Rapid mental regeneration in elderly mice indicates that age-related losses are broadly reversible
A new study by scientists from the University of California, San Francisco, shows that just a few doses of an experimental drug can reverse age-related decline in memory and mental flexibility in mice. The drug called ISRIB has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairment in Down syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.
In the new study published December 1, 2020 in the journal Open Access eLife Researchers have demonstrated a rapid restoration of young cognitive abilities in elderly mice, accompanied by brain and immune cell regeneration that can help explain improvements in brain function.
“The very rapid effects of ISRIB demonstrate for the first time that a significant component of age-related cognitive loss may be the result of some kind of physiological ‘blockage’ that is reversible rather than permanent degradation,” said Susanna Rosie, Ph.D., Lewis and Ruth Cosine. The second is a professor in the Departments of Neurosurgery, Physiotherapy and Rehabilitation Sciences (http: // ptrehab.
Peter Walter added, “The data indicate that the aging brain did not permanently lose basic cognitive capabilities, as was generally assumed, but rather, these cognitive resources still exist but have been blocked in some way, due to a vicious cycle of cellular stress,” PhD. , Professor in the Department of Biochemistry and Biophysics at the University of California, San Francisco and Investigator at the Howard Hughes Medical Institute. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that have become isolated over time.”
Could restarting cellular protein production 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 studies of cellular stress responses. Discovered in 2013 in Walter’s lab, ISRIB works by restarting the protein production mechanism in cells after they are suffocated by one of these stress responses – a cellular quality control mechanism called the Integrated Stress Response (ISR; ISRIB stands for ISR InhiBitor).
ISR usually detects problems with protein production in the cell – a potential marker of viral infection or cancer-promoting genetic mutations – and responds by putting brakes on the cell’s protein synthesis mechanism. This safety mechanism is necessary to get rid of cells that misbehave, but if they get stuck in a functioning mode in a tissue like the brain, it can lead to serious problems, as the cells lose their ability to carry out their normal activities, Walter and colleagues found.
In particular, recent animal studies by Walter and Rosie, made possible thanks to early philanthropic support from the Rogers Family Foundation, have elucidated the involvement of chronic ISR activation in the persistent cognitive and behavioral defects observed in patients after a traumatic brain injury, by showing this, In mice, the ISRIB brief treatment can restart the ISR apparatus and restore normal brain function almost overnight.
Cognitive deficits in traumatic brain injury patients have often been likened to premature aging, leading Rosie and Walter to question whether it could underlie age-related cognitive decline. Aging is known to affect the production of cellular protein throughout the body, as numerous insults build up in life and stressors such as chronic inflammation dissipate in the cells, which may lead to widespread activation of ISR.
“We’ve seen how ISRIB regains cognition in animals with a traumatic brain injury, which in many ways resembles an accelerated version of age-related cognitive decline,” said Rosie, director of cognitive neurocognitive research at UCSF Brain and Spine. Trauma Center and member of UCSF Weill Neurosciences. “It might sound like a crazy idea, but asking whether a drug could reverse aging symptoms on its own was just a logical next step.”
ISRIB improves cognition and enhances the function of neurons and immune cells
In the new study, researchers led by Karen Krokowski, Ph.D. in Rosie’s lab, trained elderly animals to escape a water maze by finding a hidden platform, a task that older animals could hardly learn. But the animals that received small daily doses of ISRIB during the three-day training process were able to get the job done, as well as the young mice, far better than animals of the same age that did not receive the drug.
The researchers then tested how long this cognitive renewal lasted and whether it could be generalized to other cognitive skills. After several weeks of initial ISRIB treatment, they trained the same mice to find their way out of a daily altered maze – testing the mental resilience of elderly mice that, like humans, tend to increasingly falter in their paths. The mice that received brief ISRIB treatment three weeks ago are still functioning at youthful levels, while the untreated mice continued to suffer.
