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Scientists link a molecule known as ISRIB to reversed cognitive decline in the elderly

September 15, 2021

Researchers have been working to alleviate cognitive decline, a side effect of aging that affects millions of elderly people in the US.
Studying model mice, scientists at the UCSF demonstrated how a molecule known as ISRIB could be used to reverse severe cognitive decline caused by traumatic brain injury.
Researchers are now working to formulate a therapeutic drug that may help relieve some of the effects of aging.

Age is the greatest risk factor for memory loss and dementia that interferes with independent functioning. One in 7 Americans over the age of 70 has dementia. As the proportion of older people in the country continues to rise, so will the number of people who live with Alzheimer’s and other forms of cognitive decline. Scientists – including gerontologists and biochemists — are researching interventions to alleviate cognitive decline and other disease manifestations of aging. Dr. Peter Walter is a professor of biochemistry and biophysics at the University of California San Francisco’s School of Medicine. Since he immigrated to the US from West Berlin decades ago, Walter has dedicated his research to a crucial cellular mechanism known as the ‘unfolded protein response’. The researcher has won multiple prestigious awards, including the Breakthrough Prize, for his work so far. The unfolded protein response is a regulatory mechanism that controls the manufacture of proteins and thus helps keep cells healthy. These proteins are responsible for nearly every task of cellular life, including waste cleanup, cell shape and organization, making new memories, digesting food, and routine maintenance. If the unfolded protein response goes wrong, it can lead to all sorts of diseases, ranging from viral infections and brain disorders to diabetes and cancer. Walter and his team at the UCSF have been working to learn more about unfolded protein response pathways and figure out how to control them. Their findings could help fix troublesome machinery in diseased cells and as a result, cure serious disease. The researchers have used the Small Molecule Discovery Center at the UCSF School of Pharmacy to accelerate their research. After combing through hundreds of thousands of molecules, the team found a compound known as ISRIB. This is a small molecule ISR (Integrated Stress Response) inhibitor that has shown promising therapeutic potential but without the side effects associated with pharmacological inhibitors. Mice studies demonstrated that ISRIB completely reversed severe cognitive impairments caused by traumatic brain injury. The molecule also improved learning and memory in healthy mice specimens. “It’s amazing. We think that ISRIB may uncover an untapped reservoir in the brain that allows damaged memory circuits to be repaired,” said Dr. Walter. In addition to healing injured brains, Walter hopes that ISRIB will one day be used to treat common neurodegenerative disorders such as Parkinson’s and Alzheimer’s. The team has already licensed the molecule for drug development to Calico (Google’s anti-aging biotech). It may be years before the ISRIB discovery at UCSF leads to a drug discovery that works on humans, but Walter and his team are enthusiastic about its clinical potential. “There are so many people suffering. If ISRIB works as well in people as it works in animals, that would be revolutionary,” he added.

References: https://giving.ucsf.edu/stories/inventing-new-drugs-reverse-cognitive-decline

Scientists link a molecule known as ISRIB to reversed cognitive decline in the elderly

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