Rejuvenation of memory
According to a new study by a group from the University of California, San Francisco, senile changes in brain functions are reversible. A drug that has already been tested in laboratory studies to restore memory function a few months after a traumatic brain injury, treat cognitive impairments in Down syndrome, prevent noise-related hearing loss, combat certain types of prostate cancer and even improve learning in healthy animals helped to regain lost cognitive abilities.
A new study shows a rapid recovery of cognitive abilities in old mice, accompanied by rejuvenation of the brain and immune cells.
The data obtained prove that with age, basic cognitive abilities are not lost forever, as was commonly believed. These resources still exist, but they are blocked by a vicious circle of cellular stress.
Can restarting protein production rejuvenate cells?
Each cell has a kind of control service – integrated stress response (ISR). This is one of the mechanisms that is activated when protein synthesis is disrupted in the cell, which may be a sign of viral invasion or oncogenic mutation. ISR blocks these cells. But in some situations, it remains on even when the cells are functioning normally. This can lead to serious problems, as the cells lose their ability to function normally.
The drug ISRIB (ISR InhiBitor) works by restarting the mechanism for controlling protein production in cells after it is triggered by one of the stress reactions.
Recent animal studies have proven that chronic ISR activation leads to persistent cognitive and behavioral deficits observed in patients after TBI, showing that in mice, short-term ISRIB treatment can reset the ISR and quickly restore normal brain function.
Cognitive deficits in patients with TBI are often compared with premature aging, so the authors suggested that ISR also underlies age-related cognitive decline. It is known that protein production in the cells of the whole body is disrupted with age, as stress factors accumulate, causing chronic inflammation and potentially leading to excessive activation of ISR.
Improves cognitive abilities, increases the function of neurons and rejuvenates immune cells
In a new study, old mice were trained to overcome a water maze using a hidden platform. This task is usually difficult for older animals, but mice who received small daily doses of ISRIB during the three-day training process coped with this task as well as young mice, much better than animals of the same age who did not receive the drug.
The researchers then tested how long this cognitive rejuvenation lasts and whether it can extend to other skills. A few weeks after starting ISRIB treatment, they trained the same mice to find a way out of a maze with an ever–changing configuration - this is a test of mental flexibility for old mice, who, like humans, tend to get more confused and forget the way. Mice that had received short-term ISRIB treatment three weeks before still coped with the task no worse than young mice, while untreated mice could not find a way out.
To understand how ISRIB affects brain function, the researchers studied the activity and anatomy of cells in the hippocampus, which is responsible for learning and memory, just a day after the animals were given a single dose of ISRIB. They found that the general signs of neuronal aging disappeared literally immediately: the electrical activity of neurons increased, cells responded faster to stimulation, and neurons demonstrated the ability to form strong connections with each other. These properties are usually observed only in young mice.
In addition, ISRIB affects the function of immune system T cells, which are also prone to age-related dysfunction. The results indicate another way in which the drug can improve cognitive abilities in older animals, and can improve the condition in various diseases that are associated with chronic inflammation caused by an aging immune system.
Possible application of ISRIB
Chronic ISR activation and the associated blocking of cellular protein production can play a role in a fairly wide range of neurological conditions: frontotemporal dementia, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, Parkinson's disease, Down syndrome, prion disease and others.
It is logical to think that interfering with ISR, a critical cellular safety mechanism, would have serious side effects, but so far in all their studies, the researchers have not observed any. This is probably due to two factors. First, it only takes a few doses of ISRIB to restore the unhealthy activation of ISR to a healthier state, after which it can still respond normally to problems in individual cells. Secondly, ISRIB has practically no effect on cells that actively use ISR in its most powerful form, for example, against aggressive viral infection.
ISRIB was licensed by Calico at the University of California, San Francisco. She specializes in the biology of aging. The idea of using ISR as a target has been picked up by many other pharmaceutical companies.
Article K.Krukowsky et al. Small molecule cognitive enhancer reverses age-related memory decline in mice published in the journal eLife.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on UCSF Materials: Drug Reverses Age-Related Mental Decline Within Days.