This drug may reverse age-related cognitive decline within days

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In a new study, researchers found that just a few doses of an experimental drug may reverse age-related declines in memory and mental flexibility.

The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

The research was conducted by UC San Francisco scientists.

In the new study, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

ISRIB’s extremely rapid effects show for the first time that a big component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation.

The findings 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.

The current work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.

According to the team, the drug ISRIB works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses.

They previously found in mice with persistent cognitive and behavioral deficits seen in patients after TBI, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

In the study, researchers found mice who received small daily doses of ISRIB were able to accomplish a cognitive task as well as youthful mice, much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills.

Several weeks after the initial ISRIB treatment, they found the mice who had received brief ISRIB treatment three weeks before still performed at youthful levels in a mental flexibility task, while untreated mice continued to struggle.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last.

Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction.

The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that has been linked to heightened inflammation caused by an aging immune system.

The team says many brain diseases may be treated with a drug like ISRIB, including Frontotemporal Dementia, Alzheimer’s Disease, Age-related Cognitive Decline, Traumatic Brain Injury, Parkinson’s Disease, Down Syndrome, and so on.

One author of the study is Susanna Rosi, Ph.D., Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

The study is published in eLife.

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