UCSF study shows Calico-licensed small molecule cognitive enhancer ISRIB reverses age-related memory decline in mice within days.
ISRIB (integrated stress response inhibitor) is an experimental drug which has already demonstrated an ability to treat memory loss associated with traumatic brain injury (TBI), and other neurological disorders, as well as reverse cognitive impairments in Down’s Syndrome. Now a team at UC San Francisco has shown that short-term exposure to ISRIB reverses age-related memory decline and cognitive deficits in mice.
Longevity.Technology: ISRIB is licensed by Calico, the well-funded, but enigmatic arm of Alphabet, Google’s parent company, which researches the biology of aging. This new research indicates that ISRIB reverses the integrated stress response in the brain and mitigates age-related cognitive decline, albeit only in mice so far. If this indication can also be shown in humans, Calico would have a licence that dovetails with their mission to “discover and develop interventions that enable people to live longer and healthier lives”.
Professor Peter Walter led a team that discovered ISRIB in 2013. The body’s integrated stress response (ISR) detects and responds to cellular protein production problems; these problems can be caused by genetic mutations or viral infections and the ISR’s response is to slow down or switch off protein production. Although this means malfunctioning cells can be dealt with, the lack of proteins being made means the cells become dysfunctional.
Enter ISRIB, which hits Ctrl+Alt+Del on a cellular level, rebooting the cell’s protein machine and getting the production restarted. Aging decreases cellular protein production, and age-related stressors, such as chronic inflammation, also deleteriously affect cells, so the UCSF team thought that activation of the ISR could be age-related.
“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,” said Susanna Rosi, PHD, Director of neurocognitive research in the UCSF Brain and Spinal Injury Center. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step .”
“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,”
The UCSF team trained aged mice to escape from a watery maze, something that older animals struggle to learn. Subjects that received small daily doses of ISRIB during the three-day training process demonstrated an enhanced ability to escape the maze which was much better than control animals of the same age.
The mice also demonstrated mental flexibility at levels similar to youthful mice for several weeks after the ISRIB treatment. At a cellular level, the researchers found that common signatures of neuronal aging in the hippocampus, a part of the brain that plays a vital part in the processes of learning and memory, disappeared. What’s more, they disappeared overnight.
In addition, the neurons’ electrical activity improved, becoming more vibrant and responsive to stimulation, and the cells demonstrated connectivity with other cells that was more robust and able to form stable connections, characteristics that are usually only seen in younger mice .
“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,” said Rosi .
“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,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time .”