The Aging Brain Needs REST

Researchers at the Harvard Medical School have discovered that a gene regulator called REST, which is active during fetal brain development, switches back on later in life to protect aging neurons from stresses including the toxic effects of abnormal proteins. The team  also showed that REST is lost in critical brain regions of people with Alzheimer's and mild cognitive impairment.

The study, published on March 19th in the journal Nature, offers an explanation for the longstanding mystery of why some people with the abnormal protein clumps characteristic of Alzheimer’s show few or no signs of cognitive decline .

A release from Harvard quotes lead researcher Bruce Yankner as saying "Our work raises the possibility that the abnormal protein aggregates associated with Alzheimer's and other neurodegenerative diseases may not be sufficient to cause dementia; you may also need a failure of the brain's stress response system. If true, this opens up a new area in terms of treatment possibilities for the more than 5 million Americans currently living with Alzheimer's disease."  

The release notes that the Centers for Disease Control lists Alzheimer's disease as the sixth leading cause of death in the United States and that a 2013 study by the RAND Corporation found that with an estimated annual toll of as much as $215 billion, Alzheimer's is America's most expensive disease. 

"Dementia is not an inevitable result of aging," said Yankner. "We know it's possible for the human brain to work normally for a century or more. So a robust mechanism must have evolved to preserve brain function and keep brain cells alive in long-lived organisms like us. We just haven't learned what that mechanism is."

The release reports that Yankner believes REST may be a key piece in the solution to that puzzle. REST first came to his attention when team member Tao Lu flagged it as the most strongly activated transcriptional regulator—a switch that turns genes on or off—in the aging human brain. The team confirmed the finding through biochemical and molecular tests and high-resolution imaging.

The finding surprised Yankner at first because until then, REST's only known activity in the brain occurred prenatally, when it keeps key genes turned off until progenitor cells are ready to differentiate into functional, mature neurons. REST was believed to wind down in the brain soon after birth. (It stays active elsewhere in the body and appears to protect against several kinds of cancer and other diseases.) When Yankner thought more about it, however, the finding began to make sense.