Doctors and scientists tell us nothing can be done about age-related cognitive decline. Losing our mental faculties to some extent is an inevitable part of aging.

But what if they’re wrong?

What if – instead of brain cells becoming damaged or worn out – a blockage occurs that stops them from functioning normally? And by removing the blockage they’ll be as good as new?

Sound too good to be true? Amazingly, it isn’t. One award-winning scientist made this remarkable discovery in a laboratory study and will soon, we hope, begin testing his breakthrough in people.

The discovery follows decades of work from Professor Peter Walter at the University of California San Francisco (UCSF) which focuses on cellular stress responses.

One of these stress responses, called integrated stress response (ISR), acts as a safety control mechanism.

If problems are detected when a protein is being produced – such as a virus or a gene mutation – ISR slams on the brakes, stopping any further protein synthesis.

But what Prof. Walter and his team discovered is that ISR can get stuck in the ‘on’ position — much like inflammation — and become chronically active. As a result, the brakes remain permanently held down so the cell can no longer resume its normal activities.

Prof. Walter and his team then screened a large library of small molecules and made an important discovery. A molecule called ISRIB (Integrated Stress Response InhiBitor) releases the brakes to reboot protein production. When tested in traumatic brain injury (TBI), ISRIB’s results were remarkable.

Restores Normal Function After TBI

Persistent cognitive decline and behavioral deficits are commonly seen after TBI. Chronic ISR activation is implicated in this process.

In mice, brief treatment with ISRIB – even after months of brain problems following TBI – restored normal function almost overnight. It completely erased the cognitive deficits.

The research team was astounded.

“This had never been seen before,” commented team member Susanna Rosi. “The mantra in the field was that brain damage is permanent – irreversible. How could a single treatment with a small molecule make them disappear overnight?”

Since the cognitive problems seen in traumatic brain injury are similar to premature aging, and as the cellular insults of aging pile up to also compromise protein production, the UCSF team wondered whether ISR could be at the heart of age-related cognitive decline.

“We’ve seen how ISRIB restores cognition in animals with TBI, which in many ways is like a sped-up version of age-related cognitive decline,” said Dr. Rosi. “It may seem like a crazy idea, but asking whether the drug could help reverse symptoms of aging itself was just a logical next step.”

Rejuvenates an Aging Brain in Rapid Time

In the new study, published in December, researchers trained elderly mice to carry out a task that’s difficult for oldsters to learn. Yet after taking small daily doses of ISRIB for just three days, they accomplished the task just as well as the young ones.

Three weeks later – and with no further treatment – researchers trained the mice in a different task to test mental flexibility. Yet again, they performed just as well as the young mice.

The researchers needed to find out what’s happening in the brain to cause this. They discovered that after a single dose of ISRIB, common features of aging in the hippocampus – a key memory and learning area – disappear completely 24 hours later.

Electrical activity becomes sprightly and responsive to stimulation. Cells show more robust connectivity to each other. The type of stable connectivity seen only in younger mice could now be seen in the aged mice.

It gets even better.

ISR Reset Could Treat Many Diseases

ISRIB also improved the immune system’s T cells. Dr. Rosi explains the importance of this:

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

These incredible findings have implications for inflammation-caused damage derived from an aging immune system. This is seen in many diseases ranging from diabetes to Alzheimer’s.

Summing up, Prof. Walter wrote, “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.

“[The] results in aging mice are just amazing. It’s not often that you find a drug candidate that shows so much potential and promise.”

More good news is that no serious side effects have been noted in any of the studies using the ISRIB drug.

If the results in humans turn out to be the same as in the animal studies, we will have a treatment that can truly be referred to as a miracle.


  1. https://www.ucsf.edu/news/2020/12/419201/drug-reverses-age-related-mental-decline-within-days 

Comments

comments