Drug reverses age-related cognitive decline in a matter of days by erasing ‘blockages’

SAN FRANCISCO, Calif. — Whether the damage is caused by a traumatic injury or just the stress of growing old, scientists have considered brain damage to be irreversible for years. Now, researchers from the University of California-San Francisco say an experimental drug reverses memory and cognitive declines connected to aging. The drug, ISRIB, has already proven effective at restoring brain functions of patients dealing with traumatic brain injury (TBI) and Down Syndrome.

Their study adds this drug can unblock brain pathways which handle memory and mental flexibility in just a few doses. Results begin to show themselves overnight, as if the damage was never there.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological ‘blockage’ rather than more permanent degradation,” says Susanna Rosi, PhD, professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science, in a university release.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” adds UCSF professor of biochemistry and biophysics Peter Walter, PhD. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Rebooting the cells to fight aging, cognitive decline

A cryo-electron microscope rendering of an ISRIB molecule. (Image by the Adam Frost lab)

Researchers in Walter’s lab discovered ISRIB in 2013. The drug works by rebooting the protein-producing mechanisms inside the body’s cells after they are disrupted by stress. Normally, cells deal with disruptions using their integrated stress response (ISR); which is how ISR InhiBitor (ISRIB) gets its name. Protein synthesis is a critical cell function that takes place in response to viral infections or cancer-causing gene mutations.

ISR usually detects problems with how the cells produce protein and puts a stop to protein-synthesis machinery. Although this is crucial for finding and getting rid of malfunctioning cells, if ISR gets stuck in the “on position” in tissues in the brain it can lead to serious problems. Researchers say cells can lose their ability to perform normal functions when this happens.

Studies on animals revealed that too much ISR activity can cause cognitive and behavioral deficits in patients dealing with TBI. Scientists discovered brief treatments with ISRIB reboots the ISR “on switch” and restore normal brain functions in mice almost overnight.

Rosi and Walter say cognitive decline as a result of TBI is similar to the effects of premature aging. Their team wondered if treating ISR problems could also improve mental decline solely caused by age-related stress.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” Rosi explains. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

Giving patients their youthful spark back

The new study, led by Rosi lab postdoc Karen Krukowski, examined how older mice perform in a maze after receiving ISRIB treatments. Older mice, just like humans, lose mental flexibility with age and the maze puzzle is generally harder for them to complete than younger mice.

Researchers say aging mice taking small daily doses of ISRIB during the three-day experiment completed their task just as well as younger mice. Their results were also much better than mice of the same age not taking the drug.

The team then tested how long these benefits lasted by putting the mice in a new maze where the exit changed daily. Study authors conducted this test three weeks after the initial ISRIB treatment. The results show that older mice on the drug still outperformed their untreated peers.

“This had never been seen before,” Rosi says. “The mantra in the field was that brain damage is permanent – irreversible. How could a single treatment with a small molecule make them disappear overnight?”

Prof. Walter adds that interfering with the ISR function may sound dangerous, but the results show ISRIB is safe to use. Researchers did not find any problems when the drug interacted with cells that have normal ISR function.

How does ISRIB help the brain regain its function?

The study examined the activity and makeup of each animal’s hippocampus, the brain region responsible for learning and memory. The results show after just one day common signs of neuronal aging disappeared. The neurons’ electrical activity also became more lively and responsive to stimuli. The cells showed stronger connectivity with cells around them and also had the ability to form more stable connections.

Researchers note that ISRIB also appears to alter the function of the immune system’s T-cells, which are prone to age-related degeneration too. The findings may reveal that ISRIB and ISR treatments can fight a wide range of diseases including Alzheimer’s and diabetes.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” Rosi adds. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

“Karen’s new results in aging mice are just amazing. It’s not often that you find a drug candidate that shows so much potential and promise,” Walter concludes.

The study appears in the journal eLife.