The experimental drug counteracts age-related cognitive decline within days

Rapid mental rejuvenation in older rats suggests that age-related damage may be largely reversible.

U.C. According to a new study by San Francisco scientists, just a small amount of experimental medicine can counteract an age-related decline in memory and mental flexibility in rats. The drug, called ISRIB, has been shown in laboratory studies to restore traumatic brain injury (TBI), reverse cognitive impairment in Down syndrome, noise-related hearing loss, fight some types of prostate cancer, and enhance laboratory studies. Cognition in healthy animals.

In a new study published in the Open-Access Journal on December 1, 2020 Elife, Researchers show rapid restoration of youthful cognitive abilities in older mice, along with brain and immune cell rejuvenation, which may help explain the improvement in brain function.

“The extremely rapid effects of ISRIB show for the first time that a significant component of age-related genetic damage may be due to a type of reversible physical” barrier “rather than a more permanent degeneration,” said Susanna Rossi, PhD, Lewis and Ruth Kozan Chair. . II and Professor in the Departments of Neurological Surgery and Physical Therapy and Rehabilitation Sciences.

“The data suggest that the aging brain does not permanently lose essential cognitive moments, as is commonly assumed, but these cognitive resources are still there but trapped in a vicious cycle of cellular stress, somehow blocked,” Ph.D. .D., Professor of the UCSF Department of Biochemistry and Biophysics and Investigator at the Howard Hughes Medical Institute. “Our work with ISRIB paves the way for breaking the cycle and restoring cognitive abilities that were broken over time.”

Could rebooting cellular protein production be key to aging and other diseases?

Vertrair has won several scientific awards, including Breakthrough, Las Las Scurr and Shazes Prizes, for his decades-long study of cellular stress responses. ISRIB, discovered in Walter’s lab in 2013, works by rebooting the cell’s protein production machinery when it is throttle by one of the stress responses – a cellular quality control method known as the integrated stress response (ISR; ISRIB stands for ISR inhibitor).

ISR usually detects problems with protein production in the cell – a possible sign of a gene mutation that promotes a viral infection or cancer – and responds by putting a brake on the cell’s protein-synthesis machinery. This safety mechanism is reprehensible for misusing cells, but can cause serious problems if stuck in a condition in tissues such as the brain, as cells lose the ability to perform their normal activities, Verter and colleagues have discovered.

In particular, recent animal studies by Verter and Rossi, made possible by the initial philanthropic support of the Rogers Family Foundation, have shown that severe ISR activation is associated with persistent cognitive and behavioral deficits seen in patients after TBI. Can and can restore normal brain function almost overnight.

Cognitive impairment in TBI patients is often compared to premature aging, leading Rossi and Verter to wonder if ISR could also take into account age-related cognitive decline. Aging is known to compromise cellular protein production throughout the body, as many of life’s insults pile up and move on to stress-like stress cells, potentially leading to widespread activation of ISR.

“We’ve seen how ISRIB restores cognition in traumatic brain injury animals, which in many ways is like the growth of age-related cognitive decline,” said Eva Rossi, director of UCSF Brain and Spinal Neurosurgical Research. “It’s a crazy idea, but asking if the drug can counteract the symptoms of aging was just a logical step,” said the director of neurosurgical research in the spinal cord.

Improves cognition, accelerates neuron and immune cell function

In the new study, researchers led by Rosy Lab Post Doc Karen Krukowski, PhD, trained older animals to escape the watery path by finding hidden platforms, which are especially difficult for older animals to learn. But animals that received a daily dose of ISRIB during the three-day training process were able to complete the task as well as youth rats, which were better than animals of the same age that did not receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. After a few weeks of initial ISRIB treatment, they trained a single rat to find a way out of the trap, the daily exit – a test of mental relief for older rats, which, like humans, increasingly stagnated in their own way. Mice that received brief ISRIB treatment three weeks ago were still performing at a young level, while untreated rats continued to struggle.

To understand how ISRIB can improve brain function, the researchers studied hippocampus, the activity and anatomy of cells that play a key role in learning and memory in the brain field, a day after giving animals a single dose of ISRIB. They found that the normal signatures of neuronal aging literally disappeared overnight: the electrical activity of neurons became more pronounced and responsive to stimuli, and cells showed stronger connections to the cells around them while also showing the ability to form stable connections with each other. Which usually appears. Small mice.

