Drug Found To Rapidly Reverse Age-Related Cognitive Deficits In Mice

Disrupted protein synthesis at the cellular level may be a major cause of dementia. Image: Orawan Pattarawimonchai/Shutterstock.com

A drug that interferes with cellular protein production has been found to completely reverse age-related mental decline in mice after just three days of treatment. Amazingly, older rodents that received the drug were able to perform just as well as young mice at complex memory tasks, while an analysis of their brains revealed that many neurons had reverted back to a more youthful state.

Describing their work in the journal eLife, the study authors explain how disrupted protein synthesis is a major hallmark of aging, and has been linked to neurodegenerative diseases such as dementia. As cells undergo wear and tear, they are exposed to a number of stressors such as inflammation and infections, all of which can eventually disrupt their ability to continue producing the proteins that mediate cellular functions.

This, in turn, leads to a risk that these cells may become cancerous or otherwise harmful to the body. To prevent this, a mechanism called the integrated stress response (ISR) becomes activated, shutting down protein production in these cells.

Unfortunately, however, as we age we tend to experience more and more cellular stress, which can cause the ISR to become a little too active, to the point where it does more harm than good. For this reason, the authors of the new study hypothesized that inhibiting ISR in order to reboot protein production may undo some of the cognitive deficiencies associated with old age.

To test this theory, they trained aged mice to escape from a water maze by finding a hidden platform. Such challenges require the use of spatial, working, and episodic memory, and are typically much harder for older rodents to complete. Yet when these geriatric mice were given a small daily dose of a compound called ISR inhibitor (ISRIB) over a period of three days, their performance levels soared to the point where they matched those of spritely animals.

Several weeks after treatment, these mice were presented with an even more complex task that required them to find their way out of a constantly-changing maze. Once again, the mice that had received ISRIB were able to complete the challenge just as efficiently as young mice, while those that had not been treated with the drug struggled.

The researchers then analyzed neurons in the brains of these treated mice, focusing particularly on a brain region called the hippocampus, which plays a crucial role in memory and learning and has been strongly implicated with age-related cognitive decline. Incredibly, results showed that after just three doses of ISRIB, hippocampal neurons had become more electrically responsive and had also developed more dendritic spines, allowing them to form stronger connections. In other words, they had essentially reverted back to a state that is normally associated with youth, suggesting that the effects of age had been reset.

Further analysis revealed that immune cells in these treated mice had also become regenerated and now behaved more like those of younger animals. In particular, T cells were found to release fewer inflammatory compounds, thereby alleviating one of the major pathways associated with Alzheimer’s and other forms of dementia.

Commenting these stunning findings, study author Peter Walter said "the data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress."

"Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time."

If these results can be replicated in humans, then the study authors say that ISRIB could offer a “tangible strategy to sustain cognitive ability as we age.”

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