A new experimental drug has confounded scientists after it appeared to reverse age-related cognitive decline in mice seemingly overnight. The research has far-reaching implications for a number of degenerative disease treatments.
A new study tested how effective a drug called ISRIB was in reversing age-related declines in memory and mental flexibility in mice. The team of scientists from the University of California, San Francisco (UCSF) found startling results.
The research suggests age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more “permanent degradation,” according to researcher Susanna Rosi.
Instead, it appears that cognitive capacities are not irrevocably lost but have been blocked and lay dormant as a result of a mechanism known as the integrated stress response (ISR). This blockage is triggered by a “vicious cycle of cellular stress,” according to Peter Walter, a professor in the UCSF Department of Biochemistry and Biophysics.
Previous studies on mice involving ISRIB found that even brief treatment with the drug can restore normal brain function after a traumatic brain injury almost overnight.
Scientists view traumatic brain injuries as analogous to accelerated, age-related cognitive decline, so they wanted to test the drug in that arena by rebooting cells’ protein production machinery after they become throttled by the mechanism.
The unwanted stress response can typically be triggered in response to irregularities in protein production in a cell, which may indicate viral infection or the presence of cancer. It slows down the cell’s protein synthesis machinery as a precaution, but if it stays switched on for too long it can seriously impair cell function with drastic consequences for cognitive function.
“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”
In the new study, researchers trained mice to escape from a maze by finding a hidden platform, a difficult task involving lots of recall which is typically challenging for older mice.
Older animals who received small daily doses of ISRIB during their three-day training performed as well as their younger counterparts and far better than their contemporaries who didn’t receive the treatment.
Weeks later, they trained the same mice to escape a maze whose exit changed on a daily basis, requiring more ongoing and adaptive mental flexibility than a mere recall task. The results mirrored the previous experiment, with treated elderly mice matching their younger counterparts and outperforming untreated older mice.
Researchers also conducted brain analyses the day after ISRIB treatment had been administered. To their astonishment, they found that the telltale signatures of neuronal ageing disappeared overnight: Electrical activity sparked more vibrantly in response to stimulation, much like a more youthful brain, while cells also appeared vastly more interconnected with each other.
The research may have far-reaching applications including treatments for degenerative neurological disorders such as Alzheimer’s, dementia, multiple sclerosis and Parkinson’s among others.
To sweeten the deal even further, researchers have observed no serious side effects, itself rather puzzling for such a critical mechanism. They suspect the dearth of side effects is due to the relatively low dose, in combination with quick effect.
“It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window,” Walter says.
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