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A new study by UC San Francisco researchers shows that a few doses of an investigational drug, called ISRIB, can reverse the age-related decline in memory and mental flexibility in mice. Not only did this drug rapidly improve the cognitive abilities of the elderly mice, but the brain and immune cells were also rejuvenated.
In previous animal experiments, the drug in question had already shown encouraging results, particularly for restoring brain function after a head injury. It has been shown to be just as effective in reversing the cognitive impairments inherent in Down syndrome (trisomy 21), in preventing noise-related hearing loss, or even in fighting certain types of cancer. This new study marks a further step towards understanding how ISRIB works.
According to the researchers, the rejuvenation observed here in mice shows for the first time that much of the age-related cognitive loss is due to some sort of physiological “block” and not permanent cell breakdown. However, this block is reversible! ” The data suggests that the aging brain has not permanently lost its essential cognitive abilities. […] [Elles] they are still there, but have somehow been blocked by a vicious cycle of cellular stress Explains Peter Walter, a professor in the Department of Biochemistry and Biophysics at UCSF and a researcher at the Howard Hughes Medical Institute.
Cells trapped by a safety mechanism
As life expectancy increases, age-related cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative diseases. Being able to reverse the phenomenon would therefore be an important step forward for the medical sector. However, the results published by the researchers in the journal eLife show that ISRIB can indeed release cognitive abilities trapped by cellular stress.
ISRIB, for Iintegrated stress response inhibitor, was discovered in 2013 by Peter Walter’s laboratory. The scientist has been studying cellular responses to stress for many years. The phenomenon occurs when a dysfunction in the production of proteins is detected inside a cell, which may be a sign of a viral infection or a genetic mutation that leads to the development of cancer. The ISR mechanism then reacts by limiting the synthesis of proteins in the cell. It is in fact only an essential safety mechanism for the body, which guarantees the integrity of the cells.
But Walter and his collaborators found that this mechanism could remain active all the time, and therefore the cells can no longer perform their tasks. This can lead to serious problems, especially when the brain area is affected. In fact, their studies revealed that patients with head trauma showed persistent cognitive and behavioral deficits related to chronic activation of the ISR.
When they saw the positive effects of the ISR inhibitor (ISRIB) on the cognition of animals with traumatic brain injury, Walter and his team wondered if ISRIB could have the same effect on cognitive decline. purely related to age. The aging process is known to impair the production of cellular proteins in the body. Over time, stressors such as chronic inflammation build up and eventually wear out cells, potentially leading to widespread activation of ISRs.
A potential treatment for many neurological diseases
As part of their experiment, the researchers trained mice of various ages to escape from a water maze via a hidden platform. Some older animals received small daily doses of ISRIB during the training process, which lasted three days; they were able to perform the task, just like young mice, but much better than animals of the same age that had not benefited from the drug.
The team then decided to test the duration of this cognitive rejuvenation and to see if this effect could be generalized to other cognitive abilities. So, several weeks after the first ISRIB treatment, they subjected the same mice to a mental flexibility test: this time it was about finding the way out of a maze, which varied every day. Result: Old mice that had received ISRIB doses three weeks earlier again achieved equivalent performance to young mice.
To understand the role of ISRIB in improving brain function, the researchers analyzed the activity and anatomy of cells in the hippocampus of mice, a brain region linked to learning and memory. day after giving them a dose of the drug. It turns out that the signs of neuronal aging have disappeared overnight! Neuronal activity had become more lively, more sensitive to stimulation; the neurons showed stronger and more stable connections with surrounding neurons, which are usually seen in younger subjects.
Among other findings, the scientists also found that ISRIB altered T-cell function in the immune system, which also deteriorated with age. This suggests that the drug could potentially be considered as a treatment for some chronic diseases, such as Alzheimer’s disease or diabetes, conditions associated with increased inflammation caused by a faulty immune system.
ISRIB can therefore have large-scale implications in the treatment of neurological diseases. In fact, the chronic activation of cellular responses to stress plays a role in many pathologies; According to Walter and his colleagues, frontotemporal dementia, Alzheimer’s disease, multiple sclerosis, Parkinson’s disease or even Down’s syndrome are all neurological diseases that could potentially be treated with an SRI inhibitor.
Since it involves interfering with a fundamental cellular safety mechanism, some may fear harmful side effects. That said, the researchers have not observed any in all of their studies. And according to Walter, such effects are unlikely: to begin with, only a few doses of ISRIB are sufficient to deactivate chronic ISR, after which the mechanism proceeds normally. Hence, ISRIB has almost no effect on cells that mobilize ISR in its most potent form (during a viral infection for example). ” It sounds almost too good to be true, but with ISRIB it seems like we have found the right place to manipulate the ISR with an ideal therapeutic window. », The expert concludes with enthusiasm.
Source: eLife, K. Krukowski et al.
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