Story at a glance

  • The experimental drug works by interfering with the body’s Integrated Stress Response (ISR).
  • Researchers trained older mice to escape from a watery maze by finding a hidden platform, a task researchers said is typically more difficult for older mice to learn.
  • The study found mice that received small doses of ISRIB over a three-day training process were able to complete the task just as well as younger mice and much better than mice of the same age who weren’t given the drug.

An experimental drug reversed age-related declines in memory and mental flexibility in old mice after just a few doses, according to a study by researchers from the University of California, San Francisco (UCSF). 

The drug, ISRIB, has previously been shown in other studies to restore normal cognitive function in mice after traumatic brain injury, enhance memory in healthy mice and mice with Down syndrome, as well as prevent noise-related hearing loss.


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The experimental drug works by interfering with the body’s Integrated Stress Response (ISR). The ISR slows down protein production in cells if something is wrong, such as a viral infection or injury, to give the cells time to heal. But as both memory and learning depend on active protein production, the ISR can lead to problems if it remains in the “on position” in the brain. 

The ISRIB, which stands for ISR InhiBitor, reboots the cell’s protein-synthesis machinery after it’s stopped by the stress response. 

For the recent study published this month in the journal eLife, researchers trained older mice to escape from a watery maze by finding a hidden platform, a task researchers said is typically more difficult for older mice to learn. But the study found mice that received small doses of ISRIB over a three-day training process were able to complete the task as well as younger mice and much better than mice of the same age who weren’t given the drug. 

“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,” Susanna Rosi, UCSF professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science, said

The mice were then tested several weeks after the initial treatment to determine how long the cognitive rejuvenation lasted. Researchers trained the same mice to find their way out of a maze with an exit that changed daily, a test of mental flexibility. The mice who had received the treatment still performed higher levels than untreated mice. 

Researchers analyzed the anatomy of cells in the animal’s hippocampus just one day after giving the mice a single dose of ISRIB and found electrical activity between neurons was more lively and cells were better able to form stable connections with one another. 

Scientists behind the study believe a drug like ISRIB could at some point treat a number of diseases such as Alzheimer’s, dementia, Parkinson’s and Amyotrophic Lateral Sclerosis.

“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,” Peter Walter, a professor from the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator, said.


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Published on Dec 28, 2020