Researchers are continuing to study how cognition is disrupted in old age and other conditions and how long the cognitive benefits of ISRIB can last. One of the other puzzles raised by the new findings is the discovery that ISRIB also alters the function of immune T cells, which are also prone to age-related distress. These findings suggest another way in which the drug can improve cognition in older animals, and affect diseases. Alzheimer’s In diabetes that exacerbates inflammation caused by the aging immune system.

“This was very exciting for me because we know that aging has a strong and lasting effect on T cells and these changes can affect brain function in hippocampus,” Rosie said. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

Broad Effects is an example of the ‘serandipity’ of basic research

Rosie and Velter were introduced by neuroscientist Regis Kelly, PhD, executive director of the University of California’s QB3 Biotech Innovation Center, after a 2013 study by Velter showed that the drug would increase the potential in healthy mice. To Rossi, the results of that study indicated the cognitive probability that the molecule was somehow being unlocked, bound to some walls in the brain, and she wondered if this additional cognitive enhancement would benefit patients with neurological damage from brain injury.

The labs joined forces to study the question in rats, and were amazed at what they found. ISRIB just couldn’t work for some cognitive impairments in mice with traumatic brain injury – it erases them. “I’ve never seen this before,” Rossi said. “There was a mantra in the field that brain damage is permanent – irreversible. Can a single treatment with small molecules make them disappear overnight? ”

Further studies have shown that the brain neurons in traumatic brain injury animals are completely jammed by ISR. Using ISRIB to loosen those brakes allows brain cells to return to their normal function immediately. Recently, studies in animals with very mild recurrent brain injuries – pro-athletes who have experienced many mild conflicts over the years – have shown that ISRIB can counteract the risk-increasing behavior associated with damage to self-control circuits in the frontal cortex.

Added to this, Karen’s new results of aging in mice are just amazing. It’s not often that you find a drug candidate who shows a lot of potential and promise, “added Walter. “The project also demonstrates the strength of the UCSF community – Suzanne and I didn’t know each other and Regis Kelly was living in a different world until he brought us together, creating a powerful connection that neither of us realized before.”

Kelly said, “Amazing advances like this require more than the brilliance and practical skills of Suzanne and Peter. “They also need donors like the Rogers Family Foundation who are ready to bridge the gap between great basic research and products that can be very beneficial to society.”

The ISRIB is licensed by the South San Francisco, California-based company, Calico, which explores the biology of aging, and many other pharmaceutical companies are considering targeting ISR for the treatment of the disease, says Vagtinger.

One might think that interfering with the important process of cellular security, ISR, would be sure to have serious side effects, but in all their studies, researchers have not observed any of this. Verter says this is due to two factors. First, it takes only a small amount of ISRB to reset unhealthy, prolonged ISR activation to a healthy state, then it can respond normally to individual cell problems. Second, ISRB has no virtual effect when applied to actively functioning cells in its most powerful form – against invasive viral infections, for example.

Naturally, both of these factors make the molecule more likely to have negative side effects – and potentially more therapeutically attractive. “That sounds pretty good to be true, but with ISRIB we seem to have hit a sweet spot for ISR manipulation with the ideal therapeutic window,” Verter said.

Reference: “Small molecules counteract age-related memory loss in cognitive-enhancing rats” by Karen Krukowski, Amber Nolan, Alma S. Frias, Morgan Boon, Gonzalo Ureta, Catherine Gru, Maria-Serena Paladini, Walter and Suzanna Rossi, 1 December 2020, Elife.
DOI: 10.7554 / ELIFE.62048

Authors: Other authors on the study were Amber Nolan, Elma S. Frias, Morgan Boone, Catherine Gru, Maria-Serena Paladini, and Edward Elizarras of UCSF; Gonzalo Ureta, Luz Delgado and fundraiser Cinestia and Sebastian Barnales of Vida in Santiago, Chinli Barnales is also an employee of Praxis Biotech, LLC.

Funding: The study was supported by the continued generous support of the Rogers Family Foundation, as well as the UCSF Well Innovation Award, the US National Institutes of Health (NIH R01AG056770), the National Institute of Aging (NIA F32AG054126); National Center for Advanced Translational Sciences (NCATS TL1 TR001871); ANID Project AFB 170004; National Institute of Neurological Disorders and Stroke (NINDS K08NS114170) and Howard Hughes Medical Institute (HHMI).

Advertisements: Gonzalo works at Ureta Fundisian Synesia and Vida and receives partial funding from Praxis Biotech. Sebastian Barnales is an employee of Praxis Biotech. Peter Verter is a U.S. citizen. The patent is a researcher on 9708247 held by Regents of the University of California that describes ISRIB and its analogues. The right of discovery is licensed by Calico by UCSF.