Experimental medicine reverses age-related cognitive decline within the day

Rapid mental rejuvenation in older mice may be largely reversible with age-related damage.

According to a new study by UC San Francisco scientists, certain doses of experimental medicine can reverse age-related declines in memory and mental resilience in mice. The drug, called ISRIB, has already been shown in laboratory studies to restore memory function after traumatic brain injury (TBI), reverse cognitive impairment in Down syndrome, prevent noise-related hearing loss, certain types of prostate cancer. Fight and even increase sensation in healthy animals.

In the new study, published in the open-access journal December 1, 2020 eLifeResearchers showed rapid restoration of young cognitive abilities in aged mice, as well as a rejuvenation of brain and immune cells that may help explain improvements in brain function.

ISRIB molecule

Cryo-electron microscope rendering of the ISRIB molecule. Credit: Adam Frost Lab

“The extremely rapid effects of ISRIB show for the first time that an important component of age-related cognitive impairment may be a type of reversible physical” blockage “rather than a more permanent decline,” said Susan Rosie, PhD, Lewis and Ruth Kozen Chair Second and Professor in the Departments of Neurological Surgery and Physiotherapy and Rehabilitation Sciences.

“The data suggest that the aged brain has not permanently lost the necessary cognitive abilities, as it was commonly believed, but rather that these cognitive resources are still there, but somehow trapped by a vicious cycle of cellular stress Are, “Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and an investigator at the Howard Hughes Medical Institute. “Our work with the ISRIB represents a way to break that cycle and restore cognitive abilities that had taken off over time.”

Can regenerating cellular proteins be the key to aging and other diseases?

Walter has won several scientific awards, including the Breakthrough, Lasker and Shaw Awards for his decades-long study of cellular stress responses. The ISRIB, discovered in 2013 in Walter’s laboratory, acts to reboot the cells’ protein production machinery after being throated by one of these stress responses – a cellular quality control mechanism known as integrated stress response (ISR; ISRIB ISR InhiBitor).

Peter walter

Peter Walter, PhD. Sincerely: Elizabeth Fall

ISR typically detects problems with protein production in a cell – a possible sign of viral infection or cancer-promoting gene mutation – and reacts by braking the cell’s protein-synthesis machinery. This protective mechanism is critical to ejecting the abusing cells, but can cause serious problems if trapped in this condition in tissue such as the brain, as the cells lose the ability to perform their normal activities, Walter And colleagues have found.

In particular, a recent animal study by Walter and Rosie, made possible by early philanthropic support from The Rotter Family Foundation, has shown ISR activation in persistent cognitive and behavioral deficits seen in patients after TBI. , Which in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

Cognitive deficits in TBI patients are often compared to premature age, leading Rosie and Walter to wonder if ISR can also reduce purely age-related cognitive decline. Aging is well known to compromise cellular protein production throughout the body, as many of life’s insults pile up and break away from chronic inflammatory cells such as stress, possibly leading to widespread activation of ISR Huh.

“We have seen how ISRIB restores cognition in animals with traumatic brain injury, which is in many ways a variant of age-related cognitive decline,” said Rosie, director of neuropsychological research at UCSF Brain & Spinal. A member of the UCSF Weil Institute for Injury Centers and Neurosciences. “This may sound like a crazy idea, but asking if the drug could reverse the symptoms of aging was only a logical next step.”

Enhances cognition, promotes neurons and immune cell function

In the new study, researchers led by Rosie Lab postdoc Karen Krukowski, PhD, trained older animals to escape the water cycle to find a hidden platform, a task that would usually be difficult for large animals to learn is. But animals that received small daily doses of ISRIB during the three-day training process were able to carry out this task, along with younger mice, which was better than animals of the same age who did not receive the drug. Used to do

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial treatment with ISRIB, he trained the same mice to find a way out of a maze, whose exit changes daily – a test of mental resilience for older mice that, like humans, rapidly Get stuck in their own way. Mice that still received brief ISRIB treatment three weeks earlier still performed at a younger level, while untreated mice continued to struggle.

Susanna Rosie

Susanna Rosie, PhD. Sincerely: Susan Merrell

To understand how ISRIB can improve brain functioning, researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a critical role in the brain and learning and memory, for animals to use ISRIB’s single One day after dosing. They found that the normal signatures of neuronal aging literally disappeared overnight: the electrical activity of neurons became more rapid and sensitive to stimulation, and the cells showed more robust connectivity with their surrounding cells, while with each other. Demonstrates the ability to make stable connections that are typically seen in only one. Little mouse.

