Arnsten believes the problem is a stress response gone wrong. During stress, even in young animals, these brain cells are flooded with a signaling molecule called cAMP, which dampens activity by opening potassium channels. (She theorizes that this is an evolutionary adaption that allows the brain to quickly flip control from the prefrontal cortex, “a slow and thoughtful region,” to a more primitive region in time of stress.) Normally, enzymes shut off the stress response and the brain goes back to normal. “But we think that in normal aging, the stress signaling pathway becomes disregulated,” says Arnsten.
The researchers were able to rein in the problem by treating the cells with a drug that blocks the potassium channels. After treatment, brain cells in old monkeys fired more rapidly—just like those in their younger counterparts.
The researchers already knew that giving monkeys this drug systemically, rather than delivering it directly into the brain, could reverse age-related deficits in working memory. A clinical trial of the compound, a generic drug called guanfacine, originally used to treat hypertension, is underway at Yale.
The findings bode well for the prospect of slowing age-related cognitive decline in humans. “The more we learn about the synaptic basis of aging, the more we learn it affects very specific elements of what these neurons can do,” says John Morrison, a neurologist at Mount Sinai School of Medicine. Morrison was not involved in the research. “Once we understand it, we can identify targets and deal with it,” he says.
Now that researchers understand how guanfacine works, they may be able to design drugs that are more powerful or have fewer side effects. Guanfacine can act as a sedative, so people need to slowly build up their tolerance to the drug to avoid this effect.
It’s not yet clear if the work has implications for the more serious memory and brain changes that occur in Alzheimer’s disease and other types of dementia. (Monkeys don’t get Alzheimer’s, so researchers know the memory changes they see in these animals are part of the typical aging process.)
However, Morrison believes that these subtle cellular changes may make the brain more vulnerable to the cell death that occurs in Alzheimer’s. And as researchers begin to explore ways to intervene earlier with Alzheimer’s patients, it may be useful to target these changes early on.