A small-molecule drug named ISRIB quickly and safely restores to old mice youthful levels of cognitive function. Alphabet Inc,’s Biotech Firm Calico holds the license to ISRIB.
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The anti-aging properties of ISRIB (pronounced “iz-rib”) were discovered in a collaboration between neurocognitive researcher Susanna Rosi and biochemist and biophysicist Peter Walter, both of the University of California, San Francisco. In a previous project Rosi and Walter showed that ISRIB could reverse memory failure and restore normal cognitive function in mice after traumatic brain injury — and it could do so even when it was given to the mice weeks after the injury. Prior to his work with Rosi, Walter and other collaborators demonstrated that ISRIB enhances memory in healthy mice and in mice with Down syndrome, and causes some treatment-resistant prostate cancer cells to self-destruct. Other research teams working with ISRIB have shown it to protect mice's inner ears against noise-related hearing loss.
Dr. Susanna Rosi
In all studies, the researchers have observed no serious side effects.
The new study on the reverse of age-related cognitive decline was published on December 1 in the journal eLife. According to the eLife paper, ISRIB rejuvenates brain cells and cognitive function by interfering with the Integrated Stress Response (ISR), which is a set of signaling pathways in the brain that call key protective processes into action.
Proteins do much of the work throughout the body and brain, and so healthy cells constantly create them. When injury, infection, or mutation create problems for cells, the ISR slows down their protein production greatly. This gives the cells time to heal. As helpful as that safety response is, in the brain it has its costs. Both memory and learning depend on active protein production. When the ISR blocks production, both suffer — sometimes so profoundly and for so long that the cognitive deficits can seem permanent.
As Rosi explained in a Zoom interview, “One way to think of how ISRIB rejuvenates brain cells and cognitive function is that, when the ISR protectively blocks production of proteins, it’s as though it’s setting a switch to ‘off.’ Ideally, that would be a temporary change only. What we’re learning from our work is that sometimes the ISR gets ‘stuck’ and doesn’t let the switch move back to ‘on.’ That can make the cognitive deficits that were caused by the ISR itself seem to be a result of permanent damage — when they’re not.”
In turning the protein production switch back to “on,” ISRIB activates a specific enzyme that the ISR had blocked. Re-activated, that enzyme triggers resumption of normal protein production.
Dr. Peter Walter
The lab experiments central to Rosi and Walter’s demonstration of rejuvenation in the brain cells and cognitive function of old mice were led by Karen Krukowski, a research physical therapist with a special interest in the impact of aging and traumatic brain injury on cognitive decline. In a test of the mice’s spatial memory and ability to learn, for two days Krukowski’s team trained mice to escape from a maze. The task required finding a platform hidden under water that had been made opaque. Young mice typically required only two tries to escape the maze. Old mice that weren’t treated with ISRIB typically required four tries. On average, old mice given a few daily doses of ISRIB required only three tries.
To specifically test spatial memory, one week later the experimenters had old and young mice escape the same opaque water maze as before. The mice did not receive any additional training or ISRIB treatment for this test. The old mice that had originally been treated with ISRIB remembered about as well as young mice how to escape the maze. The untreated old mice did not.
To test episodic and working memory, eighteen days after their last ISRIB treatments, the old mice were trained every day for four days to use visual cues to locate a single escape tunnel on a platform with 40 holes. By the fourth day the old mice were finding the tunnel on average 20 seconds faster than the old mice who had never been treated with ISRIB.
The researchers studied the cells of the hippocampus, a part of the brain necessary for learning and memory. When they did, they found that the common markers of aging were largely absent and that the connectivity and electrical responsiveness of the cells were improved.
“The signs of aging diminished overnight,” Rosi explained in the interview. “For the first time we saw that the cognitive decline of old age is not necessarily a permanent loss of capacity or mental resources. Rather, the cells may just get caught up in a cycle of stress. ISRIB seems to break the cycle and re-boot the brain.”
Walter first identified the therapeutic potential of ISRIB in 2013. He and UCSF together hold the patent. In 2015 they licensed ISRIB to Calico.