Researchers continue to study how ISR inhibits cognition in aging and other conditions, and to understand how long the cognitive benefits of ISRIB can last. Other puzzles raised by the new findings are the finding that ISRIB also alters the function of T cells of the immune system, which is also at risk of age-related dysfunction. The findings suggest another way by which medicine can improve cognition in older animals, and the effects of the diseases it causes. Alzheimer’s Diabetes has been linked to increased inflammation caused by an aging immune system.

“It was very exciting for me because we know that aging has a profound and persistent effect on T cells and these changes can affect brain function in the 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.”

Broader effects illustrate the ‘seriousness’ of basic research

Rosie and Walter were introduced by neuroscientist Regis Kelly, PhD, executive director of the QB3 Biotech Innovation Hub at the University of California, following Walter’s 2013 study showing that the drug appears to immediately enhance cognitive abilities in healthy mice it occurs. For Rosie, the results of that study predicted some wall-off cognitive ability in the brain that the molecule was somehow unlocking, and she wondered if this additional cognitive boost would benefit patients with neurological damage from traumatic mental injury. Can.

The labs joined forces to study the question in mice, and were amazed by what they found. ISRIB did not just make up for some cognitive deficits in mice with brain injury – it erased them. “It was never seen before,” Rosie said. “The mantra in the area was that brain damage is permanent – irreversible. How can a single treatment with a small molecule make them disappear overnight? “

Further studies have shown that neurons in the entire brain of animals with traumatic brain injury are well jammed by ISR. Using ISRIB to release those breaks immediately returns brain cells to their normal business. Recently, studies in animals with very mild repetitive brain injury – for pro athletes who experience multiple mild attacks over the years – showed that ISRIB with damage to self-control circuits in the front-court cortex May increase associated risk-behavior.

“Added to this, Karen’s new results in aging mice are just amazing. It’s not often that you find a drug candidate who shows so much potential and promise.” This project empowers the UCSF community Also shows – Susanna and I didn’t know each other and were living in different worlds until Regis Kelly brought us together, it creates the powerful relationship that the two of us ever felt before had not been.”

“Such amazing successes require Susanna and Peter’s superb skills and experimental skills,” Kelly said. “They also need donors ready to bridge the gap between great basic research and products, such as the Rogers Family Foundation, which can be highly beneficial to society.”

Walter states that ISRIB has been licensed by Calico, a company based in South San Francisco, California, that is exploring the biology of aging, and the idea of ​​targeting ISRs to treat the disease by many other pharmaceutical companies Has been raised, Walter says.

One might think that interfering with ISR, an important cellular safety mechanism, would ensure serious side effects, but in all the studies so far, researchers have not seen any. This is possible due to two factors, says Walter. First, it takes just a few doses of ISRIB to revert to unhealthy, chronic ISR activation in a healthy state, after which it can still respond normally to problems in individual cells. For example, against an invasive viral infection – second, ISRIB has virtually no effect when ISR is applied to cells actively employed in its most potent form.

Naturally, both of these factors make the molecule less likely to have negative side effects – and more attractive as a potential therapeutic. “It sounds too good to be nearly right, but with ISRIB we think ISR has found a sweet spot to manipulate with an ideal therapeutic window,” Walter said.

References: “Small molecule cognitive enhancement prevents age-related memory decline by Karen Krukowski, Amber Nolan, Elma S. Fraas, Morgan Boon, Gonzalo Ureta, Catherine Gru, Maria-Serena Paladini, Edward Allezairas, Luz Delgado, Sebasta, Sestan . ” Peter Walter and Susanna Rosie, 1 December 2020, eLife.
DOI: 10.7554 / eLife.62048

Author: Other authors of the study Amber Nolan, Elma S. Fraas, Morgan Boone, Catherine Gru, Maria-Serena Paladini, and UCSF’s Edward Elizaras; And Sebastian Barnales of Gonzalo Ureta, Luz Delgado and Fandakione Sinesia and depart in Santiago, Chile. Burnless is also an employee of Praxis Biotech, LLC.

Grant: The study was supported by generous support from the Rogers Family Foundation as well as the UCSF Well Innovation Award, US National Institutes of Health (NIH R01AG056770), National Institutes on Aging (NFS 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).

Disclosure: Gonzalo Ureta works in fundaceous Sinesia and Vida and receives partial funding from Praxis Biotech. Sebastian is an employee of Burnless Praxis Biotech. Peter Walter is an inventor on US patent 9708247 held by the Regent of the University of California that describes ISRIB and its analogs. The invention rights have been licensed to Calico by UCSF.

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