Drug shows promise in reversing cognitive decline

The experimental drug has also shown an ability to restore memory function after traumatic brain injury, and undo cognitive impairment.

Dave Yasvinski 4 minute read December 9, 2020
cognitive decline

Researchers may have just discovered how to turn back the hands of time using an experimental drug that reversed the effects of aging in mice almost overnight.

In the study, published last week by eLife, researchers at the University of California, San Francisco (UCSF) were able to restore youthful cognitive function and reinvigorate the brain and immune cells of older mice with just a few doses of a drug known as ISRIB.

“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 Susanna Rosi, one of the study’s authors and a professor in the departments of neurological surgery and physical therapy and rehabilitation science, according to UCSF.

Discovered in the Walter lab in 2013, ISRIB has previously shown an ability to restore memory function after traumatic brain injury, undo cognitive impairment from Down Syndrome and improve cognition in healthy animals. Now it is beginning to look like a veritable fountain of youth.

“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,” said Peter Walter, 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.”

ISRIB works by rebooting a cell’s protein production machinery after it has been halted by a mechanism called the integrated stress response (ISR). This natural response is a safety measure intended to prevent protein synthesis in malfunctioning or mutated cells but it can cause serious problems — such as cognitive decline — if it remains stuck in the ‘on’ position. Because ISRIB (or ISR InhiBitor) proved effective at treating traumatic brain injury, researchers hypothesized it might also be able to stop the effects of aging.

“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 Rosi. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

To test their theory, the researchers trained older mice to escape from a watery maze by finding a hidden platform, a difficult task for older animals. However, the mice that were given ISRIB during the training process performed as well on the test as their younger counterparts and much better than those their age who were not given the drug.

It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step

To test the longevity of the drug’s effects, the researchers tested these mice again weeks later and discovered they still performed as well as younger mice, while those who went without the drug continued to struggle.

The team is still studying exactly how the ISR interferes with cognition and how long the effects of ISRIB last. They are also planning to explore how the drug alters the effects of aging on the immune system’s T cells, which may open new avenues for treating everything from Alzheimer’s to 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,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

Dave Yasvinski is a writer with Healthing.ca


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