Scientists studying the mechanisms behind cellular stress and its effects on aging have found success in reversing cognitive decline in mice using an experimental drug. The findings not only bode well for further study of aging and its effects in human subjects, but sheds light on a growing list of conditions thought to be spurred on by chronic stress of this type.
The research was carried out at the University of California San Francisco, where scientists have spent years investigating the effects of what’s known as integrated stress response, or ISR. Generally speaking, this is a healthy function of the human body that identifies signs of infection or cellular mutation, and shuts down the protein production machinery in the cells to clear away any that might cause trouble.
But sometimes this process doesn’t function as it should, instead kicking into overdrive and affecting regular healthy cells as well. This is known as chronic ISR activation and previous research has linked it to a range of neurological conditions, including Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, Down syndrome and traumatic brain injury.
It was its connection to traumatic brain injury that inspired the team’s latest line of research, with earlier studies finding that cognitive decline brought on by these injuries has similarities to premature aging. The scientists have been investigating an experimental drug to tackle chronic ISR activation called ISRIB (ISR InhiBitor), which had previously been shown to reboot protein production and bring improvements to memory function following traumatic brain injury. Given the parallels, the team set out to explore its effects on aging.
“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,” says study author Susanna 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.”
Experiments on aged mice followed, with the rodents trained to escape from a water maze using a hidden platform. This task is set up to explore the effects of age-related cognitive decline, with older animals typically having difficulty finding the platform. The scientists found, however, that a small, daily dose of ISRIB across the three-day training program saw the older mice escape the maze just as well as younger mice, and far more easily than mice of the same age who went without the ISRIB treatment.
The scientists then upped the difficulty, tasking the aged mice with escaping from a maze where the exit changed daily. Even though this experiment was carried out three weeks after the ISRIB treatment was delivered, the aged mice still performed on par with the younger mice, while the mice who went without the treatment still performed poorly.
Observations of brain cells in the mice's hippocampus after the first dose of ISRIB was delivered revealed that typical signatures of aging disappeared virtually overnight. Electrical activity in the neurons became lively and responsive to stimulation, while connectivity between the cells become more robust, reminiscent of that seen in younger mice.
“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” says Rosi.
Further to these effects, the team also found that ISRIB impacts the function of the immune system’s T cells, which opens up new pathways to investigate treatments for diseases such as Alzheimer’s and diabetes, which have been associated with an aging immune system.
“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,” says Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”
The researchers half expected to see side effects occur as a result of interfering with an important mechanism in ISR, but so far their experiments have brought none. They are now continuing to study ISRIB to learn more about how it can counter the effects of cellular stress on aging and other conditions.
“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,” says study author Peter Walter.
The research was published in the journal eLife.
