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Longevity Briefs: New drug reverses age-related cognitive decline in mice overnight

Posted on 9 December 2020

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: The three dimensional structure of proteins are crucial for determining their function. Misfolded proteins can result in a variety of deleterious consequences.

Research has shown that with age there is a noticeable reduction of protein synthesis in the brain, which correlates with defects in proper protein folding. The build up of misfolded proteins can trigger the integrated stress response (ISR), an evolutionary conserved pathway that decreases protein synthesis. Therefore, the ISR may facilitate age-associated cognitive decline.

What did the researchers do: On this basis, a recent study, published in the open-access journal eLife, scientists treated aged mice with an ISR inhibitor (ISRIB). This reverses ISR activation in the brain.

The aged mice were given ISRIB three times a day for a three day period and were then made to escape from a watery maze by locating a hidden platform, a test of cognitive capacity and memory that is usually far harder for older mice. The older mice, treated with ISRIB, performed the task just as well as the younger mice.

A cryo-electron microscope rendering of an ISRIB molecule. Image by the Adam Frost lab. Source: UCSF

The researchers sought to understand precisely how ISRIB can be improving brain function by studying the activity and anatomy of cells in the hippocampus, a brain region with an essential role in learning and memory.

Key takeaway(s) from this research: Just one day after administering a single dose of ISRIB to the animals, the team discovered the common signs of age-related degradation in neurons disappeared overnight.

Neuroelectrical activity became livelier and more responsive to stimulation, with neurons exhibiting enhanced connectivity, and an ability to form more stable connections with neighbouring neurons that was usually only present in younger mice.

Several weeks after the first ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed on a daily basis. Mice who were administered brief ISRIB treatments three weeks before continued to perform as well as young mice, but untreated mice still struggled.

ISRIB treatment is now awaiting approval to begin phase 1 clinical trials in humans.

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