Why do our brains age? And is there anything we can do about it? New research delves into these questions by investigating the genetic cogs at play in the complex mechanism of age-related cognitive decline.
Researchers working at the Babraham Institute in Cambridge, United Kingdom, in collaboration with colleagues at Sapienza University in Rome, Italy, have just got a lot closer to unraveling the mystery of brain aging.
Of course, scientists already knew some things about what occurs in the brain as we age. For instance, it is known that neurons and other brain cells deteriorate and die, only to be replaced by new ones.
This process is facilitated by a type of stem cell called neural stem/progenitor cells (NSPCs).
However, with the passage of time, these cells become less and less functional, which causes our brain to produce fewer and fewer neurons.
But what causes NSPCs to age, and what exactly are the molecular changes that are responsible for impairment in these stem cells?
This is the question that the researchers — jointly led by Giuseppe Lupo, Emanuele Cacci, and Peter Rugg-Gunn — asked themselves.
Dbx2 gene activity may explain brain aging
Lupo and colleagues compared the genetic changes in the NSPCs of old mice (aged 18 months) and young mice (aged 3 months).
By doing so, they identified more than 250 genes that changed their behavior over time, which means that these genes are likely to cause NSPCs to malfunction.
Once they had narrowed their search down to 250 genes, the scientists noticed that increased activity in a gene called Dbx2 seemed to change aged NSPCs.
So, they performed in vivo and in vitro assays, which revealed that boosting the activity in this gene in young NSPCs makes them behave more like old stem cells. Increasing the activity of Dbx2 stopped the NSPCs from growing or proliferating as young cells should.
Also, in older NSPCs, the researchers identified changes in epigenetic marks that may explain why the stem cells deteriorate with time.
If we think of our DNA as an alphabet, epigenetic marks "are like accents and punctuation," in that they "tell our cells whether and how to read the genes."
In this research, the scientists found how these marks are placed differently in the genome, "telling" NSPCs to grow more slowly.
Turning back the clock for human cells
The co-lead study authors weigh in on the significance of their findings. Of the results, Lupo says, "The genes and gene regulators that we identified are corrupted in neural stem cells from older mice."
"By studying the Dbx2 gene," he continues, "we have shown that these changes may contribute to aging in the brain by slowing the growth of brain stem cells and by switching on the activity of other age-associated genes."
Peter Rugg-Gunn is hopeful that the findings will one day lead to the reversal of the aging process. In what is reminiscent of the anti-aging and life extension movements, he says, "Aging ultimately affects all of us and the societal and healthcare burden of neurodegenerative diseases is enormous. "
"By understanding how aging affects the brain, at least in mice," he adds, "we hope to identify ways to spot neural stem cell decline. Eventually, we may find ways to slow or even reverse brain deterioration [...] helping more of us to stay mentally agile for longer into old age."
Emanuele Cacci echoes the same sentiment, saying, "We have succeeded in accelerating parts of the aging process in neural stem cells."
"By studying these genes more closely, we now plan to try turning back the clock for older cells. If we can do this in mice, then the same thing could also be possible for humans."