in new brain cell production with age. Villeda’s team took a closer look at this decline and found that it closely paralleled the age-related loss of Tet2 expression.
“At first I didn’t believe it,” Dr. Gontier said. “I did the experiment again and again to make sure that it was right. But it became clear that some circulating factor in the blood is able to change the level of Tet2 in the brain.”
Recent research has linked mutations in the human Tet2 gene as a risk factor for various age-related diseases, including cancer, cardiovascular disease, and stroke.
Earlier work in Villeda’s lab showed that infusing old mice with the blood of younger ones led to brain rejuvenation. Credit: Villeda lab.
To find out if the loss of Tet2 in aging causes cognitive decline, the researchers custom-designed viruses to stimulate Tet2 in mature adult mice. The researchers found that boosting Tet2 increased epigenetic DNA tagging, and restored brain cell growth to more youthful levels. These mice showed improved memory of places where they had previously received mild electrical shocks, however, did not perform significantly differently from untreated mice in other tests of learning and memory.
“This finding is exciting on many levels,” Dr. Gontier added. “I’ve spent my entire Ph.D. and now my postdoc trying to understand how the brain ages and how can we reverse it. And in this study, we find that one molecule, Tet2, is able to rescue regenerative decline and enhance some cognitive functions in the adult mouse brain.”
Villeda cautions that the UCSF team is not exactly clear how the Tet2 improves memory and learning in mice, or whether boosting the enzyme will do the same for humans. Moreover, the neuroscience community isn’t sure that adult humans are capable of growing new brain cells like mice.
However, Dr. Villeda believes that neurogenesis – a term describing the ability to grow new brain cells – is just one aspect of the brain’s regenerative abilities, and most likely not the only one being impacted by tweaking Tet2 levels. As Villeda said,
“In our study we found that removing Tet2 from the hippocampal stem cells that give birth to new neurons caused some cognitive impairment, but removing it from the whole hippocampus caused even more. That suggests that this is about more than just stem cells. This molecule is driving changes throughout the whole brain structure.”adding “I think of neurogenesis as a signpost of regeneration in the brain, but ultimately I think that it’s changes to the neurons themselves—preventing synapse loss, boosting plasticity—that are going to improve cognition. One of our next big steps is to catalogue exactly what’s happening, both at a genetic level and at a neural level, in mice who’ve had this treatment.”
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Cover Photo: iLexx /Getty Images.
Nicholas Weiler. “Cognitive Benefits of ‘Young Blood’ Linked to Brain Protein in Mice.” University of California San Francisco. February 20, 2018. Link.
Geraldine Gontier, Manasi Iyer, Jeremy M. Shea, Gregor Bieri, Elizabeth G. Wheatley, Miguel Ramalho-Santos, Saul A. Villeda. “Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.” Cell Reports. Volume 22, Issue 8, p1974–1981, 20 February 2018. Link.
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