Brain damage has been considered to be irreversible for years whether it be caused by injury or from growing old. An experimental drug, ISRIB, is suggested to reverse age-related memory and cognitive decline by unblocking brain pathways that handle memory and mental flexibility in just a few doses, and it has already been proven effective at restoring brain function in patients with traumatic brain injury as well as Down Syndrome.
“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, Ph.D., a professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.
“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, Ph.D. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”
ISRIB was discovered to work by rebooting the protein-producing mechanisms inside the body’s cells after they are disrupted by stress. Cells will normally deal with disruption using integrated stress response, which is how ISR InhiBitor gets the name. Protein synthesis is a critical cell function that takes place in response to viral infections or cancer-causing gene mutations. ISR detects problems with how cells produce proteins and stops protein synthesis machinery, while important to finding/getting rid of malfunctioning cells if stuck in the on position in tissues in the brain this can lead to serious problems as cells can lose the ability to perform normal functions when this happens.
Animal studies suggest that too much ISR activity can cause cognitive and behavioral deficits in those with traumatic brain injury. Brief treatment with ISRIB was found to reboot the ISR on switch to restore normal brain function in mice seemingly almost overnight.
“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.”
This study examined how older mice performed in a maze after receiving treatment with ISRIB. As humans do, older mice lose mental flexibility with age, and as such maze puzzles become harder for them to complete than younger mice.
Older mice taking small daily doses of ISRIB during the 3-day experiments were observed to complete their tasks the same as younger mice, and their results were much better than untreated mice of the same age. The treated mice were tested on how long the benefits lasted by using new mazes where the exit changed daily which was conducted 3 weeks after the initial ISRIB treatment. Results showed that the older treated mice still outperformed the untreated older mice. The drug appears to be safe, no problems were found when it interacted with cells that had normal ISR function, according to Professor Walter.
“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?”
Activity and makeup of the animal’s hippocampus brain region were also examined, results showed that after one-day common signs of neuronal aging appeared to disappear, neuron electrical activity became more lively and responsive to stimuli, and cells showed stronger connectivity with cells around them and had the ability to form more stable connections.
ISRIB was noted to appear to alter the function of the immune system T-cells which are prone to age-related degeneration. Findings may reveal that ISRIB and ISR treatment could fight a wide range of diseases such as diabetes and Alzheimer’s disease.
“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.
