An experimental drug developed by researchers at the University of Edinburgh reverses age-related memory decline in mice, returning their brains to a more youthful state of cognitive function. The compound is designed to dampen the production of glucocorticoids, stress hormones that are thought to damage the brain’s learning and memory centers over time.
“What’s most surprising is that even short-term inhibition was able to reverse memory loss in old mice,” says Jonathan Seckl, a professor of molecular medicine who was involved in the research. “I don’t think people had realized this was so reversible. It takes [the animals] back to being relatively young.”
The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.
Scientists have long known that glucocorticoids–a class of steroid hormones that mediate our response to stressful situations–play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.
Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, “this enzyme acts as an intracellular amplifier of glucocorticoids,” says Seckl. “If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear.”
The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals’ memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice–the maximum lifespan for a typical lab mouse–was enough to improve the animals’ performance on a test of spatial memory. The treatment “returned mice to the equivalent of when they were young and fully functioning,” says Brian Walker, another researcher involved in the study. “It’s important to emphasize that we are trying to target the pathology–the role that glucocorticoids play in age-related memory decline–not just globally improving memory.” The research was published last week in the Journal of Neuroscience.