A drug that can prevent age-related cognitive decline

The drug called ISRIB has been used in the past to treat prostate cancer, traumatic brain injury (TBI), improve cognition in animals, prevent noise-related hearing loss, and shown to improve memory at the same time, just with a few doses. A new drug study published in the eLife Journal on December 1, 2020, also showed an acute cognitive restoration in mice and brain and immune cell rejuvenation. Susanna Rosi, Ph.D., professor of Neurological Surgery and Physical Therapy and Rehabilitation Science, said, “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.” Peter Walter, Ph.D., a professor in the UCSF Department of Biochemistry and Biophysics and Howard Hughes Medical Institute Investigator, has investigated ISRIB since 2013, the year in which he discovered the medication after working with a cellular quality control mechanism known as the Integrated Stress Response (ISR), the name ISRIB comes from ISR Inhibitor. Walter also mentioned when talking about the new investigations that “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,” also “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

ISR and Traumatic Brain Injury (TBI)

The primary function of ISR is to stop the protein synthesis when pathological signals like cancer-gene mutations or infections are shown; hence is considered a safety mechanism; the main goal is to rule out affected cells, in this case, brain cells that eventually could affect every activity. With support from The Rogers Family Foundation, Walter performed another study. This study involved mice who were treated with ISRIB and showed improvement in their brain function in a short period after the treatment was delivered. This idea came after observing that TBI patients have a persistent activation of ISR, which translates to a cognitive deficit. Premature aging is observed in patients with TBI, a fact that led Rosi and Walter to wonder if ISR could also improve age-related cognitive decline. With aging comes a series of modifications to the body’s overall function, and conditions like chronic inflammation that could activate the ISR. Rosi mentioned that “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.” She also added, “It may seem like a crazy idea but asking whether the drug could reverse symptoms of aging itself was just a logical next step.” During the last study lead by Rosi, young and older animals were trained to escape from a watery maze through a hidden platform, a task that is usually harder for older animals. During this process, some animals received low doses of ISRIB during the training days; these mice showed improvement in their performance compared to the animals that didn’t receive the medication. Three weeks after the initial test was performed, the test was done again, and animals that received the ISRIB drug still shown improvement while tested on a maze with exits that changed every day. Mice that weren’t treated showed poor performance; this test’s objective was to explore if the cognitive rejuvenation was still present, and if other cognitive skills could also be affected. The main area studied after giving a single dose of the medication ISRIB was the hippocampus, in charge of memory and learning; in this area, the electrical activity related to neurons was more responsive to stimulation, and connections with surrounding cells were stronger just as seen in younger mice. The longevity of the cognitive improvement and the exact process of the disturbance of the ISR in age-related conditions are the central questions of the trial and will be studied in further trials, however, is already a fact the ISRIB modifies the function of T cells in the immune system related with aging. Rosi said, “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.” Age-related neurological and metabolic conditions like diabetes and Alzheimer’s may also be affected by their relationship with an aging immune system.

It’s about teamwork

Rosi and Walter were introduced to Regis Kelly, Ph.D., after Walter’s study in 2013, following Kelly’s  investigation where ISRIB showed almost immediate improvement in mice’s cognitive abilities. Rosi set up a new goal where she wanted to find out if this cognitive improvement could also affect neurological patients with traumatic brain injury. So, they decided to run a new investigation where both they participated and realized that ISRIB improved cognitive deficiencies in mice with traumatic brain injury. Rosi said, “This had never been seen before,” and “The mantra in the field was that brain damage is permanent – irreversible. How could a single treatment with a small molecule make them disappear overnight?” It is known that brains with traumatic damage have an increase of ISR activation, so in the new studies, ISRIB was used to reverse this state of deterioration; some studies have focused on animals with repetitive brain injuries similar to the one that some athletes can suffer over repetitive concussions over time and showed that ISRIB improved the inadequate behavior related with damage in the frontal cortex. Regis Kelly, Ph.D., executive director of University of California’s QB3 biotech innovation hub, was the one in charge of putting together Rosi and Walter, who leads the ISRIB investigation. They shared that ISRIB has been licensed by a company from South San Francisco, California called Calico, who is convinced that new ways to treat medical conditions will be developed if ISR is targeted. Manipulating the ISR, which is a critical safety mechanism, could lead to side effects; however, none have been reported so far. “It almost seems too good to be true, but with ISRIB, we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window” says Walter. This lack of side effects may be because of the low quantity of ISRIB required to have an evident improvement and because ISRIB has essentially no effect when applied to the ISR during aggressive infections. There are no reported side effects in both cases; hence, the idea to use the drug as therapy is more appealing.