To understand how ISRIB might improve brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a region of the brain that has a major role in learning and memory, just one day after the animals were given a single dose of ISRIB. They found that the common signals of aging neurons literally disappeared overnight: the electrical activity of neurons became more agile and responsive to stimulation, and the cells showed stronger connection with cells around them while also showing the ability to form stable connections with one another usually only seen in. Smaller mice.
Researchers continue to study exactly how ISR disrupts cognition in aging and other conditions and understand how long the cognitive benefits of ISRIB might last. Among other mysteries raised by the new findings is the discovery that ISRIB also alters the function of T cells in the immune system, which is also prone to age-related dysfunction. The results suggest another pathway through which the drug could improve cognition in elderly animals, and it could have effects on diseases from Alzheimer’s to diabetes that have been linked to the increased inflammation caused by an aging immune system.
Rosie said, “This was very exciting to me because we know that aging has a profound and lasting effect on T cells and that these changes can affect brain function in the hippocampus.” “For now, that’s just an interesting note, but it gives us a very interesting set of biological puzzles to solve.
ISRIB may have widespread neurological ramifications
It turns out that chronic ISR activation and the resulting blockage of cellular protein production may play a role in a surprisingly wide range of neurological conditions. Here is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa Mattioli of Baylor College of Medicine, which can be treated with an ISR reset agent such as ISRIB:
- Frontotemporal dementia
- Alzheimer’s disease
- Amyotrophic lateral sclerosis (ALS)
- Age-related cognitive decline
- Multiple sclerosis
- Traumatic brain injury
- Parkinson’s disease
- Down’s syndrome
- The white matter disorder faded
- Prion disease
ISRIB is licensed by Calico, South San Francisco, California. A company exploring the biology of aging, and the idea of targeting ISR to treat disease has been picked up by other drug companies, Walter says.
One would think that interfering with ISR, an important cellular safety mechanism, would certainly have dangerous side effects, but so far in all of their studies, researchers have not observed any of them. Walter says this is likely due to two factors. First, it only takes a few doses of ISRIB to reactivate an unhealthy and chronic ISR back into a healthy state, after which it can still respond normally to problems in individual cells. Second, ISRIB has virtually no effect when applied to cells that actively use ISR in its strongest form – against an aggressive viral infection, for example.
Naturally, both of these factors make the molecule less vulnerable to negative side effects – and more attractive as a potential treatment. According to Walter: “It sounds too good to be true, but with ISRIB we seem to have reached a good point for manipulating ISR with a perfect healing window.
Authors: Other authors on the study are Amber Nolan, Elma S. Frias, Morgan Boone, Catherine Gro, Maria Serena Palladini, and Edward Elissaras of the University of California, San Francisco. Gonzalo Orita, Luz Delgado and Sebastian Bernales of the Sensia and Veda Foundation in Santiago, Chile; Science and Life Foundation. Bernales is also an employee of Praxis Biotech, LLC.
Funding: The study was supported by the ongoing generous support of the Rogers Family Foundation, as well as the UCSF Weill Innovation Award, the US National Institutes of Health (NIH R01AG056770), and the National Institute on Aging (NIA F32AG054126); National Center for the Development of Transformational Sciences (NCATS TL1 TR001871); National Institute of Neurological Disorders and Stroke (NINDS K08NS114170) and Howard Hughes Medical Institute (HHMI).
Disclosures: Gonzalo Ureta works for Fundacion Ciencia & Vida and receives partial funding from Praxis Biotech. Sebastian Bernales is an employee of Praxis Biotech. Peter Walter is the inventor in US Patent No. 9708247 owned by UC referees describing ISRIB and its equivalents. The patent is licensed by UCSF to Calico.
About UCSF: The University of California, San Francisco (UCSF) has an exclusive focus on health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which operates as the primary academic medical center at UCSF, includes highly rated specialized hospitals and other clinical programs, and has branches throughout the Gulf region. Learn more at ucsf.edu, or check out our fact sheet.
ucsf.edu (http: // ucsf.
[email protected]http: // dx.